CN1852974A - Compositions and methods for treating and diagnosing cancer - Google Patents

Abstract

The present invention relates to compositions and methods for the treatment, characterization and diagnosis of cancer. In particular, the present invention provides gene expression profiles associated with solid tumor stem cells, and novel stem cell cancer markers for the diagnosis, characterization and treatment of solid tumor stem cells.

Description

Translated fromChinese

用于治疗和诊断癌症的组合物和方法Compositions and methods for treating and diagnosing cancer

本申请要求2003年6月9日提交的美国临时申请系列号60/477,228和2003年6月9号提交的美国临时申请系列号60/477,235的优先权。This application claims priority to US Provisional Application Serial No. 60/477,228, filed June 9, 2003, and US Provisional Application Serial No. 60/477,235, filed June 9, 2003.

本发明是在国立卫生研究院批准的基金号No.5P01CA07513606下由政府资助进行的。因此政府具有本发明的某些权利。This invention was made with government support under Grant No. 5P01CA07513606 granted by the National Institutes of Health. The Government therefore has certain rights in this invention.

                        发明领域Field of Invention

本发明涉及用于治疗、表征和诊断癌症的组合物和方法。特别地，本发明提供与实体瘤干细胞相关的基因表达特征和用于诊断、表征和治疗实体瘤干细胞的新干细胞癌标记。The present invention relates to compositions and methods for the treatment, characterization and diagnosis of cancer. In particular, the present invention provides gene expression signatures associated with solid tumor stem cells and novel stem cell cancer markers for the diagnosis, characterization and treatment of solid tumor stem cells.

                        发明背景Background of the Invention

乳腺癌是大多数工业化国家最普遍的女性恶性肿瘤，据估计大约10％的女性人口在其一生中受到影响。尽管由于早期诊断和提高的治疗方法的原因其死亡率没有随着其发生率升高而升高，但其仍然是一个造成中年妇女死亡的主要原因。尽管对乳腺癌进行更早期的诊断，但大约有1-5％新近被诊断具有乳腺癌的妇女在诊断时具有长距离的转移。此外，接近50％最初被诊断具有局部疾病的患者最终复发并转移。85％的这些复发发生在最初显现所述疾病之后的第一个五年内。Breast cancer is the most prevalent female malignancy in most industrialized countries, estimated to affect approximately 10% of the female population during their lifetime. It remains a leading cause of death among middle-aged women, although its mortality rate has not increased with its incidence due to earlier diagnosis and improved treatment. Despite an earlier diagnosis of breast cancer, approximately 1-5% of women newly diagnosed with breast cancer have long-distance metastases at diagnosis. Furthermore, nearly 50% of patients initially diagnosed with localized disease eventually relapse and metastasize. 85% of these relapses occur within the first five years after initial manifestation of the disease.

大多数具有转移的乳腺癌的患者只涉及一或两个器官系统。随着时间进程疾病进一步发展，通常开始涉及多个位点。事实上，在尸体解剖时可在几乎所有身体器官中发现转移。观察到的最普遍的转移涉及位点是在皮肤和胸腔壁的软组织中以及腋部及上锁骨区域的局部区域复发区。最普遍的远距离转移位点是骨(30-40％的远距离转移)，接着是肺和肝。转移的乳腺癌通常被认为是不治之症。然而，目前可获得的治疗通常可延长无病状态和总体的存活率以及提高生命质量。显现远距离转移后的平均存活时间大约为3年。Most patients with metastatic breast cancer involve only one or two organ systems. As the disease progresses over time, multiple sites often become involved. In fact, metastases can be found in almost all body organs at autopsy. The most common sites of metastatic involvement observed were locoregional recurrences in the skin and soft tissues of the chest wall and in the axillary and supraclavicular regions. The most prevalent site of distant metastases is bone (30-40% of distant metastases), followed by lung and liver. Metastatic breast cancer is generally considered incurable. However, currently available treatments generally prolong disease-free and overall survival and improve quality of life. The mean survival time after manifesting distant metastases is approximately 3 years.

尽管在理解导致癌症(例如，乳腺癌)的遗传变化上已取得巨大进步，但用于从头的人癌细胞的可靠肿瘤测定法的缺少已阻碍了理解这些突变在细胞水平的作用的能力。同样，缺少实体瘤干细胞的已鉴定的癌症标记也阻碍了用于癌症患者(例如乳腺癌患者)的诊断和治疗方法的发展。同样，需要的是可靠的肿瘤测定法以及对实体肿瘤干细胞的癌标记的鉴定。Although tremendous progress has been made in understanding the genetic changes that lead to cancer (eg, breast cancer), the lack of reliable tumor assays for de novo human cancer cells has hampered the ability to understand the role of these mutations at the cellular level. Likewise, the lack of identified cancer markers for solid tumor stem cells hampers the development of diagnostic and therapeutic approaches for cancer patients, such as breast cancer patients. Also, what is needed are reliable tumor assays and the identification of cancer markers for solid tumor stem cells.

                         发明简述Brief description of the invention

本发明涉及用于治疗、表征和诊断癌症的组合物和方法。特别地，本发明提供了与实体瘤干细胞相关的基因表达特征和用于诊断、表征和治疗实体瘤干细胞的新干细胞癌标记。The present invention relates to compositions and methods for the treatment, characterization and diagnosis of cancer. In particular, the present invention provides gene expression signatures associated with solid tumor stem cells and novel stem cell cancer markers for the diagnosis, characterization and treatment of solid tumor stem cells.

在一些实施方案中，本发明提供了检测实体瘤干细胞的方法，其包括：a)提供来自受试者的组织样品，和b)在确定实体瘤干细胞在组织样品中存在或不存在的条件下在组织样品中检测至少一种表4-8中的干细胞癌症标记(例如，1、2、3、4、5、10，……等)。在特定的实施方案中，所述检测包括确定至少一种干细胞癌症标记的存在(或不存在)或其表达水平。在其它实施方案中，所述检测包括检测至少一种干细胞癌标记的mRNA表达。在特定的实施方案中，所述检测包括将干细胞癌标记mRNA暴露于与所述干细胞癌标记mRNA互补的核酸探针。In some embodiments, the invention provides methods of detecting solid tumor stem cells comprising: a) providing a tissue sample from a subject, and b) under conditions that determine the presence or absence of solid tumor stem cells in the tissue sample At least one of the stem cell cancer markers in Tables 4-8 (eg, 1, 2, 3, 4, 5, 10, ... etc.) is detected in the tissue sample. In specific embodiments, said detecting comprises determining the presence (or absence) or expression level of at least one stem cell cancer marker. In other embodiments, the detecting comprises detecting mRNA expression of at least one stem cell cancer marker. In specific embodiments, said detecting comprises exposing stem cell cancer marker mRNA to a nucleic acid probe complementary to said stem cell cancer marker mRNA.

在某些实施方案中，检测包括检测至少一种干细胞癌标记的多肽表达。在其它实施方案中，检测包括将干细胞癌标记多肽暴露于抗体和检测所述抗体与所述干细胞癌多肽的结合，所述抗体特异性针对所述干细胞癌标记多肽。在其它实施方案中，受试者包括人受试者。在另外的实施方案中，所述组织样品包括肿瘤组织。在一些实施方案中，所述肿癌组织样品是手术后肿瘤组织样品(例如，肿瘤活检组织)。In certain embodiments, detecting comprises detecting polypeptide expression of at least one stem cell cancer marker. In other embodiments, detecting comprises exposing a cancer stem cell marker polypeptide to an antibody specific for said cancer stem cell marker polypeptide and detecting binding of said antibody to said cancer stem cell marker polypeptide. In other embodiments, the subject comprises a human subject. In additional embodiments, the tissue sample comprises tumor tissue. In some embodiments, the tumor tissue sample is a post-surgical tumor tissue sample (eg, a tumor biopsy).

在其它实施方案中，所述方法进一步包括c)为受试者提供预后。在一些实施方案中，至少一种干细胞癌标记来自表8。在优选的实施方案中，至少一种干细胞癌标记包含：Bmi-1、eed、easyh1、easyh2、rnf2、yy1、smarcA3、smarcA5、smarcD3、smarcE1、mllt3、FZD1、FZD2、FZD3、FZD4、FZD6、FZD7、FZD8、FZD9、FZD10、WNT2、WNT2B、WNT3、WNT5A、WNT10B、WNT16、AXIN1、BCL9、MYC和(TCF4)。In other embodiments, the method further comprises c) providing the subject with a prognosis. In some embodiments, at least one stem cell cancer marker is from Table 8. In a preferred embodiment, at least one stem cell cancer marker comprises: Bmi-1, eed, easyh1, easyh2, rnf2, yy1, smarcA3, smarcA5, smarcD3, smarcE1, mllt3, FZD1, FZD2, FZD3, FZD4, FZD6, FZD7 , FZD8, FZD9, FZD10, WNT2, WNT2B, WNT3, WNT5A, WNT10B, WNT16, AXIN1, BCL9, MYC, and (TCF4).

在特定的实施方案中，本发明提供了用于减小实体瘤(例如，在研究药物筛选或治疗应用中)大小的方法，所述方法包括将实体瘤细胞与生物学(例如治疗上)有效量的组合物接触，所述组合物包含至少一种针对显示于表4-8中的至少一种干细胞癌标记的因子。在一些实施方案中，所述生物学有效量是足以使实体瘤中实体瘤干细胞死亡或增殖受到抑制的量。在其它实施方案中，所述生物学有效量是干扰实体瘤干细胞的存活途径(例如，notch相关基因)或自我更新途径(例如，WNT途径)的量。In particular embodiments, the invention provides methods for reducing the size of solid tumors (e.g., in research drug screening or therapeutic applications) comprising combining solid tumor cells with biologically (e.g., therapeutically) effective An amount of a composition comprising at least one factor directed to at least one stem cell cancer marker shown in Tables 4-8 is contacted. In some embodiments, the biologically effective amount is an amount sufficient to cause death or inhibit proliferation of solid tumor stem cells in a solid tumor. In other embodiments, the biologically effective amount is an amount that interferes with a survival pathway (eg, notch-related genes) or self-renewal pathway (eg, WNT pathway) of solid tumor stem cells.

可根据本发明从中分离或富集实体瘤干细胞的实体瘤示例包括但不限于，肉瘤和癌例如，但不限于：纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴血管瘤、淋巴血管内皮肉瘤、滑膜瘤、间皮瘤、尤因瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌(cystadenocarcinoma)、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒膜癌、精原细胞癌、胚胎癌、肾母细胞瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜细胞瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质细胞瘤、脑膜瘤、黑色素瘤、成神经细胞瘤和成视网膜细胞瘤。本发明可用于肉瘤和上皮癌，例如卵巢癌和乳腺癌。Examples of solid tumors from which solid tumor stem cells may be isolated or enriched according to the present invention include, but are not limited to, sarcomas and carcinomas such as, but not limited to: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, vascular Sarcomas, endothelial sarcoma, lymphangioma, lymphangioendothelial sarcoma, synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell Carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver carcinoma, cholangiocarcinoma, choriocarcinoma , seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharynx Angioma, ependymal tumor, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma. The invention is useful in sarcomas and epithelial cancers, such as ovarian and breast cancers.

在另外的实施方案中，至少一种因子是抗体、肽或小分子。在其它实施方案中，所述抗体、肽、反义、siRNA或小分子针对至少一种干细胞癌标记的细胞外结构域。在一些实施方案中，所述至少一种干细胞癌标记选自：Bmi-1、eed、easyh1、easyh2、rnf2、yy1、smarcA3、smarcA5、smarcD3、smarcE1、mllt3、FZD1、FZD2、FZD3、FZD4、FZD6、FZD7、FZD8、FZD9、FZD10、WNT2、WNT2B、WNT3、WNT5A、WNT10B、WNT16、AXIN1、BCL9、MYC和(TCF4)。In additional embodiments, at least one agent is an antibody, peptide or small molecule. In other embodiments, the antibody, peptide, antisense, siRNA or small molecule is directed against the extracellular domain of at least one stem cell cancer marker. In some embodiments, the at least one stem cell cancer marker is selected from the group consisting of: Bmi-1, eed, easyh1, easyh2, rnf2, yy1, smarcA3, smarcA5, smarcD3, smarcE1, mllt3, FZD1, FZD2, FZD3, FZD4, FZD6 , FZD7, FZD8, FZD9, FZD10, WNT2, WNT2B, WNT3, WNT5A, WNT10B, WNT16, AXIN1, BCL9, MYC, and (TCF4).

在其它的实施方案中，本发明提供用于减少实体瘤大小的方法，其包括将实体瘤的细胞与生物学(例如，治疗上)有效量的组合物接触，所述组合物包含至少一种调节至少一种显示于表4-8的干细胞癌标记的活性的因子。在一些实施方案中，本发明提供了杀死或抑制实体瘤干细胞增殖的方法，所述方法包括将所述实体瘤干细胞与生物学有效量的组合物接触，所述组合物包含至少一种靶向至少一种显示于表4-8的干细胞癌标记的因子。在某些实施方案中，所述方法进一步包括鉴定在所述接触后所述实体瘤干细胞的死亡和生长抑制。在另外的实施方案中，所述细胞死亡是由细胞凋亡引起的。在其它实施方案中，所述生物学有效量是干扰所述实体瘤干细胞的存活途径(例如，notch相关基因)或自我更新途径(例如，WNT途径)的量。在其它实施方案中，至少一种干细胞癌标记选自Bmi-1、eed、easyh1、easyh2、rnf2、yy1、smarcA3、smarcA5、smarcD3、smarcE1、mllt3、FZD1、FZD2、FZD3、FZD4、FZD6、FZD7、FZD8、FZD9、FZD10、WNT2、WNT2B、WNT3、WNT5A、WNT10B、WNT16、AXIN1、BCL9、MYC和(TCF4)。In other embodiments, the invention provides a method for reducing the size of a solid tumor comprising contacting cells of the solid tumor with a biologically (eg, therapeutically) effective amount of a composition comprising at least one A factor that modulates the activity of at least one of the stem cell cancer markers shown in Tables 4-8. In some embodiments, the present invention provides methods of killing or inhibiting the proliferation of solid tumor stem cells comprising contacting said solid tumor stem cells with a biologically effective amount of a composition comprising at least one target Factors to at least one of the stem cell cancer markers shown in Tables 4-8. In certain embodiments, the method further comprises identifying death and growth inhibition of said solid tumor stem cells following said contacting. In additional embodiments, the cell death is caused by apoptosis. In other embodiments, the biologically effective amount is an amount that interferes with a survival pathway (eg, notch-related genes) or a self-renewal pathway (eg, WNT pathway) of the solid tumor stem cell. In other embodiments, at least one stem cell cancer marker is selected from the group consisting of Bmi-1, eed, easyh1, easyh2, rnf2, yy1, smarcA3, smarcA5, smarcD3, smarcE1, mllt3, FZD1, FZD2, FZD3, FZD4, FZD6, FZD7, FZD8, FZD9, FZD10, WNT2, WNT2B, WNT3, WNT5A, WNT10B, WNT16, AXIN1, BCL9, MYC and (TCF4).

在特定的实施方案中，所述实体瘤干细胞表达细胞表面标记CD44、ESA或B38.1。在其它实施方案中，所述实体瘤干细胞不表达至少一种选自CD2、CD3、CD10、CD14、CD16、CD31、CD45、CD64和CD140b(参见，例如，美国专利公开号US20040037815A1和US20020119565，两者在此引用作为参考)的LINEAGE标记。In specific embodiments, said solid tumor stem cells express cell surface markers CD44, ESA or B38.1. In other embodiments, the solid tumor stem cells do not express at least one member selected from the group consisting of CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b (see, e.g., U.S. Patent Publication Nos. US20040037815A1 and US20020119565, both LINEAGE tags are incorporated herein by reference).

在其它实施方案中，本发明提供用于选择性靶向实体瘤干细胞的方法，其包括(a)鉴定至少一个存在于实体瘤干细胞上的来自表4-8的干细胞癌标记；和(b)获得选择性地结合或调节至少一种所述干细胞癌标记的因子或成套因子。在一些实施方案中，所述因子在遗传上修饰实体瘤干细胞。在特定的实施方案中，所述因子包含双特异性缀合物。在其它实施方案中，所述因子包含腺病毒载体。In other embodiments, the present invention provides methods for selectively targeting solid tumor stem cells comprising (a) identifying at least one stem cell cancer marker from Tables 4-8 present on solid tumor stem cells; and (b) A factor or set of factors is obtained that selectively binds or modulates at least one of said stem cell cancer markers. In some embodiments, the factor genetically modifies solid tumor stem cells. In specific embodiments, the agent comprises a bispecific conjugate. In other embodiments, the agent comprises an adenoviral vector.

在一些实施方案中，本发明提供用于在动物中形成肿瘤的方法，其包括：将纯化的实体瘤干细胞(例如，细胞剂量)导入动物中，其中(a)所述实体瘤干细胞来源于实体瘤；和(b)基于至少一个表4-8中的干细胞癌标记存在的情况下，相对于未分级分离的肿瘤细胞所述实体瘤干细胞被富集了至少2倍。在其它实施方案中，所述动物是无免疫应答的动物。在某些实施方案中，所述动物是无免疫应答的哺乳动物例如小鼠(例如，裸鼠、SCID小鼠、NOD/SCID小鼠、Beige/SCID小鼠和微珠蛋白缺陷型NOD/SCID小鼠)。在特定的实施方案中，细胞剂量中的细胞数目是从大约100个细胞至大约5×10⁵细胞。In some embodiments, the invention provides a method for forming a tumor in an animal comprising: introducing into the animal purified solid tumor stem cells (e.g., a dose of cells), wherein (a) the solid tumor stem cells are derived from a solid tumor stem cell and (b) said solid tumor stem cells are at least 2-fold enriched relative to unfractionated tumor cells based on the presence of at least one stem cell cancer marker in Tables 4-8. In other embodiments, the animal is an immunocompromised animal. In certain embodiments, the animal is an immunocompromised mammal such as a mouse (e.g., nude mice, SCID mice, NOD/SCID mice, Beige/SCID mice, and microglobin-deficient NOD/SCID mice) mice). In specific embodiments, the number of cells in a cell dose is from about 100 cells to about 5 x¹⁰⁵ cells.

在某些实施方案中，本发明提供了用于在受试者中检测实体瘤干细胞的试剂盒，其包含：a)能够在来自受试者的组织或细胞样品中特异性检测至少一个来自表4-8的干细胞癌标记的试剂，和任选地，b)使用该试剂检测组织样品中实体瘤干细胞存在或不存在的说明书。在其它实施方案中，所述试剂包含与来自至少一种干细胞癌标记的mRNA互补的核酸探针。在其它实施方案中，所述试剂包含抗体或抗体片段。In certain embodiments, the present invention provides a kit for detecting solid tumor stem cells in a subject, comprising: a) capable of specifically detecting at least one stem cell from the table in a tissue or cell sample from the subject; A reagent for stem cell cancer labeling of 4-8, and optionally, b) instructions for using the reagent to detect the presence or absence of solid tumor stem cells in a tissue sample. In other embodiments, the reagent comprises a nucleic acid probe complementary to mRNA from at least one stem cell cancer marker. In other embodiments, the reagent comprises an antibody or antibody fragment.

在一些实施方案中，本发明提供了筛选化合物的方法，其包括：a)提供：i)实体瘤干细胞；和ii)一种或多种受试化合物：和b)将所述实体瘤干细胞与受试化合物接触；和c)相对于受试化合物不存在的情况下，在所述受试化合物存在的情况下，检测至少一种显示于表4-8的干细胞癌标记的表达变化。在特定的实施方案中，所述检测包括确定至少一种干细胞癌标记的表达水平。在特定的实施方案中，所述检测包括检测至少一种干细胞癌标记的mRNA表达。在一些实施方案中，所述检测包括检测所述至少一种干细胞癌标记的多肽表达。在另外的实施方案中，所述实体瘤干细胞是在体外的。在其它实施方案中，所述实体瘤干细胞是在体内的。在其它实施方案中，所述受试化合物包括药物(例如，小分子、抗体、抗体-毒素缀合物，siRNA等)。In some embodiments, the invention provides methods of screening compounds comprising: a) providing: i) solid tumor stem cells; and ii) one or more test compounds: and b) combining said solid tumor stem cells with Exposure to the test compound; and c) detecting a change in the expression of at least one stem cell cancer marker shown in Tables 4-8 in the presence of the test compound relative to the absence of the test compound. In specific embodiments, said detecting comprises determining the expression level of at least one stem cell cancer marker. In specific embodiments, said detecting comprises detecting mRNA expression of at least one stem cell cancer marker. In some embodiments, said detecting comprises detecting polypeptide expression of said at least one stem cell cancer marker. In additional embodiments, said solid tumor stem cells are ex vivo. In other embodiments, the solid tumor stem cells are in vivo. In other embodiments, the test compound includes a drug (eg, small molecule, antibody, antibody-toxin conjugate, siRNA, etc.).

在一些实施方案中，本发明提供了包含至少两种因子(例如，小分子、抗体、抗体-毒素缀合物，siRNA等)的组合物，其中各因子调节至少一个显示于表4-8中的干细胞癌标记的活性。在另外的实施方案中，所述组合物包含至少三种因子。In some embodiments, the invention provides compositions comprising at least two factors (e.g., small molecules, antibodies, antibody-toxin conjugates, siRNA, etc.), wherein each factor modulates at least one of the factors shown in Tables 4-8 activity of cancer markers in stem cells. In other embodiments, the composition comprises at least three factors.

在特定的实施方案中，本发明提供了区分致瘤性和非致瘤性癌细胞的方法，其包括：检测癌细胞中β连环蛋白的存在，确定β连环蛋白在癌细胞中定位主要在细胞核或主要在细胞质中。在一些实施方案中，所述方法进一步包括确定癌细胞为致瘤性癌细胞，如果β连环蛋白主要定位在核中，或确定癌细胞为非致瘤性的，如果β连环蛋白主要定位在细胞质中。In a specific embodiment, the present invention provides a method for distinguishing tumorigenic from non-tumorigenic cancer cells, comprising: detecting the presence of β-catenin in cancer cells, determining that β-catenin is localized in cancer cells primarily in the nucleus or mainly in the cytoplasm. In some embodiments, the method further comprises determining that the cancer cell is tumorigenic if beta-catenin is predominantly nuclear-localized, or determining that the cancer cell is non-tumorigenic if beta-catenin is predominantly cytoplasmic middle.

在某些实施方案中，本发明提供了区别致瘤性和非致瘤性癌细胞的方法，其包括：a)提供：i)癌细胞，和ii)包含经塑造结合β连环蛋白的因子的组合物；和b)在β连环蛋白在癌细胞中的定位能被确定主要存在于细胞核或主要存在于细胞质的情况下，将所述癌细胞与组合物接触，和c)在所述β连环蛋白主要定位于细胞核时确定所述癌细胞为致瘤性的，或在β连环蛋白主要定位于细胞质时，所述癌细胞被确定为非致瘤性的。In certain embodiments, the invention provides a method of distinguishing tumorigenic from non-tumorigenic cancer cells comprising: a) providing: i) a cancer cell, and ii) a cell comprising a factor engineered to bind beta-catenin composition; and b) where the localization of β-catenin in a cancer cell can be determined to be predominantly nuclear or predominantly cytoplasmic, contacting said cancer cell with the composition, and c) in said β-catenin Cancer cells were determined to be tumorigenic when the protein was predominantly localized to the nucleus, or non-tumorigenic when beta-catenin was predominantly localized to the cytoplasm.

                       附图描述Description of drawings

图1表示致瘤性细胞的分离。Figure 1 represents the isolation of tumorigenic cells.

图2表示致瘤性和非致瘤性乳腺癌细胞的DNA含量。Figure 2 shows the DNA content of tumorigenic and non-tumorigenic breast cancer cells.

图3表示来自CD24⁺注射位点(a)的组织学，(20x物镜放大倍率)只显示正常小鼠组织，而CD24^-/low注射位点(b)，(40x物镜放大倍率)包含恶性肿瘤细胞。(c)表示在小鼠中在CD44⁺CD24^-1/lowLineage^-注射位点但不在CD44⁺CD24⁺Lineage^-注射位点的肿瘤。用Papanicolaou染色对T3细胞染色并进行显微观察(100x物镜)。非致瘤性(c)和致瘤性(d)群体都包含具有致瘤性表型(具有大细胞核和显著核仁)的细胞。Figure 3 represents the histology from the CD24⁺ injection site (a), (20x objective magnification) showing normal mouse tissue only, while the CD24-^/low injection site (b), (40x objective magnification) contains malignant tumors cell. (c) represents tumors in mice at CD44⁺ CD24-1^/low Lineage^- injection sites but not at CD44⁺ CD24⁺ Lineage^- injection sites. T3 cells were stained with Papanicolaou stain and observed microscopically (100x objective). Both non-tumorigenic (c) and tumorigenic (d) populations contain cells with a tumorigenic phenotype with large nuclei and prominent nucleoli.

图4显示产生自CD44⁺CD24^-/lowLineage^-细胞的肿瘤的表型多样性。Figure 4 shows the phenotypic diversity of tumors arising from CD44⁺ CD24^-/low Lineage^- cells.

图5显示Wnt(左版面)和Frizzled(右版面)的表达。Figure 5 shows the expression of Wnt (left panel) and Frizzled (right panel).

图6显示正常肿瘤成纤维细胞和内皮细胞的分离。Figure 6 shows the isolation of normal tumor fibroblasts and endothelial cells.

图7显示用腺病毒载体感染乳腺癌干细胞。Figure 7 shows infection of breast cancer stem cells with adenoviral vectors.

图8显示β连环蛋白的亚细胞定位。Figure 8 shows the subcellular localization of β-catenin.

图9显示癌细胞内β连环蛋白信号传导的抑制。Figure 9 shows inhibition of beta-catenin signaling in cancer cells.

                        发明总述Summary of Invention

本发明涉及用于治疗、表征和诊断癌症的组合物和方法。特别地，本发明提供了与实体瘤干细胞相关的基因表达特征和用于诊断、表征和治疗实体瘤干细胞的新标记物。可被靶向的(例如，用于诊断和治疗目的)合适的标记物是由如表4-8中显示的在实体瘤干细胞中差异表达的基因编码的基因和肽。可检测(例如，定量)差异表达的基因和由其编码的肽以确定实体瘤干细胞的存在和确定和筛选适合于减少任何存在的实体瘤干细胞的增殖(或杀死)、干扰其自我更新途径或干扰其存活途径的分子。显示于这些表中的差异表达的基因和由其编码的肽也用于产生靶向一个或多个这些标记物的治疗剂(例如，以抑制或促进所述标记的活性)。The present invention relates to compositions and methods for the treatment, characterization and diagnosis of cancer. In particular, the present invention provides gene expression signatures associated with solid tumor stem cells and novel markers for the diagnosis, characterization and treatment of solid tumor stem cells. Suitable markers that can be targeted (eg, for diagnostic and therapeutic purposes) are genes and peptides encoded by genes differentially expressed in solid tumor stem cells as shown in Tables 4-8. Differentially expressed genes and peptides encoded thereby can be detected (e.g., quantified) to determine the presence of solid tumor stem cells and to determine and screen for genes suitable for reducing the proliferation (or killing) of any solid tumor stem cells present, interfering with their self-renewal pathways Or molecules that interfere with their survival pathways. The differentially expressed genes shown in these tables and the peptides encoded thereby are also useful for generating therapeutics that target one or more of these markers (eg, to inhibit or promote the activity of the marker).

为鉴定实体瘤干细胞标记，就差异表达对来自5个患者的细胞、来自6个患者的AML干细胞和非致瘤性癌细胞、正常造血干细胞(HSC5)、正常造血细胞、正常结肠上皮细胞和正常乳腺上皮细胞进行分析。To identify solid tumor stem cell markers, cells from 5 patients, AML stem cells and non-tumorigenic cancer cells from 6 patients, normal hematopoietic stem cells (HSC5), normal hematopoietic cells, normal colonic epithelial cells, and normal Mammary epithelial cells were analyzed.

本发明也提供了在一个或多个提供于表4-8的标记物上与其它细胞差异表达的实体瘤干细胞。所述实体瘤干细胞可以是人或其它动物的。所述表达可以达到更高的程度或更低的程度。其它细胞可选自正常的细胞、造血干细胞、急性髓样白血病(AML)干细胞或任何其它种类的细胞。The invention also provides solid tumor stem cells that differentially express one or more of the markers provided in Tables 4-8 compared to other cells. The solid tumor stem cells can be human or other animal. Said expression can be to a higher degree or to a lower degree. Other cells may be selected from normal cells, hematopoietic stem cells, acute myeloid leukemia (AML) stem cells or any other kind of cells.

本发明提供了选择细胞群体的方法，所述方法产生纯化的实体瘤干细胞群(例如，从患者中，其中选择或检验优选地用于所述患者的治疗试剂)。本发明也提供了选择纯化的非实体瘤干细胞的肿瘤细胞群例如非致瘤性(NTG)肿瘤细胞方法。本发明提供了产生针对所选细胞的抗体的方法。本发明提供了使用选择的细胞的诊断方法。本发明也提供了治疗方法，其中所述治疗针对实体瘤干细胞(例如，直接或间接针对此处鉴定的一个干细胞癌标记)。The invention provides methods of selecting a population of cells that result in a purified population of solid tumor stem cells (eg, from a patient wherein a therapeutic agent is preferably selected or tested for said patient). The invention also provides methods for selecting purified tumor cell populations other than solid tumor stem cells, such as non-tumorigenic (NTG) tumor cells. The invention provides methods of producing antibodies against selected cells. The invention provides diagnostic methods using selected cells. The invention also provides methods of treatment, wherein the treatment is directed to solid tumor stem cells (eg, directly or indirectly to one of the stem cell cancer markers identified herein).

因此，本发明提供了使用针对给定的途径中的特异性基因的选择方法、诊断方法和治疗法选择细胞、诊断疾病、进行研究和治疗实体瘤的方法。包括一个或多个下列基因和基因产物：Bmi-1、eed、easyhi、easyh2、mf2、yy1、smarcA3、smarcA5、smarcD3、smarcE1和mllt3，以及显示于表4-8中的基因和基因产物。和正常的细胞和非致瘤性癌细胞相比，如此处显示的，许多这些基因在实体瘤干细胞中差异地表达。Accordingly, the present invention provides methods of selecting cells, diagnosing disease, conducting research, and treating solid tumors using selection methods, diagnostic methods, and therapeutic methods targeting specific genes in a given pathway. Included are one or more of the following genes and gene products: Bmi-1, eed, easyhi, easyh2, mf2, yy1, smarcA3, smarcA5, smarcD3, smarcE1, and mllt3, and the genes and gene products shown in Tables 4-8. Many of these genes are differentially expressed in solid tumor stem cells, as shown here, compared to normal cells and non-tumorigenic cancer cells.

本发明提供了实体瘤干细胞功能和各种分离自实体瘤的细胞群体的细胞功能的体内和体外测定法。本发明提供了使用各种分离自实体瘤(例如针对实体瘤干细胞富集的细胞群体)的各种细胞群体鉴定影响实体瘤细胞增殖的因子的方法。通过本发明的方法，可在实体瘤中表征表型不均一的细胞群体。特别地，可在肿瘤中鉴定、分离和表征表型上明显不同的细胞群体，所述细胞群体具有干细胞的广泛增殖和产生所有其它肿瘤细胞类型的能力的特点。实体瘤干细胞是在治疗后能够重新建立肿瘤的致瘤性细胞。The present invention provides in vivo and in vitro assays of solid tumor stem cell function and cellular function of various cell populations isolated from solid tumors. The present invention provides methods for identifying factors affecting proliferation of solid tumor cells using various cell populations isolated from solid tumors (eg, for solid tumor stem cell enriched cell populations). Phenotypically heterogeneous cell populations can be characterized in solid tumors by the methods of the invention. In particular, phenotypically distinct cell populations can be identified, isolated and characterized in tumors, characterized by the extensive proliferation of stem cells and the ability to give rise to all other tumor cell types. Solid tumor stem cells are tumorigenic cells capable of reestablishing tumors after treatment.

因此本发明提供了使诊断或治疗剂选择性靶向实体瘤干细胞的方法。本发明也提供了选择性靶向实体瘤干细胞(例如，针对一个此处公开的实体瘤干细胞癌标记)的因子，例如生物分子。在优选的实施方案中，被靶向的干细胞癌标记是自我更新或细胞存活途径的部分。这样的标记的一个示例是Bmi-1，经显示所述标记是维持成熟的自我更新的造血干细胞所需的(参见，例如，Park等人，Nature，2003May15；423(6937)：302-5，此处引用作为参考)。The present invention thus provides methods for selectively targeting a diagnostic or therapeutic agent to solid tumor stem cells. The invention also provides factors, such as biomolecules, that selectively target solid tumor stem cells (eg, to one of the solid tumor stem cell cancer markers disclosed herein). In preferred embodiments, the targeted stem cell cancer marker is part of a self-renewal or cell survival pathway. One example of such a marker is Bmi-1, which has been shown to be required for the maintenance of mature self-renewing hematopoietic stem cells (see, e.g., Park et al., Nature, 2003 May 15;423(6937):302-5, cited here as a reference).

在某些实施方案中，本发明提供了用于筛选抗癌剂、用于检验抗癌治疗法、用于开发靶向新途径的药物、用于鉴定新抗癌治疗靶、用于在病理样品中鉴定和诊断恶性肿瘤细胞、用于检验和测定实体瘤干细胞药物敏感性、用于预测药物敏感性的特异性因子的测量和用于筛查患者(例如，作为乳腺造影法的辅助方法)的方法。In certain embodiments, the present invention provides methods for screening anticancer agents, for testing anticancer therapies, for developing drugs targeting new pathways, for identifying new anticancer therapeutic In the identification and diagnosis of malignant tumor cells, for the detection and determination of the drug sensitivity of solid tumor stem cells, for the measurement of specific factors for the prediction of drug sensitivity and for the screening of patients (for example, as an adjunct to mammography) method.

根据下列详细的描述，本发明的其它特征、目的和有利方面将变得明显。在the University of Michigan的校务委员会的公开的PCT专利申请WO 02/12447和the University of Michigan的校务委员会的PCT专利申请PCT/US02/39191中提供了另外的指导，两份申请在此引用作为参考。Other features, objects and advantages of the present invention will become apparent from the following detailed description. Additional guidance is provided in Published PCT Patent Application WO 02/12447 of the Regents of the University of Michigan and PCT/US02/39191 of the Regents of the University of Michigan, both of which are incorporated herein by reference Reference.

                         定义Definition

为有助于理解本发明，下面定义许多术语和短语：To assist in understanding the present invention, a number of terms and phrases are defined below:

如此处所用的，术语“抗体”以最广义的意思使用并明确地包括单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如，双特异性抗体)和抗体片段，只要其表现想要的生物学活性(例如，能够结合上述的干细胞癌标记)。可将抗体缀合至其它分子(例如，毒素)中。As used herein, the term "antibody" is used in the broadest sense and specifically includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments , as long as it exhibits the desired biological activity (for example, is capable of binding the aforementioned stem cell cancer markers). Antibodies can be conjugated to other molecules (eg, toxins).

如此处所用的，术语“抗体片段”是指完整抗体的部分。抗体片段的示例包括但不限于线性抗体、单链抗体分子、Fc或Fc’肽、Fab和Fab片段和由抗体片段形成的多特异性抗体。As used herein, the term "antibody fragment" refers to a portion of an intact antibody. Examples of antibody fragments include, but are not limited to, linear antibodies, single chain antibody molecules, Fc or Fc' peptides, Fab and Fab fragments, and multispecific antibodies formed from antibody fragments.

如此处所用的，“人源化”形式的非人(例如，鼠)抗体是含有来源于非人免疫球蛋白的最小序列或不含有来源于非人免疫球蛋白的序列的嵌合抗体。在极大的程度上，人源化抗体是人免疫球蛋白(受体抗体)，其中来自受体的超变区的残基由来自非人物种(供体抗体)例如小鼠、大鼠、兔或非人灵长类动物的具有想要的特异性、亲和力和能力的超可变区的残基取代。在一些情况下，人免疫球蛋白的Fv架构区(FR)残基被相应的非人残基取代。此外，人源化的抗体可包含在受体抗体或在供体抗体中未发现的残基。通常进行这些修饰以进一步改进抗体功能。通常，人源化抗体基本上包含所有至少一个和通常两个可变区，其中所有或基本上所有的超可变环对应于非人免疫球蛋白的超可变环，并且所有或基本上所有FR残基是人免疫球蛋白序列的FR残基。人源化抗体也可包含至少部分免疫球蛋白恒定区(Fc)，通常是人免疫球蛋白的恒定区(Fc)。用于产生人源化抗体的方法的示例描述于授予Winter等人的美国专利5,225,539中(此处引用作为参考)。As used herein, "humanized" forms of non-human (eg, murine) antibodies are chimeric antibodies that contain minimal or no sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from the hypervariable region of the recipient are replaced by those from a non-human species (donor antibody) such as mouse, rat, Substitution of rabbit or non-human primate hypervariable region residues with desired specificity, affinity and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies may comprise residues which are not found in either the recipient antibody or the donor antibody. These modifications are often made to further refine antibody function. Typically, a humanized antibody will comprise substantially all of at least one and usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin. The FR residues are those of a human immunoglobulin sequence. The humanized antibody will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Examples of methods for producing humanized antibodies are described in US Patent 5,225,539 to Winter et al. (incorporated herein by reference).

在富集的细胞群体中的“富集”，可在表型上基于分级分离的细胞群中增加的具有特定标记(例如，如表4-8中所显示的)的细胞数目(和未经分级分离的细胞群中具有标记的细胞数目相比)进行定义。然而，术语“富集”优选地可根据作为在受试小鼠中在有限的稀释频率下形成肿瘤的最小细胞数目的致瘤性功能在功能上进行定义。例如，如果500个肿瘤干细胞在63％的受试动物中形成肿瘤，但需要5000个未经分级分离的肿瘤细胞在63％的受试动物中形成肿瘤，那么就致瘤性活性而言该实体瘤干细胞群体被富集10倍。本发明的干细胞癌标记可用于产生富集的癌干细胞群体。在优选的实施方案中，相对于未经分级分离的肿瘤细胞，干细胞群体被富集至少1.4倍(例如，1.4倍、1.5倍、2倍、5倍……20倍)。"Enrichment" in an enriched cell population can be phenotypically based on the increased number of cells with a particular marker (e.g., as shown in Tables 4-8) in the fractionated cell population (and without compared to the number of cells with markers in the fractionated cell population) were defined. However, the term "enrichment" is preferably functionally definable in terms of tumorigenicity as a function of the minimum number of cells forming a tumor at a limiting dilution frequency in the tested mouse. For example, if 500 tumor stem cells form tumors in 63% of the animals tested, but 5000 unfractionated tumor cells are required to form tumors in 63% of the animals tested, then the entity is Tumor stem cell populations were enriched 10-fold. Stem cell cancer markers of the invention can be used to generate enriched populations of cancer stem cells. In preferred embodiments, the stem cell population is enriched by at least 1.4-fold (eg, 1.4-fold, 1.5-fold, 2-fold, 5-fold...20-fold) relative to unfractionated tumor cells.

关于细胞的“分离”，是指从其天然环境(例如实体瘤)中取出并被分离或分开的细胞，并且至少大约30％、50％、75％和最优选地大约90％地不含其它细胞，所述其它细胞是和被分离的细胞一起天然存在的但缺少被分离的细胞所基于分离的标记的细胞。本发明的干细胞癌标记可用于产生分离的癌干细胞群体。"Isolated" with respect to cells refers to cells that have been removed from their natural environment (e.g., a solid tumor) and separated or separated, and are at least about 30%, 50%, 75%, and most preferably about 90% free of other A cell that is a cell that naturally occurs with the isolated cell but lacks the marker on which the isolated cell is based. Stem cell cancer markers of the invention can be used to generate isolated populations of cancer stem cells.

如此处所用的，术语“受体结合结构域”是指任何针对受体的天然配体，包括细胞粘着分子，或任何这种保持至少相应天然配体的定性的受体结合能力的该天然配体区域或衍生物。As used herein, the term "receptor binding domain" refers to any natural ligand for a receptor, including cell adhesion molecules, or any such natural ligand that retains at least the qualitative receptor binding ability of the corresponding natural ligand. Body regions or derivatives.

如此处所用的，术语“抗体-免疫粘附素嵌合体”包括组合至少一个具有至少一个抗体的结合结构域和至少一个免疫粘附素的分子。示例包括但不限于描述于Berg等人，PNAS(USA) 88：4723-4727(1991)和Charnow等人，J.Immunol.，153：4268(1994)的双特异性CD4-IgG嵌合体，此处引用两者作为参考。As used herein, the term "antibody-immunoadhesin chimera" includes combining at least one molecule having the binding domain of at least one antibody and at least one immunoadhesin. Examples include, but are not limited to, the bispecific CD4-IgG chimeras described in Berg et al., PNAS (USA) 88:4723-4727 (1991) and Charnow et al., J. Immunol., 153:4268 (1994), which Both are cited here for reference.

如此处所用，术语“癌症”和“癌性的”是指或描述哺乳动物中的生理学状况，其特征通常在于不受调控的细胞生长。癌症的示例包括但不限于癌、淋巴瘤、胚细胞瘤、肉瘤和白血病。这些癌症更特定的示例包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺部腺癌、肺部鳞状癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝癌、乳腺癌、结肠癌、结肠直肠癌，子宫内膜或子宫癌、唾液腺癌、肾癌、肝癌、前列腺癌、阴门癌、甲状腺癌、肝癌和各种类型的头和颈癌。As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is often characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More specific examples of these cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, peritoneal carcinoma, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma Cancer of the cervix, ovary, liver, bladder, liver, breast, colon, colorectum, endometrium or uterus, salivary gland, kidney, liver, prostate, vulva, thyroid, liver and various types of head and neck cancer.

此处所用的术语“表位”是指与特定抗体接触的抗原部分。The term "epitope" as used herein refers to the portion of an antigen that is contacted by a specific antibody.

当用蛋白或蛋白片段免疫宿主动物时，蛋白的许多区域可诱导特异性结合所述蛋白上的给定区域或三维结构的抗体产生；这些区域或结构称作“抗原决定簇”。抗原决定簇可与完整的抗原(即，用于引起免疫应答的“免疫原”)竞争与抗体的结合。When a protein or fragment of a protein is used to immunize a host animal, there are many regions of the protein that induce the production of antibodies that specifically bind to a given region or three-dimensional structure on the protein; these regions or structures are called "epitopes". An antigenic determinant can compete with the intact antigen (ie, the "immunogen" used to elicit an immune response) for antibody binding.

术语“特异性结合”或“特异性地结合”在用于指抗体和蛋白或肽的相互作用时表示依赖于所述蛋白的特定结构(即，抗原决定簇或表位)存在的相互作用；换句话说，抗体识别和结合至特定的蛋白结构而不是蛋白整体。例如，如果抗体对表位“A”是特异性的，那么在含有标记“A”和所述抗体的反应物中含有表位A(或游离的未标记A)的蛋白的存在将减少结合所述抗体的标记A的量。The term "specifically binds" or "specifically binds" when used in reference to the interaction of an antibody and a protein or peptide means an interaction that is dependent on the presence of a specific structure (i.e. an antigenic determinant or epitope) of said protein; In other words, antibodies recognize and bind to specific protein structures rather than the protein as a whole. For example, if an antibody is specific for epitope "A", the presence of a protein containing epitope A (or free unlabeled A) in a reaction containing label "A" and the antibody will reduce binding The amount of labeled A of the antibody.

如此处所用的，当术语“非特异性结合”和“背景结合”用于指抗体和蛋白或肽的相互作用时是指不依赖于特定结构(即，抗体结合蛋白总体而不是特定的结构例如表位)的相互作用。As used herein, the terms "non-specific binding" and "background binding" when used to refer to the interaction of an antibody and a protein or peptide mean that it is not dependent on a specific structure (i.e., the antibody binds the protein as a whole rather than a specific structure such as a table). bit) interaction.

如此处所用的，术语“受试者”是指任何动物(例如，哺乳动物)，包括但不限于，人、非人灵长类、啮齿类动物等，其是特定处理的受体。通常，术语“受试者”和“患者”在此处指人受试者时可交换使用。As used herein, the term "subject" refers to any animal (eg, mammal), including, but not limited to, a human, non-human primate, rodent, etc., that is the recipient of a particular treatment. Generally, the terms "subject" and "patient" are used interchangeably herein when referring to a human subject.

如此处所用的，术语“怀疑患有癌症的受试者”是指呈现一种或多种癌症症状标志(例如，明显的团或块)或正经历癌症筛查(例如，在常规身体检查中)的受试者。怀疑患有癌症的受试者也可以具有一个或多个风险因子。怀疑患有癌症的受试者通常未经历过癌症检查。然而，“怀疑患有癌症的受试者”包括接受过最初诊断但其癌症阶段仍未知的个体。所述术语进一步包括曾经患过癌症的人(例如，处于好转的个体)。As used herein, the term "subject suspected of having cancer" refers to a subject who exhibits one or more symptomatic signs of cancer (e.g., a noticeable mass or mass) or is undergoing cancer screening (e.g., during a routine physical examination). ) subjects. A subject suspected of having cancer may also have one or more risk factors. A subject suspected of having cancer has generally not been tested for cancer. However, a "subject suspected of having cancer" includes individuals who have received an initial diagnosis but whose cancer stage is unknown. The term further includes persons who have had cancer (eg, individuals in remission).

如此处所用的，术语“处于癌症风险的受试者”是指具有一个或多个发展特定癌症的风险因素的受试者。风险因素包括但不限于性别、年龄、遗传诱因、环境暴露、以前的癌症事件、预先存在的非癌症疾病和生活方式。As used herein, the term "subject at risk of cancer" refers to a subject who has one or more risk factors for developing a particular cancer. Risk factors include, but are not limited to, sex, age, genetic predisposition, environmental exposures, previous cancer events, pre-existing non-cancer diseases, and lifestyle.

如此处所用的，术语“表征受试者中的癌症”是指鉴定受试者中癌症样品的一个或多个特征，包括但不限于良性的、癌前期的或癌性组织的存在、癌症的阶段和受试者的预后。癌症可通过鉴定一个或多个癌标记基因的表达来进行表征，包括但不限于此处公开的癌标记。As used herein, the term "characterizing a cancer in a subject" refers to identifying one or more characteristics of a sample of cancer in a subject, including but not limited to the presence of benign, precancerous or cancerous tissue, the presence of cancerous Stage and prognosis of subjects. Cancer can be characterized by identifying the expression of one or more cancer marker genes, including but not limited to the cancer markers disclosed herein.

如此处所用的，术语“干细胞癌标记”是指基因或由所述基因表达的肽，所述基因的表达水平，单独的或与其它基因一起的，与致瘤性癌细胞的存在相关。所述相关性可涉及所述基因的增加的或减少的表达(例如，增加的或减少的mRNA或由所述基因编码的肽的水平)。As used herein, the term "stem cell cancer marker" refers to a gene or a peptide expressed by said gene whose expression level, alone or in combination with other genes, correlates with the presence of tumorigenic cancer cells. The correlation may involve increased or decreased expression of the gene (eg, increased or decreased levels of mRNA or peptide encoded by the gene).

如此处所用的，术语“特异性检测表达水平的试剂”是指用于检测一个或多个基因(例如，包括但不限于本发明的癌标记)的表达的试剂。合适试剂的示例包括但不限于能够特异性与目的基因杂交的核酸探针、aptamers、能够特异性扩增目的基因的PCR引物和能够特异性结合由目的基因表达的蛋白的抗体。其它非限定性示例可在下面的描述和实施例中找到。As used herein, the term "agent specifically detecting the expression level" refers to a reagent for detecting the expression of one or more genes (eg, including but not limited to the cancer markers of the present invention). Examples of suitable reagents include, but are not limited to, nucleic acid probes capable of specifically hybridizing to a gene of interest, aptamers, PCR primers capable of specifically amplifying a gene of interest, and antibodies capable of specifically binding a protein expressed by a gene of interest. Other non-limiting examples can be found in the following description and examples.

如此处所用的，术语“检测相对于非癌性对照的减少的或增加的表达”是指相对于非癌性对照样品中的水平测量基因的表达水平(例如，mRNA或蛋白的水平)。可通过使用任何合适的方法测量基因表达，其包括但不限于此处描述的方法。As used herein, the term "detecting decreased or increased expression relative to a non-cancerous control" refers to measuring the expression level of a gene (eg, the level of mRNA or protein) relative to the level in a non-cancerous control sample. Gene expression can be measured by using any suitable method, including but not limited to the methods described herein.

如此处所用的，术语“相对于所述受试化合物不存在的情况下，在所述受试化合物存在的情况下检测细胞样品中基因表达的变化”是指相对于所述受试化合物不存在时，在受试化合物存在的情况下测量表达的改变水平(例如，增加或减少)。可通过使用任何合适的方法测量基因表达。As used herein, the term "detecting changes in gene expression in a cell sample in the presence of the test compound relative to the absence of the test compound" means relative to the absence of the test compound , the altered level of expression (eg, increase or decrease) is measured in the presence of the test compound. Gene expression can be measured by using any suitable method.

如此处所用的，术语“使用所述试剂盒检测所述受试者中癌症的使用说明书”包括用于在来自受试者的样品中检测和表征癌症的试剂盒中所包含的试剂的使用说明书。As used herein, the term "instructions for using the kit to detect cancer in the subject" includes instructions for the use of reagents contained in the kit for detecting and characterizing cancer in a sample from a subject .

如此处所用的，术语“提供预后”是指提供有关癌症(例如，由本发明诊断方法确定的癌症)的存在对受试者未来健康的影响(例如，预期的发病率、死亡率、患癌症的可能性和转移的风险)的信息。As used herein, the term "providing a prognosis" refers to providing information about the impact (e.g., expected morbidity, mortality, risk Possibilities and risks of transfer).

如此处所用的，术语“术后肿瘤组织”是指从受试者(例如，在手术期间)中取出的癌性组织(例如，活检组织)。As used herein, the term "post-operative tumor tissue" refers to cancerous tissue (eg, biopsy tissue) removed from a subject (eg, during surgery).

如此处所用的，术语“经诊断患有癌症的受试者”是指经检验并发现具癌性细胞的受试者。可使用任何合适的方法诊断癌症，所述方法包括但不限于，生物活检、X射线、血检和本发明的诊断方法。As used herein, the term "subject diagnosed with cancer" refers to a subject who has been examined and found to have cancerous cells. Cancer can be diagnosed using any suitable method including, but not limited to, biopsies, x-rays, blood tests and the diagnostic methods of the present invention.

如此处所用的，术语“活检组织”是指从受试者中取出的组织样品，所述组织样品用以确定样品是否含有癌组织。在一些实施方案中，因为怀疑受试者患有癌症因而获取活检组织。然后检测活检组织以确定存在或不存在癌症。As used herein, the term "biopsy tissue" refers to a tissue sample taken from a subject to determine whether the sample contains cancerous tissue. In some embodiments, a biopsy is obtained because the subject is suspected of having cancer. The biopsy is then tested to determine the presence or absence of cancer.

如此处所用的，术语“基因转移系统”是指任何递送包含核酸序列的组合物至细胞或组织的手段。例如，基因转移系统包括但不限于载体(例如，逆转录病毒、腺病毒、腺伴随病毒和其它基于核酸的递送系统)、裸核酸显微注射、基于聚合物的递送系统(例如基于脂质体和金属颗粒的系统)、biolistic注射等。如此处所用的，术语“病毒基因转移系统”是指包含有助于递送样品至想要的细胞或组织中的病毒元件(例如，完整的病毒、经修饰的病毒和病毒组分例如核酸或蛋白)的基因转移系统。如此处所用的，术语“腺病毒基因转移系统”是指包含属于腺病毒科的完整或经改变的病毒的基因转移系统。As used herein, the term "gene transfer system" refers to any means of delivering a composition comprising a nucleic acid sequence to a cell or tissue. For example, gene transfer systems include, but are not limited to, vectors (e.g., retroviruses, adenoviruses, adeno-associated viruses, and other nucleic acid-based delivery systems), naked nucleic acid microinjection, polymer-based delivery systems (e.g., liposome-based and metal particle systems), biolistic injection, etc. As used herein, the term "viral gene transfer system" refers to a system comprising viral elements (e.g., whole virus, modified virus, and viral components such as nucleic acids or proteins) that facilitate delivery of a sample into a desired cell or tissue. ) gene transfer system. As used herein, the term "adenoviral gene transfer system" refers to a gene transfer system comprising whole or altered viruses belonging to the family Adenoviridae.

如此处所用的，术语“位点特异性重组靶序列”是指为重组因子和重组发生的位点提供识别序列的核酸序列。As used herein, the term "site-specific recombination target sequence" refers to a nucleic acid sequence that provides recognition sequences for recombination factors and sites where recombination occurs.

如此处所用的，术语“核酸分子”是指任何含有核酸的分子，其包括但不限于，DNA或RNA。所述术语包括包含任何已知的DNA和RNA的碱基类似物的序列，其包括但不限于，4-乙酰胞嘧啶、8-羟基-N6-甲基腺苷、吖丙啶基胞嘧啶、假异胞嘧啶、5-(羧基羟基甲基)尿嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、5-羧基甲基氨基甲基-2-硫尿嘧啶、5-羧基甲基氨基甲基尿嘧啶、二氢尿嘧啶、次黄嘌呤核苷、N6-异戊烯基腺嘌呤、1-甲基腺嘌呤、1-甲基假尿嘧啶、1-甲基鸟嘌呤、1-甲基次黄嘌呤核苷、2，2-二甲基鸟嘌呤、2-甲基腺嘌呤、2-甲基鸟嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、N6-甲基腺嘌呤、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧基氨基甲基-2-硫尿嘧啶、β-D-mannosylqueosine、5′-甲氧基羰基甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲基硫-N6-异戊烯基腺嘌呤、尿嘧啶-5-氧乙酸甲基酯、尿嘧啶-5-氧乙酸、oxybutoxosine、假尿嘧啶、queosine、2-硫胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、N-尿嘧啶-5-氧乙酸甲基酯、尿嘧啶-5-氧乙酸、假尿嘧啶、queosine、2-硫胞嘧啶和2，6-二氨基嘌呤。As used herein, the term "nucleic acid molecule" refers to any nucleic acid-containing molecule including, but not limited to, DNA or RNA. The term includes sequences comprising any known base analogs of DNA and RNA including, but not limited to, 4-acetylcytosine, 8-hydroxy-N6-methyladenosine, aziridinylcytosine, Pseudoisocytosine, 5-(carboxyhydroxymethyl)uracil, 5-fluorouracil, 5-bromouracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluridine Pyrimidine, dihydrouracil, inosine, N6-prenyl adenine, 1-methyladenine, 1-methylpseudouracil, 1-methylguanine, 1-methylhypoxanthine Purine nucleoside, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-methyladenine, 7 -Methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, β-D-mannosylqueosine, 5′-methoxycarbonylmethyluracil, 5 -Methoxyuracil, 2-methylthio-N6-prenyladenine, methyl uracil-5-oxoacetate, uracil-5-oxoacetic acid, oxybutoxosine, pseudouracil, queosine, 2 -Thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, N-uracil-5-oxoacetic acid methyl ester, uracil -5-oxoacetic acid, pseudouracil, queosine, 2-thiocytosine and 2,6-diaminopurine.

术语“基因”是指包含用于产生多肽、前体或RNA(例如，rRNA、tRNA)所必需的编码序列的核酸(例如，DNA)序列。多肽可由全长编码序列或所述编码序列的任何部分编码，只要全长或片段的想要的活性或功能特征(例如，酶活性、配体结合性、信号传导、免疫原性等)得以保留。所述术语也包括结构基因的编码区和与编码区5’和3’两个末端相邻的序列，所述序列距离任一端大约为1kb或更长，这样所述基因就相应于全长mRNA的长度。位于编码区5’并存在于mRNA上的序列被称作5’非翻译序列。位于3’或编码区下游并存在于mRNA上的序列称作3’非翻译序列。术语“基因”包括cDNA和基因组形式的基因。基因的基因组形式或克隆包含由称作“内含子”或“间隔区”或“间隔序列”的非编码序列打断的编码区。内含子是转录成核RNA(hnRNA)的基因片段；内含子可含有调控元件例如增强子；内含子被从细胞核或初级转录物中除去或“拼接掉”；因此内含子在信使RNA(mRNA)转录物中不存在。在翻译过程中mRNA的功能是确定新生多肽的序列或氨基酸顺序。The term "gene" refers to a nucleic acid (eg, DNA) sequence comprising the coding sequence necessary for the production of a polypeptide, precursor, or RNA (eg, rRNA, tRNA). A polypeptide can be encoded by the full-length coding sequence or any portion of the coding sequence, so long as the desired activity or functional characteristics (e.g., enzymatic activity, ligand binding, signaling, immunogenicity, etc.) of the full-length or fragment are retained . The term also includes the coding region of a structural gene and sequences adjacent to both the 5' and 3' ends of the coding region which are approximately 1 kb or more from either end such that the gene corresponds to a full-length mRNA length. Sequences located 5' to the coding region and present on the mRNA are referred to as 5' untranslated sequences. Sequences located 3' or downstream of the coding region and present on the mRNA are referred to as 3' untranslated sequences. The term "gene" includes both cDNA and genomic forms of a gene. The genomic form or clone of a gene contains coding regions interrupted by non-coding sequences called "introns" or "spacers" or "spacers". Introns are segments of genes that are transcribed into nuclear RNA (hnRNA); introns may contain regulatory elements such as enhancers; introns are removed or "spliced out" from the nucleus or primary transcript; Not present in RNA (mRNA) transcripts. The function of mRNA during translation is to determine the sequence or amino acid sequence of the nascent polypeptide.

如此处所用的，术语“异源基因”是指不是以其天然环境存在的基因。例如，异源基因包括导入到另一物种中的来自一个物种的基因。异源基因也包括生物体所固有的但以一些方式(例如，经突变、加入多个拷贝、连接至非天然调控序列等)改变的基因。异源基因与内源基因的区别在于异源基因序列通常被连接到DNA序列上，所述DNA序列不是与染色体中的基因天然连接的或与在自然界中未发现的染色体的部分(例如，在基因非正常表达的基因座上表达的基因)相连。As used herein, the term "heterologous gene" refers to a gene not found in its natural environment. For example, a heterologous gene includes a gene from one species that is introduced into another species. A heterologous gene also includes a gene that is native to an organism but altered in some way (eg, mutated, added in multiple copies, linked to non-native regulatory sequences, etc.). A heterologous gene is distinguished from an endogenous gene in that the heterologous gene sequence is usually joined to a DNA sequence that is not naturally linked to the gene in the chromosome or to a part of the chromosome not found in nature (e.g., in Genes expressed at loci where genes are not normally expressed) are connected.

如此处所用的，术语“基因表达”是指通过基因的“转录”(例如，通过RNA聚合酶的酶促作用)将编码在基因中的遗传信息转变成RNA(例如，mRNA、rRNA、tRNA或snRNA)和通过mRNA的“翻译”将编码蛋白的基因转变成蛋白的过程。在所述过程中的许多阶段可调节基因的表达。“上调”或“激活”是指增加基因表达产物(例如，RNA或蛋白)的产量的调节，而“下调”或“抑制”是指减少产物的调节。参与上调或下调的分子(例如，转录因子)通常分别称为“激活剂”和“抑制剂”。As used herein, the term "gene expression" refers to the conversion of genetic information encoded in a gene into RNA (e.g., mRNA, rRNA, tRNA or snRNA) and the process of converting a protein-coding gene into a protein by "translation" of mRNA. The expression of genes can be regulated at many stages in the process. "Upregulation" or "activation" refers to regulation that increases the production of a gene expression product (eg, RNA or protein), while "downregulation" or "repression" refers to regulation that decreases the product. Molecules (eg, transcription factors) involved in up-regulation or down-regulation are often referred to as "activators" and "repressors", respectively.

除了包含内含子外，基因组形式的基因也可包含位于存在于RNA转录物上的序列的5’和3’末端的序列。这些序列称作“侧翼”序列或区域(这些侧翼序列位于存在于mRNA转录物上的非翻译序列的5’或3’)。所述5’侧翼区域可包含调控序列例如控制或影响基因转录的启动子和增强子。所述3’侧翼区域可包含指导转录终止、转录后切割和聚腺苷酸化的序列。In addition to comprising introns, the genomic form of a gene may also comprise sequences located at the 5' and 3' ends of sequences present on the RNA transcript. These sequences are referred to as "flanking" sequences or regions (these flanking sequences are located either 5' or 3' to the untranslated sequences present on the mRNA transcript). The 5' flanking region may contain regulatory sequences such as promoters and enhancers that control or affect transcription of the gene. The 3' flanking region may contain sequences directing transcription termination, post-transcriptional cleavage and polyadenylation.

术语“siRNAs”是指短干涉RNAs。在一些实施例中，siRNA包含大约18-25个核苷酸长的双螺旋或双链区域；通常siRNAs在各链的3’末端包含大约2至4个未配对的核苷酸。siRNA的双螺旋或双链区域的至少一条链与靶RNA分子基本上同源或基本上互补。与靶RNA分子互补的链是“反义链”；与所述靶RNA分子同源的链是“有义链”，并且也与siRNA反义链互补。siRNAs也可包含额外的序列；这类序列的非限定性示例包括连接序列或环以及茎和其它折叠结构。siRNAs似乎在无脊椎或脊椎动物中在引发RNA干涉中和在植物的转录后基因沉默过程中引发序列特异性RNA降解中发挥至关重要的中间物的作用。The term "siRNAs" refers to short interfering RNAs. In some embodiments, siRNAs comprise a double helix or double stranded region that is about 18-25 nucleotides long; typically siRNAs comprise about 2 to 4 unpaired nucleotides at the 3' end of each strand. At least one strand of the double helix or double stranded region of the siRNA is substantially homologous or substantially complementary to the target RNA molecule. The strand that is complementary to the target RNA molecule is the "antisense strand"; the strand that is homologous to the target RNA molecule is the "sense strand" and is also complementary to the siRNA antisense strand. siRNAs may also contain additional sequences; non-limiting examples of such sequences include junction sequences or loops as well as stems and other folded structures. siRNAs appear to function as crucial intermediaries in eliciting RNA interference in invertebrates or vertebrates and in eliciting sequence-specific RNA degradation during post-transcriptional gene silencing in plants.

术语“RNA干涉”或“RNAi”是指通过siRNAs沉默或减少基因表达。在动物和植物中，其是由siRNA启动的序列特异性、转录后基因沉默的过程，所述siRNA在其双螺旋区域与被沉默的基因序列同源。所述基因对生物体来说可以是内源的或外源的，以整合入染色体内的形式存在或存在于未整合入基因组内的感染性载体中。所述基因的表达被完全或部分地抑制。也可考虑用RNA来抑制靶RNA的功能；靶RNA的功能可以是完全的或部分的。The term "RNA interference" or "RNAi" refers to silencing or reducing gene expression by siRNAs. In animals and plants, it is a process of sequence-specific, post-transcriptional gene silencing initiated by siRNAs that are homologous in their double-helical regions to the sequence of the gene being silenced. The gene may be endogenous or exogenous to the organism, present integrated into a chromosome or present in an infectious vector not integrated into the genome. The expression of the gene is completely or partially repressed. The use of RNA to inhibit the function of the target RNA is also contemplated; the function of the target RNA may be complete or partial.

如此处所用的，术语“核酸分子编码”、“DNA序列编码”和“DNA编码”是指沿着脱氧核糖核酸链的脱氧核糖核苷酸的顺序或序列。这些脱氧核糖核苷酸的顺序决定沿多肽(蛋白)链的氨基酸顺序。因此，DNA序列编码氨基酸序列。As used herein, the terms "nucleic acid molecule code", "DNA sequence code" and "DNA code" refer to the order or sequence of deoxyribonucleotides along a deoxyribose nucleic acid chain. The order of these deoxyribonucleotides determines the order of amino acids along the polypeptide (protein) chain. Thus, a DNA sequence encodes an amino acid sequence.

如此处所用的，术语“具有编码基因的核苷酸序列的寡核苷酸”和“具有编码基因的核苷酸序列的多核苷酸”表示包含基因的编码区域的核酸序列或换句话说编码基因产物的核酸序列。所述编码区可以cDNA、基因组DNA或RNA形式存在。当以DNA形式存在时，寡核苷酸或多核苷酸可以是单链的(即，有义链)或双链的。如果需要允许正确的转录起始和/或正确加工初级RNA转录物，可将合适的控制元件例如增强子/启动子、拼接连接物、聚腺苷酸化信号等与基因的编码区紧密相连。可选择地，用于本发明的表达载体的编码区可包含内源增强子/启动子、拼接连接物、间隔序列、聚腺苷酸化信号等或内源和外源控制元件的组合。As used herein, the terms "oligonucleotide having a nucleotide sequence encoding a gene" and "polynucleotide having a nucleotide sequence encoding a gene" mean a nucleic acid sequence comprising the coding region of a gene or in other words encoding The nucleic acid sequence of a gene product. The coding region may be in the form of cDNA, genomic DNA or RNA. When in DNA form, an oligonucleotide or polynucleotide can be single-stranded (ie, the sense strand) or double-stranded. Appropriate control elements such as enhancers/promoters, splice junctions, polyadenylation signals, etc. may be placed in close association with the coding region of the gene if necessary to allow proper transcription initiation and/or proper processing of the primary RNA transcript. Alternatively, the coding regions of the expression vectors used in the present invention may contain endogenous enhancers/promoters, splice junctions, spacers, polyadenylation signals, etc. or a combination of endogenous and exogenous control elements.

如此处所用的，当术语“部分”表示核苷酸序列(如在“给定的核苷酸序列的部分”中)时是指该序列的片段。所述片段在大小上可在4个核苷酸至完整的核苷酸序列减去一个核苷酸(10个核苷酸、20、30、40、50、100、200等)的范围内变化。As used herein, the term "portion" when referring to a nucleotide sequence (as in "a given portion of a nucleotide sequence") refers to a fragment of that sequence. The fragments can vary in size from 4 nucleotides to the full nucleotide sequence minus one nucleotide (10 nucleotides, 20, 30, 40, 50, 100, 200, etc.) .

如此处所用的，术语“以有效的组合”、“以有效的顺序”和“有效地连接”是指以产生能够指导给定的基因转录和/或想要的蛋白分子合成的核酸分子的方式连接核酸序列。所述术语也指以产生功能性蛋白的方式连接氨基酸序列。As used herein, the terms "in operative combination", "in operative order" and "operably linked" refer to a manner in which nucleic acid molecules are produced capable of directing the transcription of a given gene and/or the synthesis of a desired protein molecule Link nucleic acid sequences. The term also refers to linking amino acid sequences in such a way as to produce a functional protein.

当术语“分离”用于核酸时，如在“分离的寡核苷酸”或“分离的多核苷酸”中，是指从至少一个组分或杂质中鉴定和分离的核酸序列，所述组分或杂质通常与所述核酸序列在其天然来源中结合。分离的核酸就这样存在或以不同于其在自然界中被发现的形式存在。相反地，未分离的核酸是例如以其天然存在的状态被发现的DNA和RNA的核酸。例如，在宿主细胞染色体上发现给定的DNA序列(例如，基因)与相邻基因接近；RNA序列，例如编码特定蛋白的特定mRNA序列，以与大量其它编码大量蛋白的mRNAs混合的形式发现于细胞中。然而，分离的编码给定蛋白的核酸包括(通过示例的方式)这样的在细胞中通常表达所述给定蛋白的核酸，其中所述核酸存在于不同于天然细胞的染色体位置的染色体位置上，或侧翼连接不同于天然发现的核酸序列的核酸序列。所述分离的核酸、寡核苷酸或多核苷酸可以单链或双链的形式存在。当使用分离的核酸、寡核苷酸或多核苷酸表达蛋白时，所述寡核苷酸或多核苷酸至少包含有义链或编码链(即，所述寡核苷酸或多核苷酸可以是单链)，还可同时包含有义和反义链(即，所述寡核苷酸或多核苷酸可以是双链)。The term "isolated" when applied to a nucleic acid, as in "isolated oligonucleotide" or "isolated polynucleotide", refers to a nucleic acid sequence that has been identified and separated from at least one component or impurity, the set Particles or impurities are usually associated with the nucleic acid sequence in its natural source. An isolated nucleic acid exists as such or in a form other than that as it is found in nature. In contrast, unisolated nucleic acids are nucleic acids such as DNA and RNA that are found in the state in which they occur in nature. For example, a given DNA sequence (e.g., a gene) is found in close proximity to adjacent genes on the host cell chromosome; RNA sequences, such as a specific mRNA sequence encoding a specific protein, are found in admixture with a large number of other mRNAs encoding a large number of proteins. in cells. However, an isolated nucleic acid encoding a given protein includes, by way of example, a nucleic acid in cells ordinarily expressing said given protein, wherein said nucleic acid is present at a chromosomal location different from that of natural cells, or flanked by nucleic acid sequences other than those found in nature. The isolated nucleic acid, oligonucleotide or polynucleotide may exist in single- or double-stranded form. When an isolated nucleic acid, oligonucleotide or polynucleotide is used to express a protein, the oligonucleotide or polynucleotide comprises at least the sense strand or the coding strand (i.e., the oligonucleotide or polynucleotide can is single-stranded), may also comprise both sense and antisense strands (ie, the oligonucleotide or polynucleotide may be double-stranded).

“氨基酸序列”和术语例如“多肽”或“蛋白”并不表示将氨基酸序列限定于与例举的蛋白分子相关的完全的、天然的氨基酸序列。"Amino acid sequence" and terms such as "polypeptide" or "protein" are not intended to limit the amino acid sequence to the complete, native amino acid sequence associated with the exemplified protein molecule.

如此处所用的，术语“天然蛋白”是指蛋白不含有由载体序列编码的氨基酸残基；即，所述天然的蛋白只包含发现于以其天然形式产生的蛋白中的氨基酸。天然蛋白可由重组手段产生或从天然存在的来源分离。As used herein, the term "native protein" refers to a protein that does not contain the amino acid residues encoded by the vector sequence; that is, the native protein contains only amino acids found in the protein produced in its native form. Native proteins can be produced by recombinant means or isolated from naturally occurring sources.

如此处所用的，当术语“部分”表示蛋白(如在“给定的蛋白的部分”中)时是指该蛋白的片段。所述片段在大小上可在4个氨基酸残基至完整氨基酸序列减去一个氨基酸的范围内变化。As used herein, the term "portion" when referring to a protein (as in "a portion of a given protein") refers to fragments of that protein. The fragments may vary in size from 4 amino acid residues to the full amino acid sequence minus one amino acid.

术语“Southern印迹法”是指对DNA进行分析，根据大小在琼脂或丙烯酰胺凝胶上分离DNA，接着将DNA从凝胶转移至固体支持物例如硝酸纤维素或尼龙膜上。然后用标记的探针探测固定的DNA以检测与所用的探针互补的DNA种类。在电泳之前可用限制性酶切割所述DNA。电泳后，在转移至固体支持物上之前或期间可对所述DNA部分脱嘌呤和变性。Southern印迹是分子生物学家的标准工具(J.Sambrook等人，Molecular Cloning：A Laboratory Manual，Cold SpringHarbor Press，NY，pp 9.31-9.58[1989])。The term "Southern blotting" refers to the analysis of DNA, separation of the DNA according to size on an agar or acrylamide gel, followed by transfer of the DNA from the gel to a solid support such as nitrocellulose or nylon membrane. The immobilized DNA is then probed with labeled probes to detect DNA species complementary to the probes used. The DNA can be cleaved with restriction enzymes prior to electrophoresis. Following electrophoresis, the DNA portion can be depurinated and denatured before or during transfer to a solid support. Southern blots are a standard tool for molecular biologists (J. Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, NY, pp 9.31-9.58 [1989]).

如此处所用的，术语“Northern印迹法”是指对RNA的分析，在琼脂糖凝胶上进行RNA电泳，根据大小分离RNA，接着将RNA从凝胶转移至固体支持物例如硝酸纤维素或尼龙膜上。然后用标记的探针探测固定的RNA以检测与所用的探针互补的RNA种类。Norhhern印迹是分子生物学家的标准工具(J.Sambrook，等人，同上，pp 7.39-7.52[1989])。As used herein, the term "Northern blotting" refers to the analysis of RNA by electrophoresis of the RNA on an agarose gel, separation of the RNA according to size, and subsequent transfer of the RNA from the gel to a solid support such as nitrocellulose or nylon film. The immobilized RNA is then probed with labeled probes to detect RNA species complementary to the probes used. Norhhern blots are a standard tool for molecular biologists (J. Sambrook, et al., supra, pp 7.39-7.52 [1989]).

术语“Western印迹”是指对固定在支持物例如硝酸纤维素或膜上的蛋白(或多肽)的分析。在丙烯酰胺凝胶上跑蛋白以分离所述蛋白，接着将所述蛋白从凝胶转移至固体支持物例如硝酸纤维素或尼龙膜上。然后将固定的蛋白暴露于对目的抗原具有反应性的抗体中。可通过各种方法，包括使用放射性标记的抗体检测抗体的结合。The term "Western blot" refers to the analysis of a protein (or polypeptide) immobilized on a support such as nitrocellulose or a membrane. The proteins are separated by running them on an acrylamide gel and then transferred from the gel to a solid support such as nitrocellulose or nylon membrane. The immobilized protein is then exposed to antibodies reactive to the antigen of interest. Antibody binding can be detected by various methods, including the use of radiolabeled antibodies.

如此处所用的，术语“转基因”是指外源基因，所述外源基因通过例如将所述外源基因导入新受精的卵中或早期胚胎中从而被置入生物体中。术语“外源基因”是指任何通过实验操作被导入动物基因组中的核酸(例如，基因序列)并且可包括发现于该动物中的基因序列，只要所述导入的基因不位于与天然发生的基因所处的位置相同的位置上。As used herein, the term "transgene" refers to a foreign gene that has been placed into an organism by, for example, introducing the foreign gene into a newly fertilized egg or an early embryo. The term "exogenous gene" refers to any nucleic acid (e.g., gene sequence) introduced into the genome of an animal by experimental manipulation and may include gene sequences found in the animal, as long as the introduced gene is not located in the same location as a naturally occurring gene in the same position.

如此处所用的，术语“载体”是指将DNA片段从一个细胞转移至另一个细胞的核酸分子。术语“载体(vehicle)”有时与“载体”交换使用。载体通常来源于质粒、噬菌体或植物或动物病毒。As used herein, the term "vector" refers to a nucleic acid molecule that transfers a segment of DNA from one cell to another. The term "vehicle" is sometimes used interchangeably with "vehicle". Vectors are usually derived from plasmids, bacteriophages, or plant or animal viruses.

如此处所用的，术语“表达载体”是指包含想要的编码序列和合适的核酸序列的重组DNA分子，所述合适的核酸序列是在特定的宿主生物体中表达有效连接的编码序列所必需的。在原核生物中进行表达所必需的核酸序列通常包括启动子、操纵子(任选的)和核糖体结合位点，经常还有其它序列。已知真核生物细胞使用启动子、增强子和终止和聚腺苷酸化信号。As used herein, the term "expression vector" refers to a recombinant DNA molecule comprising a desired coding sequence and suitable nucleic acid sequences necessary for expression of an operably linked coding sequence in a particular host organism of. Nucleic acid sequences necessary for expression in prokaryotes generally include a promoter, an operator (optional), and a ribosomal binding site, and often other sequences. Eukaryotic cells are known to use promoters, enhancers, and termination and polyadenylation signals.

术语“过量表达”和语法上的同意词，是指表示表达水平比在对照或非转基因动物的给定的组织中观察到的水平高(或大)大约1.5倍的mRNA水平。使用本领域技术人员已知的许多技术中的任一种技术测量mRNA的水平，所述技术包括但不限于Norhern印迹分析。在Northern印迹法中包括合适的对照以控制RNA(来自各接受分析的组织)上样量的差异(例如，28S rRNA的量，存在于各样品中的丰富的RNA转录物(在所有组织中以基本上相同的量存在)可用作规范化或标准化在Northern印迹上观察到的mRNA特异性信号的方法)。对存在于在大小上对应于正确拼接的转基因RNA的条带上的mRNA量进行定量；其它少数种类与转基因探针杂交的RNA在所述转基因mRNA表达的定量中不予考虑。The term "overexpression" and grammatical synonymous terms, refers to mRNA levels that express levels that are about 1.5 times higher (or greater) than that observed in a given tissue of a control or non-transgenic animal. Levels of mRNA are measured using any of a number of techniques known to those of skill in the art, including but not limited to Northern blot analysis. Appropriate controls were included in the Northern blotting to control for differences in the amount of RNA (from each tissue analyzed) loaded (e.g., the amount of 28S rRNA, the abundance of RNA transcripts present in each sample (in all tissues as present in essentially the same amount) can be used as a means of normalizing or normalizing the mRNA-specific signal observed on a Northern blot). The amount of mRNA present in a band corresponding in size to the correctly spliced transgene RNA was quantified; other minor species of RNA that hybridized to the transgene probe were not considered in the quantification of the transgene mRNA expression.

如此处所用的，术语“体外”是指人工环境和在人工环境内发生的过程或反应。体外环境可由(但不限于)试管和细胞培养物组成。术语“体内”是指天然的环境(例如，动物或细胞)和在天然环境中发生的过程或反应。As used herein, the term "in vitro" refers to an artificial environment and a process or reaction that occurs within an artificial environment. In vitro environments can consist of, but are not limited to, test tubes and cell cultures. The term "in vivo" refers to the natural environment (eg, an animal or cell) and processes or reactions that occur in the natural environment.

术语“受试化合物”和“候选化合物”是指任何用于治疗或预防疾病、病症、不适或身体功能病症(例如癌症)的化学实体、药物、药等。受试化合物包括已知的和潜在的治疗化合物。通过使用本发明的筛选方法进行筛选可确定受试化合物。在一些本发明的实施方案中，受试化合物包括反义化合物。The terms "test compound" and "candidate compound" refer to any chemical entity, drug, drug, etc., useful in the treatment or prevention of a disease, disorder, disorder, or disorder of a bodily function, such as cancer. Test compounds include known and potential therapeutic compounds. Test compounds can be identified by screening using the screening method of the present invention. In some embodiments of the invention, test compounds include antisense compounds.

如此处所用的，以其最广义的意义使用术语“样品”。在一种意义上，其表示包括获自任何来源的材料或培养物和生物学和环境样品。生物学样品可获自动物(包括人)，并包括液体、固体、组织和气体。生物学样品包括血液产品，例如血浆、血清等。环境样品包括环境材料例如表面物质、土壤、水、晶体和工业样品。但是这些示例并不解释为限制应用于本发明的样品类型。As used herein, the term "sample" is used in its broadest sense. In one sense, it is meant to include material or cultures and biological and environmental samples obtained from any source. Biological samples can be obtained from animals, including humans, and include liquids, solids, tissues and gases. Biological samples include blood products such as plasma, serum, and the like. Environmental samples include environmental materials such as surface matter, soil, water, crystals and industrial samples. However, these examples are not to be construed as limiting the types of samples applicable to the invention.

                        发明详述Detailed description of the invention

本发明提供了用于治疗、表征和诊断癌症的组合物和方法。特别地，本发明提供了与实体瘤干细胞相关的基因表达特征以及用于诊断、表征和治疗实体瘤干细胞的新标记。The present invention provides compositions and methods for treating, characterizing and diagnosing cancer. In particular, the present invention provides gene expression signatures associated with solid tumor stem cells and novel markers for the diagnosis, characterization and treatment of solid tumor stem cells.

1.干细胞和实体瘤干细胞1. Stem cells and solid tumor stem cells

普通癌症产生于包含进行增殖的细胞的大亚群的组织中，所述细胞负责补充短寿的成熟细胞。在这些器官中，细胞成熟是按层次安排进行的，其中极少数干细胞群产生成熟细胞并通过称作自我更新1-11的过程使其自身永生化。由于其稀有性，应当分离干细胞以研究其生物学、分子和生物化学特征。尽管其可能产生大多数组织，但干细胞只在少数组织中得以严格地鉴定和纯化。产生淋巴造血系统的干细胞，称作造血干细胞(HSCs)，已从小鼠和人中分离出来并且是被最佳表征的干细胞。随着含有HSCs的组织广泛地用于骨髓移植以在骨髓移除(myeloablative)方案¹²后再生造血淋巴(hematolymphoid)系统，已证实了其在癌症治疗中的功效。从患者中预先分离HSCs可导致用于自体移植的无癌群体。Common cancers arise in tissues containing large subpopulations of proliferating cells responsible for replenishing short-lived mature cells. In these organs, cellular maturation proceeds in a hierarchical arrangement in which a very small population of stem cells give rise to mature cells and immortalize themselves through a process called self-renewal1-11. Due to their rarity, stem cells should be isolated to study their biological, molecular and biochemical characteristics. Although they may arise from most tissues, stem cells have been rigorously identified and purified from only a few. Stem cells that give rise to the lymphoid hematopoietic system, called hematopoietic stem cells (HSCs), have been isolated from mice and humans and are the best characterized stem cells. As tissues containing HSCs are widely used in bone marrow transplantation to regenerate the hematolymphoid system after myeloablative protocols12, their efficacy in^cancer therapy has been demonstrated. Pre-isolation of HSCs from patients can result in a cancer-free population for autologous transplantation.

理解发生癌症的组织的细胞生物学和特别是存在于这些组织中的干细胞为癌症生物学提供了新知识。干细胞生物学的几个方面与癌症相关。首先，正常细胞和癌细胞都进行自我更新，并且显现的证据表明相似的分子机制都调控正常干细胞和其恶性对应物的自我更新。其次，在正常干细胞中很可能积累导致癌症的突变。最后，肿瘤可能包含具有无限增殖潜能的驱动肿瘤生长和转移^18-26的“癌干细胞”群。Understanding the cell biology of the tissues in which cancer develops and in particular the stem cells residing in these tissues provides new knowledge about cancer biology. Several aspects of stem cell biology are relevant to cancer. First, both normal and cancer cells undergo self-renewal, and evidence has emerged that similar molecular mechanisms regulate the self-renewal of both normal stem cells and their malignant counterparts. Second, cancer-causing mutations are likely to accumulate in normal stem cells. Finally, tumors may contain populations of "cancer stem cells" with unlimited proliferative potential that drive tumor growth and^{metastasis18-26} .

HSCs是研究最多和了解最详细的体细胞干细胞群¹。血细胞生成是受到严格调控的过程，其中造血干细胞最终产生淋巴造血干细胞系统，其由形成的血液组分例如红细胞、血小板、粒细胞、巨噬细胞和B以及T淋巴细胞组成。这些细胞分别地对氧合、预防出血、免疫性和感染性来说是很重要的。在成人中，HSCs具有两个基本特征。第一，HSCs需要自我更新以保持干细胞库；HSCs的总数在严格的遗传调控²⁷之下。第二，其必须进行分化以在正常的条件下保持恒定的成熟细胞库和响应于应激例如出血或感染而产生增加数目的特定谱系。HSCs are the most studied and best understood somatic stem cell population¹ . Hematopoiesis is a tightly regulated process in which hematopoietic stem cells ultimately give rise to the lymphoid hematopoietic stem cell system, which consists of formed blood components such as erythrocytes, platelets, granulocytes, macrophages, and B and T lymphocytes. These cells are important for oxygenation, prevention of bleeding, immunity and infectivity, respectively. In adults, HSCs have two fundamental features. First, HSCs require self-renewal to maintain the stem cell pool; the total number of HSCs is under strict genetic regulation²⁷ . Second, it must be differentiated to maintain a constant pool of mature cells under normal conditions and to generate increased numbers of specific lineages in response to stress such as bleeding or infection.

在造血系统中，多能细胞组成了0.05％的小鼠骨髓细胞并且其自我更新的能力是不同的。有三种不同的多能细胞群：长期自我更新的HSCs，短期自我更新的HSCs和不具有可检测的自我更新潜能^7，28的多能祖细胞。这些群体形成了层次，其中长期HSCs产生短期HSCs，所述短期HSCs接着产生多能祖细胞[图.1中⁷]。随着HSCs从长期自我更新库成熟为多能祖细胞，其变得更具有丝分裂活性但失去了自我更新能力。只有长期HSCs能够在动物的一生中产生成熟造血细胞，而短期HsCs和多能祖细胞只能重建少于8周⁷的经致死性放射的小鼠。In the hematopoietic system, pluripotent cells make up 0.05% of mouse bone marrow cells and vary in their ability to self-renew. There are three distinct populations of pluripotent cells: long-term self-renewing HSCs^, short-term self-renewing HSCs, and pluripotent progenitors with no detectable self-renewal potential7,28. These populations form a hierarchy in which long-term HSCs give rise to short-term HSCs, which in turn give rise to multipotent progenitors [Fig. 1,⁷ ]. As HSCs mature from long-term self-renewing pools to multipotent progenitors, they become more mitotically active but lose their ability to self-renew. Only long-term HSCs are able to generate mature hematopoietic cells throughout the animal's lifetime, whereas short-term HsCs and multipotent progenitors can only be reconstituted in lethally irradiated mice of less than 8^weeks7 .

尽管已对小鼠和人HSCs的表型和功能性特征进行了详细表征²，但我们对基本的干细胞特性，自我更新的理解仍然很少^25，29，30。在大多数情况下，当暴露于在长期培养³¹中可诱导强烈增殖的生长因子的组合中时，HSCs进行分化。尽管已在确定在有限时间培养中保持HSC活性的培养条件方面[例如参见Miller和Graves³²]取得新进展，但已证明确定促进具有可移植的HSC活性的祖细胞的显著和长期扩增的组织培养条件是极其困难的。Although the phenotypic and functional characteristics of mouse and human HSCs have been characterized in^detail2 , our understanding of a fundamental stem cell property, self-renewal, remains^poor25,29,30 . In most cases, HSCs differentiate when exposed to combinations of growth factors that induce robust proliferation in long-term^culture . Although new advances have been made in identifying culture conditions that maintain HSC activity in time-limited cultures [see for example Miller and Graves³² ], it has been shown to identify tissues that promote significant and long-term expansion of progenitor cells with engraftable HSC activity The cultivation conditions are extremely difficult.

组织或肿瘤的维持通过细胞的增殖和死亡³³的平衡来决定。在正常的组织中，干细胞数目在严格的遗传调控之下，所述遗传调控使干细胞的数目在器官^27，34，35中维持恒定。相反地，癌细胞已逃避了该动态平衡调控并且在肿瘤内具有自我更新能力的细胞数目不断增加，最终导致肿瘤的生长。如所预期的，许多驱动肿瘤增长的突变调节细胞增殖或存活。例如，通过增强癌基因Bcl-2的表达防止凋亡促进了淋巴瘤的发育并且也在体内导致增加的HSCs数目，表明细胞死亡在调节HSC的动态平衡中起作用。事实上，小鼠中实验性急性髓样白血病的发展需要至少3个和可能4个独立的事件以阻止几个内部触发和外部诱导的骨髓细胞³⁸程序化细胞死亡途径。原癌基因例如驱动肿瘤细胞增殖的c-myb和c-myc也是HSCs发育^39-42所必需的。Tissue or tumor maintenance is determined by the balance of cell proliferation and^death33 . In normal tissues, stem cell numbers are under strict genetic regulation that maintains stem cell numbers constant in^{organs27,34,35} . Conversely, cancer cells have escaped this homeostasis regulation and the number of self-renewing cells within the tumor increases, ultimately leading to tumor growth. As expected, many mutations that drive tumor growth regulate cell proliferation or survival. For example, preventing apoptosis by enhancing the expression of the oncogene Bcl-2 promoted lymphoma development and also resulted in increased numbers of HSCs in vivo, suggesting that cell death plays a role in regulating HSC homeostasis. Indeed, the development of experimental acute myeloid leukemia in mice requires at least 3 and possibly 4 independent events to arrest several internally triggered and externally induced programmed cell death pathways in^myeloid cells. Proto-oncogenes such as c-myb and c-myc, which drive tumor cell proliferation, are also required for HSCs^{development39-42} .

因为癌细胞和正常细胞都具有自我更新的能力，因此不奇怪，经典的与癌症相关的大量基因也可调节正常干细胞发育[参见综述^25，43]。通过发现：针对人造血干细胞(CD34⁺Lin^-CD38^-)高度富集的细胞表现出增加的响应体外⁴⁴Shh刺激的自我更新，已证明Shh信号传导(和其它生长因子一起)也涉及自我更新的调控。几种其它涉及肿瘤发生的基因已显示对干细胞功能具有重要作用。例如，tal-1/SCL(在某些情况下涉及人急性白血病)缺陷小鼠缺少胚胎血细胞生成⁴⁵，暗示着其为内部的或外部的启动血细胞生成的必需事件、维持最早确定的血细胞，或决定形成胚胎HSCs^45，46的下游血细胞所必需。Hox家族成员也涉及人白血病。增强的HoxB4的表达可影响干细胞功能^47，48。p53肿瘤抑制基因的一个主要靶是p21^cip1。来自p21^cip1缺陷小鼠的骨髓具有减少的系列重建经致死性辐射的受体的能力。系列转移上的失败可由干细胞库的枯竭、端粒的丢失或可移植能力的丢失⁴⁹造成。在小鼠中，与c-myc合作诱导淋巴瘤^50，51的bmi-1基因是用来维持成熟HSCs和白血病细胞所需的。因此，许多参与干细胞命运决定的基因也参与恶性肿瘤的转化。Because both cancer cells and normal cells have the capacity for self-renewal, it is not surprising that a large number of genes classically associated with cancer also regulate normal stem cell development [see reviews^{25, 43} ]. Shh signaling (along with other growth factors) has also been demonstrated to be involved in self-renewal by the discovery that cells highly enriched for human hematopoietic stem cells (CD34⁺ Lin^- CD38^- ) exhibit increased self-renewal in response to⁴⁴ Shh stimulation in vitro. regulation. Several other genes involved in tumorigenesis have been shown to be important for stem cell function. For example, mice deficient in tal-1/SCL (in some cases involved in human acute leukemia) lack embryonic hematopoiesis⁴⁵ , implying that it is an intrinsic or extrinsic event necessary to initiate hematopoiesis, maintain the earliest identified blood cells, or Required for downstream hemocytes that determine the formation of embryonic HSCs^45,46 . Members of the Hox family have also been implicated in human leukemia. Enhanced expression of HoxB4 can affect stem cell function^47,48 . A major target of the p53 tumor suppressor gene is p21^cip1 . Bone marrow from p21^cip1 deficient mice has a reduced serial ability to reconstitute lethally irradiated receptors. Failure in serial transfer can result from depletion of^the stem cell pool, loss of telomeres, or loss of transplantability49. In mice, the bmi-1 gene cooperates with c-myc to induce^{lymphoma50,51} and is required for the maintenance of mature HSCs and leukemia cells. Thus, many genes involved in stem cell fate determination are also involved in malignancy transformation.

两个在小鼠和人中都涉及肿瘤发生的其它信号传导途径，即Wnt/β-连环蛋白和Notch途径，可在正常和癌干细胞的自我更新中都起着中心作用。首先在果蝇中鉴定了Notch受体家族并且已证明其参与发育和分化⁵²。在美丽线虫(C elegans)中，Notch在生殖细胞自我更新⁵³中发挥作用。在神经发育过程中，通过胚胎神经嵴干细胞¹⁰，短暂的Notch活化启动了从神经发生到胶质生成的不可逆转换。使用Notch配体Jagged-1或Delta对培养体系中HSCs的Notch激活短暂地增加了可在体外和体内观察到的原始祖细胞的活性，暗示着Notch活性促进祖细胞多能性或HSC自我更新^54，55的维持。尽管Notch途径在发育中发挥中心作用并且小鼠int-3癌基因是截短的Notch4⁵⁶，但在人癌从头形成中Notch的作用是复杂的并且了解较少。各种Notch信号传导途径的成员在上皮细胞来源的癌中表达，通过染色体易位产生的Notch活性在某些情况下参与白血病^57-61。微阵列分析已显示肿瘤细胞^58，59通常过量表达Notch途径的成员。一些乳腺癌细胞系⁶²表达截短的Notch4mRNA。Notch1的过量表达导致小细胞肺癌细胞系的生长受到抑制，而Notch1信号的抑制可诱导白血病细胞系进行凋亡⁵²，^54，63。Miele和同事的工作显示Notch-1信号传导的激活在Ras转化的人细胞⁶⁴中维持致瘤性表型。其也发现在癌的从头形成中，具有激活Ras的突变的细胞也表现增加的Notch-1和Notch-4的表达。Two other signaling pathways involved in tumorigenesis in both mice and humans, the Wnt/β-catenin and Notch pathways, may play a central role in the self-renewal of both normal and cancer stem cells. The Notch receptor family was first identified in Drosophila and has been shown to be involved in development and^{differentiation52} . In C elegans, Notch plays a role in germ cell self-^renewal53 . During neural development, transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis through embryonic neural crest stem^cells . Notch activation of HSCs in culture using the Notch ligands Jagged-1 or Delta transiently increased the activity of primitive progenitors observed in vitro and in vivo, implying that Notch activity promotes progenitor pluripotency or HSC self-^{renewal54 , 55} maintenance. Although the Notch pathway plays a central role in development and the mouse int-3 oncogene is the truncated^Notch456 , the role of Notch in human cancer de novo formation is complex and poorly understood. Members of various Notch signaling pathways are expressed in carcinomas of epithelial cell origin, and Notch activity through chromosomal translocations has been implicated in certain cases in^{leukemia57–61} . Microarray analysis has shown that tumor^cells58,59 often overexpress members of the Notch pathway. Some breast cancer cell^lines62 express truncated Notch4 mRNA. Overexpression^of Notch1 leads to growth inhibition in small cell lung cancer cell lines, while inhibition of Notch1 signaling induces apoptosis in leukemia cell^{lines52,54,63} . Work by Miele and colleagues showed that activation of Notch-1 signaling maintains a tumorigenic phenotype in Ras-transformed human^cells64 . It was also found that cells with mutations that activate Ras also exhibit increased expression of Notch-1 and Notch-4 in de novo formation of cancer.

Wnt/β-连环蛋白信号传导也在正常干细胞的自我更新和恶性转化^65-67中发挥中枢作用。Wnt途径首先参与MMTV诱导的乳腺癌，其中由于原病毒的插入引起的Wnt-1的表达下调导致乳腺肿瘤^68，69。随后，已显示Wnt蛋白在模式形成中发挥中心作用。Wnt-1属于高度疏水的分泌蛋白大家族，所述蛋白通过与其相关受体、Frizzled和低密度脂蛋白受体相关蛋白家族的成员结合导致β连环蛋白^{43，58，65，70，71}的激活来发挥作用。在受体激活不存在时，β连环蛋白以被由AdenomatousPolyposis Coli(APC)、Axin和糖原合酶激酶-3β蛋白^{58，67，72-74}构成的复合体降解为特征^66，75。Wnt蛋白在骨髓中表达，在体外由Wnt蛋白或由组成型活性的β连环蛋白的表达激活的Wnt/β连环蛋白信号传导扩展了早祖先细胞和在组织培养中和在体内^25，67，72富集的正常的可移植的造血干细胞的库。通过Axin(β连环蛋白信号传导的抑制剂)的异位表达对Wnt/β连环蛋白的抑制导致了在体外和体内都抑制了干细胞的增殖。其它研究表明Wnt/β连环蛋白途径介导干细胞或祖细胞在其它组织^{73，74，76，77}中自我更新。β连环蛋白的水平在具有更高增殖潜能的角质细胞中比在具有较低增殖能力的角质细胞中更高。如其正常的造血干细胞对应物一样，增强的经激活的β连环蛋白的表达增强了表皮干细胞自我更新的能力和减少了其分化的能力。不能表达TCF-4(所述TCF-4是一个当与β连环蛋白结合时被激活的转录因子)的小鼠迅速耗尽了其未分化的隐窝上皮祖细胞，进一步暗示Wnt信号通路参与上皮干细胞^43，76的自我更新中。Wnt/β-catenin signaling also plays a central role in the self-renewal and malignant transformation^of normal stem cells65-67. The Wnt pathway was first implicated in MMTV-induced breast cancer, where downregulation of Wnt-1 expression due to proviral insertion resulted in mammary^tumors68,69 . Subsequently, Wnt proteins have been shown to play a central role in pattern formation. Wnt-1 belongs to^a large family of highly hydrophobic secreted proteins that lead to activation of β-catenin by binding to its associated receptors, members of the Frizzled and low-density lipoprotein receptor-associated protein families43,58,65,70,71 to play a role. In the absence of receptor activation, β-catenin is characterized for^degradation by a complex consisting of Adenomatous Polyposis Coli (APC), Axin, and glycogen synthase kinase-3β proteins^{58,67,72-7466,75} . Wnt proteins are expressed in the bone marrow, and Wnt/β-catenin signaling activated by Wnt proteins in vitro or by expression of constitutively active β-catenin extends early progenitor cells and in tissue culture and in^vivo25,67,72 An enriched pool of normal, transplantable hematopoietic stem cells. Inhibition of Wnt/β-catenin by ectopic expression of Axin, an inhibitor of β-catenin signaling, resulted in inhibition of stem cell proliferation both in vitro and in vivo. Other studies have shown that the Wnt/β-catenin pathway mediates self-renewal^of stem or progenitor cells in other tissues73,74,76,77. The level of β-catenin was higher in keratinocytes with higher proliferative potential than in keratinocytes with lower proliferative potential. Like their normal hematopoietic stem cell counterparts, enhanced expression of activated β-catenin enhances the ability of epidermal stem cells to self-renew and reduces their ability to differentiate. Mice unable to express TCF-4, a transcription factor that is activated when bound to β-catenin, rapidly deplete their undifferentiated crypt epithelial progenitors, further implicating the involvement of Wnt signaling in epithelial Self-renewal of stem cells^43,76 .

由蛋白降解途径失活(最常用的是通过APC的突变)造成的结肠癌中β连环蛋白的激活是很普遍的^{43，58，66，75}。某些Wnt基因的表达在一些其它上皮癌细胞中的提高暗示β连环蛋白的激活对在这些癌细胞^65，78-83中的配体激活产生应答。有证据表明Wnt/β连环蛋白途径的组成型激活可为癌细胞提供干细胞/祖细胞的表型。在结肠癌细胞系中β连环蛋白/TCF-4的抑制诱导了细胞周期抑制剂p21^cip-1的表达和诱导细胞停止增殖和获得更具分化的表型⁸³。原癌基因c-myc的增强表达抑制了p21^cip-1的表达并允许结肠癌细胞在β连环蛋白/TCF-4信号传导被阻止时增殖，在细胞增殖和分化的调控中连接Wnt信号传导与c-myc。尽管许多研究已涉及乳腺癌中的Wnt/β连环蛋白途径，但β连环蛋白的突变激活在该疾病中是非常稀有的并且没有研究明确地将该途径与人乳腺癌^84-89相联系。Activation of β-catenin in colon cancer by inactivation of protein degradation pathways, most commonly through mutation of APC, is^{common43,58,66,75} . Increased expression of certain Wnt genes in some other epithelial cancer cells suggests that activation of β-catenin responds to ligand activation in these cancer^{cells65,78-83} . There is evidence that constitutive activation of the Wnt/β-catenin pathway confers a stem/progenitor phenotype to cancer cells. Inhibition of β-catenin/TCF-4 in colon cancer cell lines induced expression of the cell cycle inhibitor p21^cip-1 and induced cells to cease proliferation and acquire a more differentiated^phenotype83 . Enhanced expression of the proto-oncogene c-myc suppresses p21^cip-1 expression and allows colon cancer cells to proliferate when β-catenin/TCF-4 signaling is blocked, linking Wnt signaling to the regulation of cell proliferation and differentiation c-myc. Although many studies have implicated the Wnt/β-catenin pathway in breast cancer, mutational activation of β-catenin is very rare in this disease and no studies have definitively linked this pathway to human breast^cancer84-89 .

基因如Notch、Wnt、c-myc和Shh在HSCs和可能的来自多个组织的干细胞的自我更新调控上发挥的作用暗示着在许多类型的正常体细胞干细胞和癌干细胞之间存在共同的自我更新途径。鉴定这些途径发挥功能的分子机制和确定所述途径是否相互作用以调控正常干细胞和癌细胞的自我更新是非常重要的。Roles of genes such as Notch, Wnt, c-myc, and Shh in the regulation of self-renewal in HSCs and possibly stem cells from multiple tissues imply a shared self-renewal between many types of normal somatic and cancer stem cells way. It is important to identify the molecular mechanisms by which these pathways function and to determine whether the pathways interact to regulate self-renewal of normal stem cells and cancer cells.

Wnt途径参与正常干细胞的自我更新，Wnt的突变激活诱导小鼠中的乳腺癌。该途径通过从一些患者分离的人乳腺癌干细胞在肿瘤形成中发挥作用。此外，证据显示不同的乳腺癌细胞群体形成肿瘤的能力不同。有趣地，Wnt/Frizzled/β-连环蛋白途径的成员的表达通过不同的癌细胞群体进行异源表达，所述途径的特定成员的表达可能与形成肿瘤的能力相关。The Wnt pathway is involved in the self-renewal of normal stem cells, and mutational activation of Wnt induces breast cancer in mice. This pathway plays a role in tumor formation by human breast cancer stem cells isolated from some patients. In addition, evidence shows that different populations of breast cancer cells differ in their ability to form tumors. Interestingly, expression of members of the Wnt/Frizzled/β-catenin pathway is heterologously expressed by different cancer cell populations, and expression of specific members of the pathway may correlate with the ability to form tumors.

不同的癌细胞和肿瘤细胞群体驱动乳腺癌细胞的增殖。在许多患者的癌细胞中观察到经激活的β-连环蛋白。包含具有该途径组成型活性的癌细胞的肿瘤与不具有组成型激活的β-连环蛋白的肿瘤的表现不同。Different cancer cell and tumor cell populations drive proliferation of breast cancer cells. Activated β-catenin is observed in cancer cells of many patients. Tumors containing cancer cells with constitutive activity of this pathway behaved differently than tumors without constitutively activated β-catenin.

II.人乳腺癌的异种移植模型II. Xenograft Model of Human Breast Cancer

尽管细胞系在我们对癌细胞的分子和生物化学变化的理解上已导致获得重大的进展，但其在鉴定有效的癌症治疗物的用途上仍是有限的^90，91。细胞系在预测对从头形成的肿瘤^90，91的药效上是有缺陷的。几个因素可能解释该缺陷。癌细胞系选自癌细胞的亚群，所述癌细胞特定地适应于在组织培养中生长，这些细胞系的生物学和功能特性可发生重大改变^92-95。此外，只来自少数乳腺癌肿瘤的癌细胞建立了细胞系或异种移植肿瘤^96-97。这些细胞系的表型和功能性特征相对于其在体内⁹⁴的特征可以发生重大改变。例如，正常造血和白血病的组织培养细胞的标记表达在组织培养中可迅速发生变化并且通常不能反映其起源^{92，94，95，98}的原始干细胞的特征。即使在设计用来使培养中的正常干细胞增殖的条件下，所述条件通常以阻止培养中的干细胞重演已在体内存在的细胞群体分层的方式促进自我更新或分化。总的说来，这些观察暗示癌细胞系的生物学特征可与其起源的癌细胞显著不同。这可能至少部分地解释为什么细胞系在临床上是较差的药效预测者。Although cell lines have led to significant advances in our understanding of the molecular and biochemical changes in cancer cells, their use in identifying effective cancer therapeutics remains^limited90'91 . Cell lines are deficient in predicting drug efficacy against^de novo tumors90,91. Several factors may explain this deficiency. Cancer cell lines are selected from subpopulations of cancer cells specifically adapted for growth in tissue culture, the biological and functional properties of these cell lines can be substantially^altered92-95 . Furthermore, only a few cancer cells from breast cancer tumors have established cell lines or tumor^{xenografts96-97} . The phenotypic and functional characteristics of these cell lines can be substantially altered relative to their in^vivo94 characteristics. For example, marker expression in tissue culture cells of normal hematopoiesis and leukemia can change rapidly in tissue culture and often does not reflect the characteristics of^the primitive stem cells of their origin. Even under conditions designed to proliferate normal stem cells in culture, the conditions generally promote self-renewal or differentiation in a manner that prevents stem cells in culture from reproducing stratification of cell populations already present in vivo. Collectively, these observations imply that the biology of cancer cell lines can differ significantly from the cancer cells from which they originate. This may explain, at least in part, why cell lines are poor predictors of efficacy in the clinic.

因此，缺乏在体外或体内长期持续培养原代人乳腺癌细胞的有效方法已经严重地限制了我们了解该疾病的生物学的能力。最有效的异种移植模型报道了将乳腺癌肿瘤碎片移植入卵巢中而不是乳房中，在接近60-75％的时间⁹⁹内在SCID小鼠体内形成脂肪垫。在该模型中不可能进行分开的细胞移植，并且分离自胸膜渗出物质的癌细胞只在大约10％的时间⁹⁰内在免疫缺陷小鼠中形成肿瘤。本发明(参见下面的实施例1)提供了异种移植模型，其中通过在严重免疫缺陷小鼠的乳腺中注射肿瘤能够从原代乳腺肿瘤建立肿瘤。本发明的这些异种移植使得可以进行生物学和分子检验以表征克隆发生性乳腺癌细胞以及其它细胞种类。重要的是，根据本发明发育的异种移植肿瘤包含发现于人肿瘤中的表型各异的癌细胞类型，所述癌细胞类型起源于所述人肿瘤，并且不同的癌细胞群体在其形成肿瘤¹⁰⁰的能力上显著不同。Thus, the lack of efficient methods for long-term sustained culture of primary human breast cancer cells in vitro or in vivo has severely limited our ability to understand the biology of the disease. The most efficient xenograft model reported transplantation of breast cancer tumor fragments into the ovary rather than the breast formed fat pads in SCID mice nearly 60-75% of the^time99 . Separate cell transplantation was not possible in this model, and cancer cells isolated from pleural effusions formed tumors in immunodeficient mice only about 10% of the^time90 . The present invention (see Example 1 below) provides a xenograft model in which tumors can be established from primary mammary tumors by injecting tumors in the mammary glands of severely immunodeficient mice. These xenografts of the invention allow biological and molecular assays to characterize clonogenic breast cancer cells as well as other cell types. Importantly, xenograft tumors developed according to the present invention comprise phenotypically diverse cancer cell types found in human tumors from which they originated and in which distinct populations of cancer cells form tumors¹⁰⁰ are significantly different in capacity.

根据本发明(参见，例如实施例1)的有效的异种移植模型的发展，已第一次可靠地使得获自患者的分离的实体瘤细胞形成肿瘤。重要的是，其使得能够在个体患者癌细胞中常规地分析生物化学途径和进行分子操作，所述操作通过从头的人实体瘤癌细胞使人们了解有关肿瘤形成的特定遗传途径的细胞后果。The development of an efficient xenograft model according to the present invention (see, eg, Example 1), has for the first time reliably resulted in tumor formation from isolated solid tumor cells obtained from patients. Importantly, it enables the routine analysis of biochemical pathways and molecular manipulation in individual patient cancer cells that informs the understanding of the cellular consequences of specific genetic pathways on tumorigenesis by de novo human solid tumor cancer cells.

III.实体瘤干细胞癌标记III. Solid Tumor Stem Cell Carcinoma Markers

本发明提供了其表达在实体瘤干细胞中被特异性改变(例如，上调或下调)的标记。这些标记在各种癌症(例如，乳腺癌)的诊断和表征以及改变(例如，治疗性靶向)中找到了用途。The invention provides markers whose expression is specifically altered (eg, upregulated or downregulated) in solid tumor stem cells. These markers find use in the diagnosis and characterization and alteration (eg, therapeutic targeting) of various cancers (eg, breast cancer).

下面提供的实施例4描述了用于鉴定实体瘤癌标记的方法。下面在表4-8中提供了优选的癌标记和Notch4。尽管这些表提供了基因名字，但要注意本发明涉及所述核酸序列和其编码的肽以及所述核酸和肽的片段在本发明的治疗和诊断方法以及组合物中的用途。Example 4 provided below describes a method for identifying cancer markers in solid tumors. Preferred cancer markers and Notch4 are provided below in Tables 4-8. Although these tables provide gene names, it is to be noted that the present invention relates to the nucleic acid sequences and the peptides encoded thereby and the use of fragments of the nucleic acids and peptides in the therapeutic and diagnostic methods and compositions of the present invention.

                                     表4 Table 4

                          UPTG和UPNTG中相比上调的Up-regulated in UPTG and UPNTG

S100A8，KRT18，CEACAM6，IFITM2，HLA-C，S100P，S100A9，H2BFT，HLA-C，FXYD3，S100A10，KRT19，TUBB，HLA-S100A8, KRT18, CEACAM6, IFITM2, HLA-C, S100P, S100A9, H2BFT, HLA-C, FXYD3, S100A10, KRT19, TUBB, HLA-

DPA1，CEACAM5，LCN2，FTH1，RPS26，IFITM2，S100A7，CAP，HUMMHCW1A，HLA-DRB3，CD63，S100A6，HSPB1，DPA1, CEACAM5, LCN2, FTH1, RPS26, IFITM2, S100A7, CAP, HUMMHCW1A, HLA-DRB3, CD63, S100A6, HSPB1,

HLA-B，MGLL，PTS，HLA-A，RA13，DAF，UBC，HLA-A，KDELR3，SERF2，CTSB，CEACAM6，PDLIM1，SHC1，GOLPH2，HLA-B, MGLL, PTS, HLA-A, RA13, DAF, UBC, HLA-A, KDELR3, SERF2, CTSB, CEACAM6, PDLIM1, SHC1, GOLPH2,

GABARAP，AQP3，COL3A1，AHCYL1，FXYD3，ITM2B，BF，RBMS1，DUSP1，PSAP，ARHGD1B，ENO1，ATP6V0E，GABARAP, AQP3, COL3A1, AHCYL1, FXYD3, ITM2B, BF, RBMS1, DUSP1, PSAP, ARHGD1B, ENO1, ATP6V0E,

MUC1，RARRES1，CD81，TRIM44，ASS，CD59，PRG1，HLA-E，TXNIP，INHBA，CSTB，H2AFO，HLA-DRB4，RAB31，MUC1, RARRES1, CD81, TRIM44, ASS, CD59, PRG1, HLA-E, TXNIP, INHBA, CSTB, H2AFO, HLA-DRB4, RAB31,

P4HB，LOC92689，B2M，CSNK2B，MGST3，DKFZp56411922，C4B，UCP2，FN1，COL1A2，LOC51186，LTF，TIMP1，NPC2，P4HB, LOC92689, B2M, CSNK2B, MGST3, DKFZp56411922, C4B, UCP2, FN1, COL1A2, LOC51186, LTF, TIMP1, NPC2,

TSPAN-1，COL1A2，SLP1，CIB1，IQGAP1，SPARC，FN1，CCN1，SPTBN1，H2AFO，BTN3A3，FN1，SEPX1，GFPT1，TSPAN-1, COL1A2, SLP1, CIB1, IQGAP1, SPARC, FN1, CCN1, SPTBN1, H2AFO, BTN3A3, FN1, SEPX1, GFPT1,

ANXA11，CD74，RAB25，APP，PSEN1，IF127，FHL2，CPB1，BACE2，PSMD8，LGALS1，PLAT，EIF3S4，ANXA2P2，PILB，ANXA11, CD74, RAB25, APP, PSEN1, IF127, FHL2, CPB1, BACE2, PSMD8, LGALS1, PLAT, EIF3S4, ANXA2P2, PILB,

IF130，ATP6V0E，LOH11CR2A，LBP，HLA-DRB1，MIC2，OPN3，SVIL，FDFT1，PTG1S，ORMDL2，PIG7，ERBB3，GSN，IF130, ATP6V0E, LOH11CR2A, LBP, HLA-DRB1, MIC2, OPN3, SVIL, FDFT1, PTG1S, ORMDL2, PIG7, ERBB3, GSN,

FN1，GOT2，BCL6，WBSCR21，ANXA1，CLU，PIK3R3，TNFSF10，NBL1，PEX11B，CDKN1A，SAS，RIC-8，RABAC1，FN1, GOT2, BCL6, WBSCR21, ANXA1, CLU, PIK3R3, TNFSF10, NBL1, PEX11B, CDKN1A, SAS, RIC-8, RABAC1,

ADD3，ARPC5，GUK1，NQO1，FER1L3，PPAP2A，TSPAN-3，PLOD2，TGM2，LOC51760，TST，TM9SF1，LGALS3BP，ADD3, ARPC5, GUK1, NQO1, FER1L3, PPAP2A, TSPAN-3, PLOD2, TGM2, LOC51760, TST, TM9SF1, LGALS3BP,

CI4orf1，D2S448，OPTN，GPX1，MBC2，PTGES，DPYSL2，PEN-2，DAG1，GM2A，DKFZP564G2022，FAT，SLC21A11，CI4orf1, D2S448, OPTN, GPX1, MBC2, PTGES, DPYSL2, PEN-2, DAG1, GM2A, DKFZP564G2022, FAT, SLC21A11,

ACADVL，ABLIM1，HLA-DPB1，COPA，PPP1R7，DAF，SSBP2，TES，MUC16，PPL，MGC10765，SECTM1，C3，NNMT，ACADVL, ABLIM1, HLA-DPB1, COPA, PPP1R7, DAF, SSBP2, TES, MUC16, PPL, MGC10765, SECTM1, C3, NNMT,

ARF3，SEPW1，H1F2，SERPINB1，KIAA0746，RDGBB，ELF3，TUBB4，VCAM1，FOXO1A，EGFL6，ATP1A1，PLS3，LMNA，ARF3, SEPW1, H1F2, SERPINB1, KIAA0746, RDGBB, ELF3, TUBB4, VCAM1, FOXO1A, EGFL6, ATP1A1, PLS3, LMNA,

TGFB1，DD96，GLRX，PROSC，IL1R1，SERPINB2，KRT7，RGS16，TNFAIP1，SYNGR2，PAFAH1B3，GP1，C6orf37，ATF3，TGFB1, DD96, GLRX, PROSC, IL1R1, SERPINB2, KRT7, RGS16, TNFAIP1, SYNGR2, PAFAH1B3, GP1, C6orf37, ATF3,

HLA-DMA，FLJ22418，DCN，FOXO3A，HLA-DQB1，CPD，DF，HTAT1P2，MUC5B，CTSB，PBEF，H11，CAPNS1，Z391G，HLA-DMA, FLJ22418, DCN, FOXO3A, HLA-DQB1, CPD, DF, HTAT1P2, MUC5B, CTSB, PBEF, H11, CAPNS1, Z391G,

MAGED2，TNFSF13，HLA-DRB3，H2BFQ，SGK，P4HA2，VPS28，NDUFB8，PON3，ENSA，EDF1，SERPINB6，FDPS，RGS3，MAGED2, TNFSF13, HLA-DRB3, H2BFQ, SGK, P4HA2, VPS28, NDUFB8, PON3, ENSA, EDF1, SERPINB6, FDPS, RGS3,

CREB3，PRNP，YWHAB，A2M，HLA-DQB1，PDGFRA，CLMN，INHBB，SURF1，NFIL3，S100A11，HPGD，CLDN7，DAB2，CREB3, PRNP, YWHAB, A2M, HLA-DQB1, PDGFRA, CLMN, INHBB, SURF1, NFIL3, S100A11, HPGD, CLDN7, DAB2,

NT5C2，PLXNB2，GSTP1，AP2B1，COL3A1，HRMT1L1，SRPR，RNASE6PL，ANXA8，PROML1，C1S，GALNT6，BAT3，BC-NT5C2, PLXNB2, GSTP1, AP2B1, COL3A1, HRMT1L1, SRPR, RNASE6PL, ANXA8, PROML1, C1S, GALNT6, BAT3, BC-

2，GLS，CD14，FYCO1，SQSTM1，CSPG2，DEFB1，BAT3，GALNT2，SPARC，WT1，DUSP6，MONDOA，MACF1，ATP2C1，2, GLS, CD14, FYCO1, SQSTM1, CSPG2, DEFB1, BAT3, GALNT2, SPARC, WT1, DUSP6, MONDOA, MACF1, ATP2C1,

THBS2，CD53，PGM3，HLA-DRB6，COL1A1，SCAP2，KIAA0436，CYR61，TNFSF13，SLC6A14，CUGBP2，LAMP1，CCL22，THBS2, CD53, PGM3, HLA-DRB6, COL1A1, SCAP2, KIAA0436, CYR61, TNFSF13, SLC6A14, CUGBP2, LAMP1, CCL22,

CLU，CD163，ANXA3，MBLL39，IL4R，SERPINB1，CNP，TUBB4，FLJ20265，MAFB，EFEMP1，DPP7，SYNE-2，PLSCR1，CLU, CD163, ANXA3, MBLL39, IL4R, SERPINB1, CNP, TUBB4, FLJ20265, MAFB, EFEMP1, DPP7, SYNE-2, PLSCR1,

PDE4DIP，P2Y5，RAGA，SIAT1，N4WBP5，SPUVE，BPAG1，DEPP，BASP1，CTSB，HLA-E，KIAA0308，GAS1，ABR，PDE4DIP, P2Y5, RAGA, SIAT1, N4WBP5, SPUVE, BPAG1, DEPP, BASP1, CTSB, HLA-E, KIAA0308, GAS1, ABR,

ABCA1，GRN，WDR1，PM5，CYFIP2，SGP28，FLRT2，ACACA，LUM，FLJ21432，FEM1C，RIN2，PCDH7，SLC7A7，ABCA1, GRN, WDR1, PM5, CYFIP2, SGP28, FLRT2, ACACA, LUM, FLJ21432, FEM1C, RIN2, PCDH7, SLC7A7,

FLJ21347，SOX9，MB，S100A8，DAP，MVP，SPP1，TM9SF1，DOC1，COL5A2，RNF24，GLB1，GRN，HLA-DRB5，ENPP2，FLJ21347, SOX9, MB, S100A8, DAP, MVP, SPP1, TM9SF1, DOC1, COL5A2, RNF24, GLB1, GRN, HLA-DRB5, ENPP2,

CSGlcA-T，KIAA0937，H2BFT，JUP，KYNU，APOL6，GM2A，C1orf24，SYNGR3，COL6A1，CRYM，LXN，FARP1，p100，CSGlcA-T, KIAA0937, H2BFT, JUP, KYNU, APOL6, GM2A, C1orf24, SYNGR3, COL6A1, CRYM, LXN, FARP1, p100,

ANK1，NPC1，RBPMS，VLDLR，ARHC，UBE1，HDLBP，LYZ，DCN，PLAB，SERPINE2，EGLN3，FSTL1，LAPTM5，ANK1, NPC1, RBPMS, VLDLR, ARHC, UBE1, HDLBP, LYZ, DCN, PLAB, SERPINE2, EGLN3, FSTL1, LAPTM5,

TRIM29，ACTN4，MUC1，SH3GLB1，B1K，ZNF91，CLIC4，NARF，LIM，SLC1A1，KIAA0746，APOC1，TYROBP，FLNB，TRIM29, ACTN4, MUC1, SH3GLB1, B1K, ZNF91, CLIC4, NARF, LIM, SLC1A1, KIAA0746, APOC1, TYROBP, FLNB,

EMP1，UBE2L6，KRT6B，MAN2A1，GCN5L1，APEH，F-LAN-1，PRKCZ，CD163，HLA-DQA1，KIAA1668，MUC5B，LAR1，EMP1, UBE2L6, KRT6B, MAN2A1, GCN5L1, APEH, F-LAN-1, PRKCZ, CD163, HLA-DQA1, KIAA1668, MUC5B, LAR1,

BCL2L13，CXX1，MPZL1，NR3C1，AHR，FLJ12389，ATP6V0C，MD-1，H2BFA，HSPC023，OSBPL8，ZNF36，TRJM14，BCL2L13, CXX1, MPZL1, NR3C1, AHR, FLJ12389, ATP6V0C, MD-1, H2BFA, HSPC023, OSBPL8, ZNF36, TRJM14,

UGTREL1，CTSL，COL5A1，PDGFC，UBE2N，SF1，ARHGEF10，SH3GLB1，HLA-G，KIAA0084，HT012，SULF1，TTC1，UGTREL1, CTSL, COL5A1, PDGFC, UBE2N, SF1, ARHGEF10, SH3GLB1, HLA-G, KIAA0084, HT012, SULF1, TTC1,

UBAP1，PGLS，M6PR，TEM7，NPR2L，GRN，EXT2，DCN，HLA-DMB，HLA-DQB1，NAGK，MMP19，LBP，ATP10B，CLN3，UBAP1, PGLS, M6PR, TEM7, NPR2L, GRN, EXT2, DCN, HLA-DMB, HLA-DQB1, NAGK, MMP19, LBP, ATP10B, CLN3,

SP100，CSPG2，VIM，IGFBP3，ANK1，DUSP3，STAT3，CED-6，KIAA0196，SOX9，NKX3-1，TGFBR2，CAV1，TREM1，SP100, CSPG2, VIM, IGFBP3, ANK1, DUSP3, STAT3, CED-6, KIAA0196, SOX9, NKX3-1, TGFBR2, CAV1, TREM1,

PTD009，GPX2，LAPTM5，HSPC022，SSA1，ABS，CPD，DXS9928E，DUSP6，PGBD5，CNN3，PIP5K1B，FLJ13840，CLDN4，PTD009, GPX2, LAPTM5, HSPC022, SSA1, ABS, CPD, DXS9928E, DUSP6, PGBD5, CNN3, PIP5K1B, FLJ13840, CLDN4,

ABCA3，BPAG1，CAPZB，PPIB，ACTA2，CDHI1，FLJl0815，HLA-DPA1，FLJ20539，MUC4，CAV2，ACAA2，CEACAM1，ABCA3, BPAG1, CAPZB, PPIB, ACTA2, CDHI1, FLJ10815, HLA-DPA1, FLJ20539, MUC4, CAV2, ACAA2, CEACAM1,

GALNT10，MYO10，C9orf9，PAM，C6orf29，MGC：5244，RetSDR2，ATP2B4，DHCR7，GP，LOXL2，M1R，DCTD，BCKDK，GALNT10, MYO10, C9orf9, PAM, C6orf29, MGC:5244, RetSDR2, ATP2B4, DHCR7, GP, LOXL2, M1R, DCTD, BCKDK,

RTP801，KIF1B，ENTPD3，PAFAH1B1，LGMN，UBE2L3，PTPRH，RPS6KA2，ALDH1A2，FHL1，GALT，AP1M2，MAF，RTP801, KIF1B, ENTPD3, PAFAH1B1, LGMN, UBE2L3, PTPRH, RPS6KA2, ALDH1A2, FHL1, GALT, AP1M2, MAF,

C4BPA，POLR2J，KIAA0790，TM4SF3，HPGD，THY1，NCALD，PAD12，KIAA0557，SMARCA1，CD83，AZGP1，SMARCA1，C4BPA, POLR2J, KIAA0790, TM4SF3, HPGD, THY1, NCALD, PAD12, KIAA0557, SMARCA1, CD83, AZGP1, SMARCA1,

MRPS11，RAGD，P1GB，FYN，TM7SF1，HLA-E，BRE，PLA2G4C，NOS1，ID3，HLA-DQB1，SSSCA1，PPP1R14B，HLA-MRPS11, RAGD, P1GB, FYN, TM7SF1, HLA-E, BRE, PLA2G4C, NOS1, ID3, HLA-DQB1, SSSCA1, PPP1R14B, HLA-

DPA1，ANK1，PRKCH，CALU，PEF，DOK5，COL9A2，ATP2C1，DPH2L1，MUC5B，LOC113146，NDN，PIG3，HLA-DRA，DPA1, ANK1, PRKCH, CALU, PEF, DOK5, COL9A2, ATP2C1, DPH2L1, MUC5B, LOC113146, NDN, PIG3, HLA-DRA,

GPS2，CX3CL1，CIQB，TGFBR3，APOC1，BIN1，CBR3，TGIF，EFEMP2，SCDGF-B，TUBB-5，MAP4K4，CCL3，CCR1，GPS2, CX3CL1, CIQB, TGFBR3, APOC1, BIN1, CBR3, TGIF, EFEMP2, SCDGF-B, TUBB-5, MAP4K4, CCL3, CCR1,

RNF10，RGL，CD1C，FBLN1，GW112，ALTE，ALP，PLAC1，ISG20，PTE1，NPD009，LOC55893，AP3B1，PRKAR2B，KRT9，RNF10, RGL, CD1C, FBLN1, GW112, ALTE, ALP, PLAC1, ISG20, PTE1, NPD009, LOC55893, AP3B1, PRKAR2B, KRT9,

COPZ2，LYN，FLJ21478，DKFZP566C243，NUMA1，ANAPC5，FLJ10134，ADPRTL1，ITGAM，PIP，FLJ22559，IF116，COPZ2, LYN, FLJ21478, DKFZP566C243, NUMA1, ANAPC5, FLJ10134, ADPRTL1, ITGAM, PIP, FLJ22559, IF116,

TMPRSS4，HA1K1，PCSK7，ANK1，FCER1G，IMPA2，HLA-DQA1，IFNAR2，NEO1，PRKCQ，SMARCD3，CECR1，TMPRSS4, HA1K1, PCSK7, ANK1, FCER1G, IMPA2, HLA-DQA1, IFNAR2, NEO1, PRKCQ, SMARCD3, CECR1,

FLJ11286，TBC1D1，MS4A6A，C1orf16，LRRN1，MRPL23，PUM1，SMA3，PDE4B，SLC22A4，MMP2，ICA1，SLC22A1L，FLJ11286, TBC1D1, MS4A6A, C1orf16, LRRN1, MRPL23, PUM1, SMA3, PDE4B, SLC22A4, MMP2, ICA1, SLC22A1L,

RRP22，GBA，TMEM8，DUSP2，TREX1，SLC6A8，C3AR1，BSCL2，ARFGAP3，TRIM2，SERPINB8，TNFRSF6，LDB1，RRP22, GBA, TMEM8, DUSP2, TREX1, SLC6A8, C3AR1, BSCL2, ARFGAP3, TRIM2, SERPINB8, TNFRSF6, LDB1,

CCND2，RGS2，MEIS1，HRIHFB2122，IF，PIP373C6，UPK1B，WDR10，CG1-49，PSMB8，RARRES1，SLC16A1，DPYD，CCND2, RGS2, MEIS1, HRIHFB2122, IF, PIP373C6, UPK1B, WDR10, CG1-49, PSMB8, RARRES1, SLC16A1, DPYD,

DNPEP，FLJ20254，COL5A1，FLJ11017，CCR5，MX2，PIAS1，CAPG，CDC42EP3，IL1RL1LG，SCGB2A1，RNH，INPP4B，DNPEP, FLJ20254, COL5A1, FLJ11017, CCR5, MX2, PIAS1, CAPG, CDC42EP3, IL1RL1LG, SCGB2A1, RNH, INPP4B,

B3GALT4，PLAU，DFNA5，KIAA0852，CRIP2，TIP-1，ZNF142，HSD17B2，MYO1B，PCOLCE，FLJ22169，APOE，DAB2，B3GALT4, PLAU, DFNA5, KIAA0852, CRIP2, TIP-1, ZNF142, HSD17B2, MYO1B, PCOLCE, FLJ22169, APOE, DAB2,

CXCR4，NAG，SNCAIP，GBP1，ASRGL1，SLC6A8，REC8，SLC7A11，CPE，MPZL1，TDO2，GALNT12，CDKN2A，CXCR4, NAG, SNCAIP, GBP1, ASRGL1, SLC6A8, REC8, SLC7A11, CPE, MPZL1, TDO2, GALNT12, CDKN2A,

KIAA1395，LGALS8，FLNC，NPR2L，GRB10，MGC15523，PTPRC，CAPN9，IFI16，NBL1，CRYL1，PSMC2，IGF1，BIN1，KIAA1395, LGALS8, FLNC, NPR2L, GRB10, MGC15523, PTPRC, CAPN9, IFI16, NBL1, CRYL1, PSMC2, IGF1, BIN1,

HNOEL-iso，DKFZp566O084，FGB，GPNMB，TLR5，FLJ20686，UROS，CX3CR1，HCA112，PRKCB1，BDKRB2，CLTB，HNOEL-iso, DKFZp566O084, FGB, GPNMB, TLR5, FLJ20686, UROS, CX3CR1, HCA112, PRKCB1, BDKRB2, CLTB,

KIAA0652，KIAA1668，DCN，HLA-DQB1，C6orf9，CPR8，TIMP2，PSMB10，LTBP2，FLJ20452，HTATIP，LAMA4，GLUL，KIAA0652, KIAA1668, DCN, HLA-DQB1, C6orf9, CPR8, TIMP2, PSMB10, LTBP2, FLJ20452, HTATIP, LAMA4, GLUL,

SH3BP2，HES2，KIAA1115，KDR，PROCR，TNFSF10，FGFR1，ELF4，F8A，BAG1，COL5A1，THY1，H2BFG，TOSO，KRT15，SH3BP2, HES2, KIAA1115, KDR, PROCR, TNFSF10, FGFR1, ELF4, F8A, BAG1, COL5A1, THY1, H2BFG, TOSO, KRT15,

A1F1，LY75，KRT17，CEACAM1，GAK，AGTR1，ASB8，KIAA0792，CDKN1C，C1R，PTGS1，TM4SF6，XT3，HLA-B，A1F1, LY75, KRT17, CEACAM1, GAK, AGTR1, ASB8, KIAA0792, CDKN1C, C1R, PTGS1, TM4SF6, XT3, HLA-B,

DKFZP434B044，ALDH1A3，N1D2，U2AF1RS2，H2BFL，FUT3，PVALB，ITPR3，PODXL，QPRT，PTRF，PSMC4，ACATE2，DKFZP434B044, ALDH1A3, N1D2, U2AF1RS2, H2BFL, FUT3, PVALB, ITPR3, PODXL, QPRT, PTRF, PSMC4, ACATE2,

MAP2K3，ATP2B4，CEACAM1，CALB2，TTR，TRIM38，JM5，FLJ21135，FLJ23221，FLJ20452，GATA6，RABL4，KIAA1199，MAP2K3, ATP2B4, CEACAM1, CALB2, TTR, TRIM38, JM5, FLJ21135, FLJ23221, FLJ20452, GATA6, RABL4, KIAA1199,

1GFBP7，MGC14376，CITED2，CASP4，ME1S2，PHLDA1，OXA1L，IL1RL1，FL1I，EFEMP1，PYGL，LMO4，GPR3，G1P3，1GFBP7, MGC14376, CITED2, CASP4, ME1S2, PHLDA1, OXA1L, IL1RL1, FL1I, EFEMP1, PYGL, LMO4, GPR3, G1P3,

APOE，ZNF193，AP1S2，PTGDS，TEM7，LOC51279，SLA，BTG1，INE2，W1T-1，LBH，CXCL1，RAB31，POMZP3，COL6A3，APOE, ZNF193, AP1S2, PTGDS, TEM7, LOC51279, SLA, BTG1, INE2, W1T-1, LBH, CXCL1, RAB31, POMZP3, COL6A3,

EXTL3，MGC4309，LOC114990，KYNU，NAB1，CYP2J2，SMURF1，BRAF，HLA-DQA1，CAV1，K1AA0779，CHKL，SEC6，EXTL3, MGC4309, LOC114990, KYNU, NAB1, CYP2J2, SMURF1, BRAF, HLA-DQA1, CAV1, K1AA0779, CHKL, SEC6,

CG11，FLJ20920，CG1-49，E1F3S10，P4HB，GYG，DYRK2，DKK1，MAF，TRIM22，CENTA2，FLJ20113，NR3C1，CYP1B1，CG11, FLJ20920, CG1-49, E1F3S10, P4HB, GYG, DYRK2, DKK1, MAF, TRIM22, CENTA2, FLJ20113, NR3C1, CYP1B1,

HSD11B2，RRP46，FOLR1，HHLA1，THY28，H3FB，FOS，GAA，FLJ13171，RHOBTB3，ZNF32，HOXA5，CFLAR，PAX6，HSD11B2, RRP46, FOLR1, HHLA1, THY28, H3FB, FOS, GAA, FLJ13171, RHOBTB3, ZNF32, HOXA5, CFLAR, PAX6,

K1AA0076，CTSS，ALOX15B，PCOLN3，P3，AKR1B1，LOXL1，H1F3，B1N1，GMDS，FLJ10631，S1AT4A，PIM1，LRMP，SL1，K1AA0076, CTSS, ALOX15B, PCOLN3, P3, AKR1B1, LOXL1, H1F3, B1N1, GMDS, FLJ10631, S1AT4A, PIM1, LRMP, SL1,

TFPT，RAGD，DSCR1L1，SETMAR，K1AA0657，GPRC5B，TIMM22，ARHGEF6，H2BFA，PPFIBP2，SALL2，FLJ21820，TFPT, RAGD, DSCR1L1, SETMAR, K1AA0657, GPRC5B, TIMM22, ARHGEF6, H2BFA, PPFIBP2, SALL2, FLJ21820,

ABCD1，CPA3，SNX7，CUTL1，PALMD，ERCC1，MSTP9，PTPN3，GAL3ST-4，C6orf9，PTPRT，RGC32，AD-017，CRELD1，ABCD1, CPA3, SNX7, CUTL1, PALMD, ERCC1, MSTP9, PTPN3, GAL3ST-4, C6orf9, PTPRT, RGC32, AD-017, CRELD1,

FLJ10097，RNASE1，S100A4，RORC，CMAR，USF2，FLJ13544，CASP3，SMUG1，RAF1，MYL9，GFR，PDGFRA，DPP4，FLJ10097, RNASE1, S100A4, RORC, CMAR, USF2, FLJ13544, CASP3, SMUG1, RAF1, MYL9, GFR, PDGFRA, DPP4,

ARL7，SLC3A2，RHD，FGL2，RBMS1，EGFR，PRO1580，FCGR3A，PTENP1，H4FH，MSCP，CSGlcA-T，ADAMTS5，ARL7, SLC3A2, RHD, FGL2, RBMS1, EGFR, PRO1580, FCGR3A, PTENP1, H4FH, MSCP, CSGlcA-T, ADAMTS5,

TNFAIP6，PRKCDBP，PRKG1，CAPN1，OAS1，H2BFH，SCHIP1，FLJ21736，BMP1，IQGAP2，KRT5，LMO2，HIC，PLAGL1，TNFAIP6, PRKCDBP, PRKG1, CAPN1, OAS1, H2BFH, SCHIP1, FLJ21736, BMP1, IQGAP2, KRT5, LMO2, HIC, PLAGL1,

AQP6，ZNF42，PHLDA1，YBX2，INPP1，CHST6，MGC4171，PL6，SPPL2B，EPHA2，CRYAB，MST1，ZNF211，MD-2，CRI1，AQP6, ZNF42, PHLDA1, YBX2, INPP1, CHST6, MGC4171, PL6, SPPL2B, EPHA2, CRYAB, MST1, ZNF211, MD-2, CRI1,

KIAA0057，PACE4，LOC93349，RALGPS1A，LAMB3，HLX1，R1N3，SERPINB5，PLD1，DLC1，PIPOX，PTHR2，UBE2G2，KIAA0057, PACE4, LOC93349, RALGPS1A, LAMB3, HLX1, R1N3, SERPINB5, PLD1, DLC1, PIPOX, PTHR2, UBE2G2,

CH13L2，KIAA1111，TGFB2，PLAUR，ID1，ALOX5，IGF1，REPS2，CDH2，BCHE，SNFT，FLJ11286，MAPRE2，MAOA，CH13L2, KIAA1111, TGFB2, PLAUR, ID1, ALOX5, IGF1, REPS2, CDH2, BCHE, SNFT, FLJ11286, MAPRE2, MAOA,

SERPING1，PTGER3，KIAA0602，PGM3，MATN2，DNASE1L1，PGD，FZD2，PPAP2C，GOLGA1，ADAT1，TEX13B，MGP，SERPING1, PTGER3, KIAA0602, PGM3, MATN2, DNASE1L1, PGD, FZD2, PPAP2C, GOLGA1, ADAT1, TEX13B, MGP,

FLJ20084，ART1，EV12A，SART2，RFXANK，FBLN5，DPYSL3，ZNF187，RBMS1，MLN，NRXN3，WASF3，DSC3，PPAP2A，FLJ20084, ART1, EV12A, SART2, RFXANK, FBLN5, DPYSL3, ZNF187, RBMS1, MLN, NRXN3, WASF3, DSC3, PPAP2A,

EEF1A2，UBE2H，GABRQ，TFEB，MGC3123，GFPT2，W1G1，FBLN1，PTPRF，MEPE，SLC6A8，IL1B，GAC1，EPHX1，EEF1A2, UBE2H, GABRQ, TFEB, MGC3123, GFPT2, W1G1, FBLN1, PTPRF, MEPE, SLC6A8, IL1B, GAC1, EPHX1,

C11orf9，OSF-2，FLJ10111，SRPX，DAPK1，RBM10，MBD4，MECP2，ILVBL，KIAA0375，JAM3，PRSS25，KIAA0913，C11orf9, OSF-2, FLJ10111, SRPX, DAPK1, RBM10, MBD4, MECP2, ILVBL, KIAA0375, JAM3, PRSS25, KIAA0913,

TNFRSF6，CSRP2，CCL4，C20orf19，CA2，SLC7A8，BNC，PHEMX，ADAMTS1，XRCC1，PEMT，H2AFA，NEU1，OPTN，TNFRSF6, CSRP2, CCL4, C20orf19, CA2, SLC7A8, BNC, PHEMX, ADAMTS1, XRCC1, PEMT, H2AFA, NEU1, OPTN,

NRP1，TPM1，WISP3，GPX6，MRPL2，HP，BIKE，PLXN3，FACL5，MGC15419，FLJ11506，GLS，MAPK7，KIAA1053，CDH3，NRP1, TPM1, WISP3, GPX6, MRPL2, HP, BIKE, PLXN3, FACL5, MGC15419, FLJ11506, GLS, MAPK7, KIAA1053, CDH3,

CST3，KIAA0752，ROR1，TAP2，SBLF，AKAP13，USP21，PP35，ELOVL1，CYBA，KHSRP，MRC1，FLJ12057，H2AFN，CST3, KIAA0752, ROR1, TAP2, SBLF, AKAP13, USP21, PP35, ELOVL1, CYBA, KHSRP, MRC1, FLJ12057, H2AFN,

MSN，TPM1，SLC16A3，ADD1，IL1RAPL1，SPTAN1，FLJ10847，SNA12，FLJ12986，GSPT2，FLJ10450，MAN1C1，MEF2A，MSN, TPM1, SLC16A3, ADD1, IL1RAPL1, SPTAN1, FLJ10847, SNA12, FLJ12986, GSPT2, FLJ10450, MAN1C1, MEF2A,

VEGFC，RANBP3，MGC17330，SCD，F5，PIK3CD，SELPLG，LOX，VAX2，MSF，RANGAP1，B1KE，ARHGEF7，FLJ20300，VEGFC, RANBP3, MGC17330, SCD, F5, PIK3CD, SELPLG, LOX, VAX2, MSF, RANGAP1, B1KE, ARHGEF7, FLJ20300,

MYLK，GMPR2，CENTD2，PPP1R9A，ANG，DNAJB2，IDH3G，ODAG，ADPRTL3，COG7，KIAA0429，NEDD4L，ALEX2，MYLK, GMPR2, CENTD2, PPP1R9A, ANG, DNAJB2, IDH3G, ODAG, ADPRTL3, COG7, KIAA0429, NEDD4L, ALEX2,

ATP6IP2，PTGES，MAN1B1，CYP3A43，AP3S2，DEFA6，PTGER3，FCGBP，CPSF1，NNMT，HAMP，CG1-38，BAZ2A，HLA-ATP6IP2, PTGES, MAN1B1, CYP3A43, AP3S2, DEFA6, PTGER3, FCGBP, CPSF1, NNMT, HAMP, CG1-38, BAZ2A, HLA-

DRA，SP110，CA5B，UBE1L，BTN3A2，K1AA0842，T1A-2，PTGER4，PTGDS，MARCO，EPB41L1，IL13RA2，CXCL6，DRA, SP110, CA5B, UBE1L, BTN3A2, K1AA0842, T1A-2, PTGER4, PTGDS, MARCO, EPB41L1, IL13RA2, CXCL6,

APOA1，NPAS2，ETV5，HFL3，EPB41L3，CH13L1，SSB1，EV12B，KIAA1608，MEIS3，FLJ13385，NQO1，BGN，MOX2，APOA1, NPAS2, ETV5, HFL3, EPB41L3, CH13L1, SSB1, EV12B, KIAA1608, MEIS3, FLJ13385, NQO1, BGN, MOX2,

dJ222E131，GMFG，TBC1D2，SK1P，RABGGTA，MRPL28，FLJ21034，CRY2，SLC4A2，MGC20727，HAP1，CYBB，GR1T，dJ222E131, GMFG, TBC1D2, SK1P, RABGGTA, MRPL28, FLJ21034, CRY2, SLC4A2, MGC20727, HAP1, CYBB, GR1T,

PTN，FUT2，CDSN，STAF65(gamma)，BENE，ENPP2，PAK4，CUBN，ICSBP1，NPAS2，FLJ23516，FLJ23537，AADAC，PTN, FUT2, CDSN, STAF65(gamma), BENE, ENPP2, PAK4, CUBN, ICSBP1, NPAS2, FLJ23516, FLJ23537, AADAC,

MFAP2，ERCC4，STK13，MCAM，GPR65，CYP17，FLJ20373，TNS，TRA1，NPY，PTPLA，PNLIPRP1，RBMS1，TM7SF2，MFAP2, ERCC4, STK13, MCAM, GPR65, CYP17, FLJ20373, TNS, TRA1, NPY, PTPLA, PNLIPRP1, RBMS1, TM7SF2,

MKL1，NCF2，AP4M1，ITGB4，SLC11A1，PSCDBP，NFE2L3，ELAC2，CBFA2T1，S100A12，PACE4，K1AA1395，HLA-G，MKL1, NCF2, AP4M1, ITGB4, SLC11A1, PSCDBP, NFE2L3, ELAC2, CBFA2T1, S100A12, PACE4, K1AA1395, HLA-G,

EDN1，FLJ20730，IGLJ3，UNC93B1，RPL29，R1L，TCF8，RYR3，TCFL4，MCRS1，HML2，FLJ10357，FLJ22405，FLJ20627，EDN1, FLJ20730, IGLJ3, UNC93B1, RPL29, R1L, TCF8, RYR3, TCFL4, MCRS1, HML2, FLJ10357, FLJ22405, FLJ20627,

HFE，DKFZp564K142，ATP10D，SLC12A4，P311，FLJ13055，ADCY9，EYA1，ACO2，C1AS1，EHD3，ZFPM2，MGC11279，HFE, DKFZp564K142, ATP10D, SLC12A4, P311, FLJ13055, ADCY9, EYA1, ACO2, C1AS1, EHD3, ZFPM2, MGC11279,

MALT1，NDUFS8，IL10RB，TCF3，HLALS，DKFZp761K1423，DDX8，G0S2，SLC16A3，CCL18，ZDHHC4，FKBP1A，HRH1，MALT1, NDUFS8, IL10RB, TCF3, HLALS, DKFZp761K1423, DDX8, G0S2, SLC16A3, CCL18, ZDHHC4, FKBP1A, HRH1,

GSA7，PTPRM，HBP17，APPBP2，TNRC15，JM1，PSME3，HFL2，BCL11B，SCARA3，APEG1，LHFP，IGF1，PDGFRL，GSA7, PTPRM, HBP17, APPBP2, TNRC15, JM1, PSME3, HFL2, BCL11B, SCARA3, APEG1, LHFP, IGF1, PDGFRL,

MUC13，IGF1，NXF2，HRMT1L3，ARHD，KIAA0582，KIAA0977，FCN1，LAMP3，DNAJC6，ALDH3B1，TNXB，MAPK3，MUC13, IGF1, NXF2, HRMT1L3, ARHD, KIAA0582, KIAA0977, FCN1, LAMP3, DNAJC6, ALDH3B1, TNXB, MAPK3,

FLJ13491，APOA1，RBP4，OAS3，CLTB，GP2，M1D1，FGR，D1SC1，PP1044，PSAP，CHODL，FLJ22173，TPD52L2，DD5，FLJ13491, APOA1, RBP4, OAS3, CLTB, GP2, M1D1, FGR, D1SC1, PP1044, PSAP, CHODL, FLJ22173, TPD52L2, DD5,

PSIP1，HSPB7，EMP3，KRT6A，C5R1，ENO2，PF4，SYN1，PLSCR3，HMGCS2，BCAR3，LOC51693，ANGPTL2，TAHCCP1，PSIP1, HSPB7, EMP3, KRT6A, C5R1, ENO2, PF4, SYN1, PLSCR3, HMGCS2, BCAR3, LOC51693, ANGPTL2, TAHCCP1,

LOC51063，KIAA0561，GJB3，CPVL，PCBD，CGI-96，PK1A，NR3C1，GAS7，FBN1，MPV17，SLC21A3，ARHGAP6，FMO1，LOC51063, KIAA0561, GJB3, CPVL, PCBD, CGI-96, PK1A, NR3C1, GAS7, FBN1, MPV17, SLC21A3, ARHGAP6, FMO1,

CSPG2，FLJ22531，STX7，SCN1B，TETRAN，FGF23，CLECSF12，CDKN1C，HF1，GSTT1，VILL，BLAME，ROD1，TAPBP-CSPG2, FLJ22531, STX7, SCN1B, TETRAN, FGF23, CLECSF12, CDKN1C, HF1, GSTT1, VILL, BLAME, ROD1, TAPBP-

R，HLA-G，HT017，CHP，SLC25A10，LST1，FLJ11196，VAMP2，NR0B2，CSNK2A1，SLIT3，MAPK7，CXCL2，GYG2，PGS1，R, HLA-G, HT017, CHP, SLC25A10, LST1, FLJ11196, VAMP2, NR0B2, CSNK2A1, SLIT3, MAPK7, CXCL2, GYG2, PGS1,

CDYL，VNN2，CLN5，NPAS2，MLL，TRPM4，LYPLA3，MYO7A，PSMB1，PAFAH2，PITX1，GRB10，TIMELESS，CDYL, VNN2, CLN5, NPAS2, MLL, TRPM4, LYPLA3, MYO7A, PSMB1, PAFAH2, PITX1, GRB10, TIMELESS,

APOBEC3G，KIAA0819，GALNT10，PTPRO，NMB，FLJ12298，RAMP1，OR2F1，HPGD，CALB1，CCR7，KIAA1614，APOBEC3G, KIAA0819, GALNT10, PTPRO, NMB, FLJ12298, RAMP1, OR2F1, HPGD, CALB1, CCR7, KIAA1614,

SLC2A3，OLFM1，DKFZP564G202，FEZ1，AKR1C3，ACADS，CALB1，PIK4CB，FOXA2，FLJ20581，RRAS，BHLHB3，SLC2A3, OLFM1, DKFZP564G202, FEZ1, AKR1C3, ACADS, CALB1, PIK4CB, FOXA2, FLJ20581, RRAS, BHLHB3,

HUNK，MLLT3，RBMS2，KIAA0620，SLC29A2，SIRT5，SLC27A2，FLJ21458，DTR，ACTN1，KIAA0429，SLC21A9，HUNK, MLLT3, RBMS2, KIAA0620, SLC29A2, SIRT5, SLC27A2, FLJ21458, DTR, ACTN1, KIAA0429, SLC21A9,

FLJ10211，LOC63920，FLJ12377，ARPC4，TSSC4，MEF2D，RPL10，NOV，CG1-72，FAIM2，TBX2，GABR，C1orf24，FLJ10211, LOC63920, FLJ12377, ARPC4, TSSC4, MEF2D, RPL10, NOV, CG1-72, FAIM2, TBX2, GABR, C1orf24,

MGC2615，NR1H3，FLJ14675，AQP5，ZNFN1A3，SSPN，SIGLEC7，COL5A2，HLA-DOB，SLC12A3，Apg4B，HERC3，MGC2615, NR1H3, FLJ14675, AQP5, ZNFN1A3, SSPN, SIGLEC7, COL5A2, HLA-DOB, SLC12A3, Apg4B, HERC3,

HEM1，EB12，ZNF323，FLJ20950，FASTK，C6orf32，LILRB2，SPP2，DHPS，UBE2B，MET，ST14，EGR3，SIGLEC5，HEM1, EB12, ZNF323, FLJ20950, FASTK, C6orf32, LILRB2, SPP2, DHPS, UBE2B, MET, ST14, EGR3, SIGLEC5,

SAMHD1，PGCP，PTPNS1，SPARCL1，FLJ22160，RANBP2，1L15RA，OXT，FLJ21168，PTPN14，BAIAP3，TPM4，NCR3，SAMHD1, PGCP, PTPNS1, SPARCL1, FLJ22160, RANBP2, 1L15RA, OXT, FLJ21168, PTPN14, BAIAP3, TPM4, NCR3,

TEK，H2BFE，SLC34A2，SLC26A2，KIAA0870，MET，SENP3，PTGER4，CGI-48，PDGFB，CD86，GTF2H4，KIAA0053，TEK, H2BFE, SLC34A2, SLC26A2, KIAA0870, MET, SENP3, PTGER4, CGI-48, PDGFB, CD86, GTF2H4, KIAA0053,

PTX3，BIMLEC，CAMK4，PROS1，AOX1，KIAA0931，COL4A1，USF2，PLINP-1，TM6SF1，PTPRG，SNX17，SLC5A4，PTX3, BIMLEC, CAMK4, PROS1, AOX1, KIAA0931, COL4A1, USF2, PLINP-1, TM6SF1, PTPRG, SNX17, SLC5A4,

MSTP032，PCTP，PQBP1，CDV-1，AD037，RNASE6，SNA11，KIAA0872，MEF2C，ZNF3，LOC157542，FCER1A，PRB1，MSTP032, PCTP, PQBP1, CDV-1, AD037, RNASE6, SNA11, KIAA0872, MEF2C, ZNF3, LOC157542, FCER1A, PRB1,

SIRT3，DKFZP434K046，ABCC6，NPC1L1，BCL2A1，LOC64167，GS3955，UP，CLECSF6，MGC20727，CHN2，CD3D，BAD，SIRT3, DKFZP434K046, ABCC6, NPC1L1, BCL2A1, LOC64167, GS3955, UP, CLECSF6, MGC20727, CHN2, CD3D, BAD,

KIAA0435，PECAM1，IGSF4，BCAS3，C8A，ZNF131，MGC10771，SEC14L1，SERPTNH1，IL1F6，KLK11，THBD，FKSG28，KIAA0435, PECAM1, IGSF4, BCAS3, C8A, ZNF131, MGC10771, SEC14L1, SERPTNH1, IL1F6, KLK11, THBD, FKSG28,

KIAA0173，HKE2，PFTK1，FLJ11560，APOL1，CHRM4，ALLC，MS4A4A，SLC1A1，BBP，ILT11，SAMSN1，1GF2R，KIAA0173, HKE2, PFTK1, FLJ11560, APOL1, CHRM4, ALLC, MS4A4A, SLC1A1, BBP, ILT11, SAMSN1, 1GF2R,

FLJ20421，PBX2，MAP1LC3B，37872.00，NCK1，FGFR2，CD86，FLJ23506，SCD，FCGR2B，CYP4A11，S100A2，AP2S1，FLJ20421, PBX2, MAP1LC3B, 37872.00, NCK1, FGFR2, CD86, FLJ23506, SCD, FCGR2B, CYP4A11, S100A2, AP2S1,

PLAGL1，PTGIS，PCOLCE2，SLC2A3，DKFZP761N09121，GPR105，OSBPL3，RPLP2，DKFZP58612223，CD36，BBOX1，PLAGL1, PTGIS, PCOLCE2, SLC2A3, DKFZP761N09121, GPR105, OSBPL3, RPLP2, DKFZP58612223, CD36, BBOX1,

VNN3，AKR1B10，ZFHX1B，DKFZp434H2215，RoXaN，RSN，GALNS，PROSC，PCDHA3，PLXNA2，CCR8，BACH1，NPAT，VNN3, AKR1B10, ZFHX1B, DKFZp434H2215, RoXaN, RSN, GALNS, PROSC, PCDHA3, PLXNA2, CCR8, BACH1, NPAT,

SPAG6，DGCR13，CAPN5，OSBPL3，CYP-M，FLJ13902，FLJ13659，ADAMTS3，IL1RAP，ELF1，HYAL1，WNT2，CCS，SPAG6, DGCR13, CAPN5, OSBPL3, CYP-M, FLJ13902, FLJ13659, ADAMTS3, IL1RAP, ELF1, HYAL1, WNT2, CCS,

TREM2，KIAA1036，FLJ20574，FLJ13215，CUGBP2，FLJ20010，GABRE，RCE1，SCIN，HLALS，MGC10940，ADARB1，TREM2, KIAA1036, FLJ20574, FLJ13215, CUGBP2, FLJ20010, GABRE, RCE1, SCIN, HLALS, MGC10940, ADARB1,

PLA2G7，KIAA1237，KIAA0889，FLJ22593，CD244，NEK9，TAT，RAP1GDS1，SMA5，MYH11，APAA，MERTK，GJA4，PLA2G7, KIAA1237, KIAA0889, FLJ22593, CD244, NEK9, TAT, RAP1GDS1, SMA5, MYH11, APAA, MERTK, GJA4,

TNFRSF1B，MRPS12，HSF1，COL11A2，DAB2，PCQAP，WDR4，ABCA8，CLPS，ARHN，PHF3，AKAP12，LST1，TNFRSF1B, MRPS12, HSF1, COL11A2, DAB2, PCQAP, WDR4, ABCA8, CLPS, ARHN, PHF3, AKAP12, LST1,

MGC12904，FLJ11539，ZFP36L2，SERPINF1，MGAM，PRG4，RAB5EP，CASP2，DIPA，AQP3，VAMP5，DXS1283E，MGC12904, FLJ11539, ZFP36L2, SERPINF1, MGAM, PRG4, RAB5EP, CASP2, DIPA, AQP3, VAMP5, DXS1283E,

COL4A2，MMP10，CD97，MGAT3，FCN2，KIAA0475，FGF9，CTSZ，SQV7L，H326，PLD3，TRPC1，OR7E24P，GRIA2，K1P2，COL4A2, MMP10, CD97, MGAT3, FCN2, KIAA0475, FGF9, CTSZ, SQV7L, H326, PLD3, TRPC1, OR7E24P, GRIA2, K1P2,

BARX2，MHC2TA，RECQL，NUP214，DHRS2，P2RY1，KIAA1155，HLA-DRB4，CAPN6，TLR7，AHCYL1，TRGC2，NEB，BARX2, MHC2TA, RECQL, NUP214, DHRS2, P2RY1, KIAA1155, HLA-DRB4, CAPN6, TLR7, AHCYL1, TRGC2, NEB,

POU2F1，CPSF1，APOB48R，CLDN9，FLJ21276，AEBP1，MN1，PKD2，PACRG，CALM1，TSPAN-3，KIAA0233，ATP6V0E，POU2F1, CPSF1, APOB48R, CLDN9, FLJ21276, AEBP1, MN1, PKD2, PACRG, CALM1, TSPAN-3, KIAA0233, ATP6V0E,

TRIM34，DKFZP564J102，CNOT8，STC1，NFE2，FCN3，CKIP-1，PLA2G4A，TRGC2，DES，CDC42EP2，HSD3B1，CSN10，TRIM34, DKFZP564J102, CNOT8, STC1, NFE2, FCN3, CKIP-1, PLA2G4A, TRGC2, DES, CDC42EP2, HSD3B1, CSN10,

PRKACB，RDH5，CDW52，XYLT2，HPN，WIZ，GOLGA2，CSHL1，GLRX，PCDHB11，TNFSF18，KLRD1，384D8-2，PRKACB, RDH5, CDW52, XYLT2, HPN, WIZ, GOLGA2, CSHL1, GLRX, PCDHB11, TNFSF18, KLRD1, 384D8-2,

WHSC1，TNFRSF10C，EVPL，TNFRSF5，SIAH2，GYPB，PMM1，DPYSL3，FLJ14297，ZNF42，BSN，OMG，AXL，ACK1，WHSC1, TNFRSF10C, EVPL, TNFRSF5, SIAH2, GYPB, PMM1, DPYSL3, FLJ14297, ZNF42, BSN, OMG, AXL, ACK1,

PKD2，KIAA0711，FLJ00060，GUCA1A，PAPPA，CBLN1，FRCP1，BTD，FLJ20591，FGG，CXCL14，NPR1，CAMK2G，PKD2, KIAA0711, FLJ00060, GUCA1A, PAPPA, CBLN1, FRCP1, BTD, FLJ20591, FGG, CXCL14, NPR1, CAMK2G,

HLCS，SECP43，BCAT1，MSR1，IGFBP4，C13orf1，PRO2577，KIR2DL4，BAALC，FLJ21919，CNTF，LOC51295，ENTPD1，HLCS, SECP43, BCAT1, MSR1, IGFBP4, C13orf1, PRO2577, KIR2DL4, BAALC, FLJ21919, CNTF, LOC51295, ENTPD1,

TAPBP-R，CAP350，PKD2L1，EVX1，NR1H2，FLJ13868，ERCC3，DKFZp434L0850，NR3C1，DMD，BST1，CARD15，SKD3，TAPBP-R, CAP350, PKD2L1, EVX1, NR1H2, FLJ13868, ERCC3, DKFZp434L0850, NR3C1, DMD, BST1, CARD15, SKD3,

CASP1，PCDHA6，NR4A1，HAS2，COPEB，R29124_1，THPO，AQP6，MGC10848，RAB6B，ABP1，APOB，UTRN，M1CA，CASP1, PCDHA6, NR4A1, HAS2, COPEB, R29124_1, THPO, AQP6, MGC10848, RAB6B, ABP1, APOB, UTRN, M1CA,

SSTR4，FLJ23056，C6orf32，ROM1，FLJ90005，KCNN4，MGA，HSPC219，CGEF2，CDC42BPB，CCR4，GLS，MAGE-E1，SSTR4, FLJ23056, C6orf32, ROM1, FLJ90005, KCNN4, MGA, HSPC219, CGEF2, CDC42BPB, CCR4, GLS, MAGE-E1,

PILR(ALPHA)，PGK2，KIAA0657，SF3A2，NOTCH4，CLECSF2，FBLN2，B4GALT1，WNT2B，NRBP，LTB，FLJ22021，PILR(ALPHA), PGK2, KIAA0657, SF3A2, NOTCH4, CLECSF2, FBLN2, B4GALT1, WNT2B, NRBP, LTB, FLJ22021,

CDH6，TUBGCP2，GCN1L1，ZIC4，HR44，AGA，SIAT9，EMP1，EPOR，IGKC，TAHCCP1，PECR，FLJ21477，EDG1，MS4A2，CDH6, TUBGCP2, GCN1L1, ZIC4, HR44, AGA, SIAT9, EMP1, EPOR, IGKC, TAHCCP1, PECR, FLJ21477, EDG1, MS4A2,

BCAS4，FLJ22404，DPYS，PRCC，POLD4，BIKE，GAS7，KIAA1000，ZFP，WNT7B，MUC4，FLJ10477，CD1D，MGC4614，BCAS4, FLJ22404, DPYS, PRCC, POLD4, BIKE, GAS7, KIAA1000, ZFP, WNT7B, MUC4, FLJ10477, CD1D, MGC4614,

CCR1，NEU3，S1X3，FLJ10640，GPR51，STOM，SERPINE1，HLA-DQB1，PTN，DNCL12，EN2，FLJ20378，IFP38，LOC90326，CCR1, NEU3, S1X3, FLJ10640, GPR51, STOM, SERPINE1, HLA-DQB1, PTN, DNCL12, EN2, FLJ20378, IFP38, LOC90326,

IGLJ3，NCYM，KIAA1107，GP2，PLAUR，CD47，BIN1，MGC14799，IGFBP1，SSX1，IDUA，RECK，CD6，IGHM，ADD2，IGLJ3, NCYM, KIAA1107, GP2, PLAUR, CD47, BIN1, MGC14799, IGFBP1, SSX1, IDUA, RECK, CD6, IGHM, ADD2,

AKAP2，HSF4，MDS032，FLJ20086，TNXB，IGFBP3，KLKB1，PRB4，KCNF1，PDE9A，SIPA1，SMARCB1，COL4A6，AKAP2, HSF4, MDS032, FLJ20086, TNXB, IGFBP3, KLKB1, PRB4, KCNF1, PDE9A, SIPA1, SMARCB1, COL4A6,

PDE10A，NFATC1，CDH16，COL6A1，ZNF272，LDB2，HCRTR2，B1，ATP12A，FLJI1710，LOC116150，KIAA1049，PDE10A, NFATC1, CDH16, COL6A1, ZNF272, LDB2, HCRTR2, B1, ATP12A, FLJI1710, LOC116150, KIAA1049,

HSPC157，FLJ20701，IGSF6，TOMM22，TGFB1，PTGER2，CHML，FAAH，COL6A1，DGUOK，LRRN3，B7，KIAA0876，HSPC157, FLJ20701, IGSF6, TOMM22, TGFB1, PTGER2, CHML, FAAH, COL6A1, DGUOK, LRRN3, B7, KIAA0876,

C1orf22，CYP2A13，CXCL5，CD5L，FBXL6，GALNT2，GJA10，COL15A1，TEX13A，7h3，TRD@，RIL，OTC，SAST，KLF8，C1orf22, CYP2A13, CXCL5, CD5L, FBXL6, GALNT2, GJA10, COL15A1, TEX13A, 7h3, TRD@, RIL, OTC, SAST, KLF8,

TUBA8，MGC45806，FLJ13479，GRP，LRP4，CD84，WBSCR14，EPOR，BRAP，zizimin1，DNAJC4，FLJ20356，SERPINA2，TUBA8, MGC45806, FLJ13479, GRP, LRP4, CD84, WBSCR14, EPOR, BRAP, zizimin1, DNAJC4, FLJ20356, SERPINA2,

FLJ10432，CD209L，NRP1，PGDS，PLA2G2A，TNFRSF4，PRO2214，DNAJB6，RDHL，FOSL2，DEPP，FLJ20241，MMP11，FLJ10432, CD209L, NRP1, PGDS, PLA2G2A, TNFRSF4, PRO2214, DNAJB6, RDHL, FOSL2, DEPP, FLJ20241, MMP11,

HLA-DQB1，RBM10，8D6A，MAX，CUGBP2，CKTSF1B1，ISL1，CREBBP，ACTA1，NUDT2，OR1A2，GPR86，SH3BP2，HLA-DQB1, RBM10, 8D6A, MAX, CUGBP2, CKTSF1B1, ISL1, CREBBP, ACTA1, NUDT2, OR1A2, GPR86, SH3BP2,

APAF1，PRO1386，IGL@，EVI5，KIAA0443，MFNG，XCL1，ITM2A，IGL13，SIN3B，CCL18，NRXN3，AQP7，HLF，SEC14L1，APAF1, PRO1386, IGL@, EVI5, KIAA0443, MFNG, XCL1, ITM2A, IGL13, SIN3B, CCL18, NRXN3, AQP7, HLF, SEC14L1,

DNM1，KIAA0551，STK17B，GNS，IL10，MGC20727，COL5A1，SEMA3B，C11ORF30，CASP10，ORM2，NPEPPS，CALCRL，DNM1, KIAA0551, STK17B, GNS, IL10, MGC20727, COL5A1, SEMA3B, C11ORF30, CASP10, ORM2, NPEPPS, CALCRL,

ALK，SH3BGRL3，FOXD1，MNDA，LCP2，ANK1，GSTA1，FLJ20856，ALOX15，L1CAM，DRF1，TM4SF9，SLC24A1，ALK, SH3BGRL3, FOXD1, MNDA, LCP2, ANK1, GSTA1, FLJ20856, ALOX15, L1CAM, DRF1, TM4SF9, SLC24A1,

NR4A1，ATP7A，PCLO，TSHR，CAMK1G，MSR1，GLIPR1，KIAA1069，LYN，FLJ00001，M1G2，DLGAP2，TF，SOD2，NR4A1, ATP7A, PCLO, TSHR, CAMK1G, MSR1, GLIPR1, KIAA1069, LYN, FLJ00001, M1G2, DLGAP2, TF, SOD2,

ELMO1，BMP2，SLC12A5，PSG11，EPB41L3，CAMK2B，TGM4，SCN11A，CALU，F11，GPR75，KIAA1053，S1X1，WBSCR5，ELMO1, BMP2, SLC12A5, PSG11, EPB41L3, CAMK2B, TGM4, SCN11A, CALU, F11, GPR75, KIAA1053, S1X1, WBSCR5,

RIN3，CCNT2，CABIN1，NR2C2，TRPM1，ABCD2，VDU1，FLJ20811，GJB3，ASAHL，RAB1A，HAND1，BA12，EDG8，RIN3, CCNT2, CABIN1, NR2C2, TRPM1, ABCD2, VDU1, FLJ20811, GJB3, ASAHL, RAB1A, HAND1, BA12, EDG8,

TNFSF13，HP1P，PTPRN2，PRO0618，PRKC1，PSTPIP1，FACL4，ETV4，CACNA1D，WISP1，PRLR，FEZ2，CCL25，PCNX，TNFSF13, HP1P, PTPRN2, PRO0618, PRKC1, PSTPIP1, FACL4, ETV4, CACNA1D, WISP1, PRLR, FEZ2, CCL25, PCNX,

SNX10，LILRA2，KIAA1086，MKRN3，PRG1，HGC6.1.1，GUCA1B，RIG，FLT1，HLA-C，KIAA0427，LILRB2，MAP2K5，SNX10, LILRA2, KIAA1086, MKRN3, PRG1, HGC6.1.1, GUCA1B, RIG, FLT1, HLA-C, KIAA0427, LILRB2, MAP2K5,

FLJ11125，EFNA5，DUOX1，L1G4，MRE11A，DEFB126，DNAJC9，RQCD1，ABCB8，HPR，MRS3/4，KP12，NR113，FBXW7，FLJ11125, EFNA5, DUOX1, L1G4, MRE11A, DEFB126, DNAJC9, RQCD1, ABCB8, HPR, MRS3/4, KP12, NR113, FBXW7,

HS3ST3B1，LAD1，SHMT1，CITED2，DNAL11，POLYDOM，PFKFB4，KIAA1029，UTY，SCAND2，ZNF215，FOSL1，HS3ST3B1, LAD1, SHMT1, CITED2, DNAL11, POLYDOM, PFKFB4, KIAA1029, UTY, SCAND2, ZNF215, FOSL1,

CDH17，PCSK5，ACE2，ERG，FLJ11619，KIAA1466，KIAA0675，IL18，FLJ21562，BTN3A3，FACL6，FANCA，ANKRD6，CDH17, PCSK5, ACE2, ERG, FLJ11619, KIAA1466, KIAA0675, IL18, FLJ21562, BTN3A3, FACL6, FANCA, ANKRD6,

CALCR，CSF1，FLJ13262，CALR，TFEC，SSTR2，HBD，MGC10986，GTF3C2，HRC，RHOK，KIAA1117，KIAA0924，ITGB1，CALCR, CSF1, FLJ13262, CALR, TFEC, SSTR2, HBD, MGC10986, GTF3C2, HRC, RHOK, KIAA1117, KIAA0924, ITGB1,

DEFCAP，FLJ12525，TBXA2R，GLIPR1，AVPR2，CCNE2，TBXAS1，RGS5，HAGE，FOXO3A，SYK，384D8-2，ABO，DEFCAP, FLJ12525, TBXA2R, GLIPR1, AVPR2, CCNE2, TBXAS1, RGS5, HAGE, FOXO3A, SYK, 384D8-2, ABO,

24432.00，MASS1，PF4V1，CASP5，CNGA1，FLJ14251，SLC9A3，UPK3B，DLG1，COL17A1，PCDHB12，OS1L，HFE，24432.00, MASS1, PF4V1, CASP5, CNGA1, FLJ14251, SLC9A3, UPK3B, DLG1, COL17A1, PCDHB12, OS1L, HFE,

KIAA0495，KCNJ15，KIAA0997，RGS11，PITX3，FLJ13055，UBE21，PRO2176，CACNB4，FOXH1，RASA2，PML，BCAT1，KIAA0495, KCNJ15, KIAA0997, RGS11, PITX3, FLJ13055, UBE21, PRO2176, CACNB4, FOXH1, RASA2, PML, BCAT1,

EDG2，OCRL，ATPAF2，PMS2，POU2F3，PTPN21，SUPT6H，HAN11，ROR1，COPEB，KIAA1654，DKFZP434B204，TN1P3，EDG2, OCRL, ATPAF2, PMS2, POU2F3, PTPN21, SUPT6H, HAN11, ROR1, COPEB, KIAA1654, DKFZP434B204, TN1P3,

EPAG，CACNB2，NEK2，XRCC4，IL6ST，TNRC11，CAPN11，37870.00，PLA2G4B，NPEPL1，RASGRP1，HABP4，CYLD，EPAG, CACNB2, NEK2, XRCC4, IL6ST, TNRC11, CAPN11, 37870.00, PLA2G4B, NPEPL1, RASGRP1, HABP4, CYLD,

C15orf5，ITGB3，FLJ23093，NPPC，MCOLN1，GAD2，TRO，LOC51063，OGN，NR1H4，MTRR，SS-56，NT5E，C22orf4，C15orf5, ITGB3, FLJ23093, NPPC, MCOLN1, GAD2, TRO, LOC51063, OGN, NR1H4, MTRR, SS-56, NT5E, C22orf4,

SLC4A5，SGCG，C8orf1，LGALS2，ELK1，TRPM8，MGC2655，NR3C2，PPARG，MXD3，SERPINB3，PRO0461，GNA11，SLC4A5, SGCG, C8orf1, LGALS2, ELK1, TRPM8, MGC2655, NR3C2, PPARG, MXD3, SERPINB3, PRO0461, GNA11,

AVPR2，PEG10，SPINK1，CLDN1，STC1，KIAA1045，F2，GNG11，FY，H4F2，D21S2056E，CAPZB，KIAA0599，C1orf29，AVPR2, PEG10, SPINK1, CLDN1, STC1, KIAA1045, F2, GNG11, FY, H4F2, D21S2056E, CAPZB, KIAA0599, C1orf29,

RGS12，GCG，NCOA2，FOXL2，UGT1A8，PKLR，NRG1，ITGA7，CNOT3，SPRY2，PIK3R1，ZF，PTRR，KSR，TCEB3L，RGS12, GCG, NCOA2, FOXL2, UGT1A8, PKLR, NRG1, ITGA7, CNOT3, SPRY2, PIK3R1, ZF, PTRR, KSR, TCEB3L,

IREB2，PRO0899，PAWR，SOX18，Gene Symbo1，RPL28，FLJ13352，C20orf114，PIGR，ERAP140，MYO5B，EGR1，IREB2, PRO0899, PAWR, SOX18, Gene Symbol1, RPL28, FLJ13352, C20orf114, PIGR, ERAP140, MYO5B, EGR1,

LOC124220，TCEB2，BACE2，NMES1，KIAA1324，MGC45416，WASF2，APOA1BP，FLJ32115，ATP6V0E，T1MP2，H2AFJ，LOC124220, TCEB2, BACE2, NMES1, KIAA1324, MGC45416, WASF2, APOA1BP, FLJ32115, ATP6V0E, T1MP2, H2AFJ,

C9of5，RASD1，KIAA1437，H2AFJ，RDH-E2，DKFZp434G171，GUK1，FLJ20671，CAPNS1，KIAA1671，H19，FLJ23153，C9of5, RASD1, KIAA1437, H2AFJ, RDH-E2, DKFZp434G171, GUK1, FLJ20671, CAPNS1, KIAA1671, H19, FLJ23153,

NDUFB10，FLJ13593，GLTP，TLP19，ENPP5，MGC39329，MRPL41，ARF3，LOC51255，HSPCA，BR13，FLJ14525，NDUFB10, FLJ13593, GLTP, TLP19, ENPP5, MGC39329, MRPL41, ARF3, LOC51255, HSPCA, BR13, FLJ14525,

LOC113246，RAP2B，FLJ14117，GLCC11，PPP3CA，PHP14，MIR，ADCY4，FLJ11320，MSTP028，Cab45，TNFSF13B，LOC113246, RAP2B, FLJ14117, GLCC11, PPP3CA, PHP14, MIR, ADCY4, FLJ11320, MSTP028, Cab45, TNFSF13B,

ZNFN2A1，MGC14327，KIAA1404，RAB34，RBMS1，ARHU，SPUVE，LOC54516，SAMHD1，LOC170394，SAMHD1，PIGR，ZNFN2A1, MGC14327, KIAA1404, RAB34, RBMS1, ARHU, SPUVE, LOC54516, SAMHD1, LOC170394, SAMHD1, PIGR,

CYP4X1，NFIA，KIAA1715，CTHRC1，DKFZp547A023，KIAA1434，MYBBP1A，MGC4248，H4F2，H4FH，NPD007，CYP4X1, NFIA, KIAA1715, CTHRC1, DKFZp547A023, KIAA1434, MYBBP1A, MGC4248, H4F2, H4FH, NPD007,

MGC14839，FLJ21791，HDLBP，C8orf13，FLJ23393，FLJ11046，DKFZp434C0328，BCAT1，BAT5，FLJ31235，LOXL4，RNF7，MGC14839, FLJ21791, HDLBP, C8orf13, FLJ23393, FLJ11046, DKFZp434C0328, BCAT1, BAT5, FLJ31235, LOXL4, RNF7,

MGC2803，CLDN1，KIAA2002，STMN3，MYO5B，CTSS，ATP1B1，MGC4309，UBE2H，DKFZp762H185，LOC115265，MGC2803, CLDN1, KIAA2002, STMN3, MYO5B, CTSS, ATP1B1, MGC4309, UBE2H, DKFZp762H185, LOC115265,

MGC13045，SH3KBPI，MGC4604，TRIM47，C9orf5，SDCBP2，AP1S2，C20orf110，LOC51234，SAT，dJ55C23.6，CKLFSF7，MGC13045, SH3KBPI, MGC4604, TRIM47, C9orf5, SDCBP2, AP1S2, C20orf110, LOC51234, SAT, dJ55C23.6, CKLFSF7,

PCDHA10，MGC11115，MGC15397，LOC116238，TRIM8，FLJ25157，NAV1，KIAA1870，ALS2CR9，GCNT1，GALNT4，PCDHA10, MGC11115, MGC15397, LOC116238, TRIM8, FLJ25157, NAV1, KIAA1870, ALS2CR9, GCNT1, GALNT4,

HSCARG，PPP1R1B，PHP14，TGFBR3，ARIH2，MGC1842，SELM，AKAP2，MAFB，FLJ23091，MBNL，TEM8，CFL2，HSCARG, PPP1R1B, PHP14, TGFBR3, ARIH2, MGC1842, SELM, AKAP2, MAFB, FLJ23091, MBNL, TEM8, CFL2,

KIAA1554，SEMA4B，FLJ10961，SCAP2，KIAA1244，RIG-1，TRABID，TRIM56，MK-STYX，TMEM9，FAD104，GLTSCR2，KIAA1554, SEMA4B, FLJ10961, SCAP2, KIAA1244, RIG-1, TRABID, TRIM56, MK-STYX, TMEM9, FAD104, GLTSCR2,

MGC：13379，MGC40555，FLJ14251，NOL6，FLJ23499，DHRSX，DKFZP564D166，CED-6，LOC57168，KIAA1337，CRB3，MGC: 13379, MGC40555, FLJ14251, NOL6, FLJ23499, DHRSX, DKFZP564D166, CED-6, LOC57168, KIAA1337, CRB3,

EMIL1N-2，GJB2，ECGF1，CHDH，LOC120224，ZNF75A，EPST11，NESHBP，FLJ10210，FBXO25，MS4A6A，NOTCH2，EMIL1N-2, GJB2, ECGF1, CHDH, LOC120224, ZNF75A, EPST11, NESHBP, FLJ10210, FBXO25, MS4A6A, NOTCH2,

FLJ39885，FOXP1，ORMDL2，MGC11134，MS4A6A，HSPC195，KIAA1913，UACA，C1orf13，USP28，LCMR1，GBA2，FLJ39885, FOXP1, ORMDL2, MGC11134, MS4A6A, HSPC195, KIAA1913, UACA, C1orf13, USP28, LCMR1, GBA2,

DKFZp547D065，TH1L，RORC，PAK1，MGC2555，KIAA0146，FLJ20186，SCAMP2，NGEF，C14orf58，CED-6，LOC55893，DKFZp547D065, TH1L, RORC, PAK1, MGC2555, KIAA0146, FLJ20186, SCAMP2, NGEF, C14orf58, CED-6, LOC55893,

GTAR，MGC24103，MS4A6A，DAG1，KIAA1394，FLJ20073，MGC13114，FBXO32，CD44，CTL2，ARNT，C21orf63，CLIC6，GTAR, MGC24103, MS4A6A, DAG1, KIAA1394, FLJ20073, MGC13114, FBXO32, CD44, CTL2, ARNT, C21orf63, CLIC6,

C20of64，FLJ90586，RBPMS，LOC51242，MGC45441，CLMN，FLJ35564，MGC4604，DRCTNNB1A，CGI-125，C20of64, FLJ90586, RBPMS, LOC51242, MGC45441, CLMN, FLJ35564, MGC4604, DRCTNNB1A, CGI-125,

DKFZp547A023，MGC39325，CD109，FLJ23499，EHD3，MGC4840，USP21，DKFZP761E1824，FLJ22215，1L17D，DKFZp547A023, MGC39325, CD109, FLJ23499, EHD3, MGC4840, USP21, DKFZP761E1824, FLJ22215, 1L17D,

MGC16028，MS4A7，GALNT2，CDKN2B，LOC90550，CKLFSF3，FS，KIAA1949，MRPL10，MGC45714，MAP4K1，MGC16028, MS4A7, GALNT2, CDKN2B, LOC90550, CKLFSF3, FS, KIAA1949, MRPL10, MGC45714, MAP4K1,

SLC4A11，HPS3，DNAJC5，LOC120224，FLJ11036，KIAA1337，FLJ10697，SENP2，SART1，MGC2474，SCD，FLJ14486，SLC4A11, HPS3, DNAJC5, LOC120224, FLJ11036, KIAA1337, FLJ10697, SENP2, SART1, MGC2474, SCD, FLJ14486,

KIAA1214，CARD6，KIAA1691，MLL5，C20orf102，FBXW5，RARA，SLC13A3，FLJ33817，NRP2，BACE，LOC55971，KIAA1214, CARD6, KIAA1691, MLL5, C20orf102, FBXW5, RARA, SLC13A3, FLJ33817, NRP2, BACE, LOC55971,

FLJ14855，LOC133957，GPR108，MRPL41，MGC10485，CMG2，C8orf2，PIAS3，DKFZp434G118，KIAA1500，APXL2，FLJ14855, LOC133957, GPR108, MRPL41, MGC10485, CMG2, C8orf2, PIAS3, DKFZp434G118, KIAA1500, APXL2,

MGC16028，COG1，UBE2H，CMG2，CTSB，LOC143903，CANX，PAG，CP，FLJ40432，LOC137392，DKFZP586F1524，MGC16028, COG1, UBE2H, CMG2, CTSB, LOC143903, CANX, PAG, CP, FLJ40432, LOC137392, DKFZP586F1524,

SAMHD1，DKFZp761A052，HSPC002，C20orf23，DKFZp434N061，SLB，PSMB7，MGC4342，DKFZP434P106，FLJ22678，SAMHD1, DKFZp761A052, HSPC002, C20orf23, DKFZp434N061, SLB, PSMB7, MGC4342, DKFZP434P106, FLJ22678,

SYTL4，DKFZP566J2046，LOC51249，PARVA，FLJ23091，YR-29，LOC55893，OGN，CPNE2，KIAA1784，Spir-2，DNAJA4，SYTL4, DKFZP566J2046, LOC51249, PARVA, FLJ23091, YR-29, LOC55893, OGN, CPNE2, KIAA1784, Spir-2, DNAJA4,

TMOD4，FLJ30726，C9orf19，SNX8，DUSP16，FLJ34633，FLJ25785，OSAP，B2M，DERMO1，ZNFN1A4，SCYL1，C16orf44，TMOD4, FLJ30726, C9orf19, SNX8, DUSP16, FLJ34633, FLJ25785, OSAP, B2M, DERMO1, ZNFN1A4, SCYL1, C16orf44,

MAF1，MGC12435，MSCP，JAK3，PPPIR16A，MGC4607，G6PT1，MGC16212，FLJ22283，SRA1，HBP1，CTL2，HCC-4，MAF1, MGC12435, MSCP, JAK3, PPPIR16A, MGC4607, G6PT1, MGC16212, FLJ22283, SRA1, HBP1, CTL2, HCC-4,

SPTB，C6orf37，KIAA1337，SNCAIP，SMOC2，PYGO2，FLJ12770，FLJ40432，BMF，SLC27A4，C1orf19，SLC5A1，CHRM1，SPTB, C6orf37, KIAA1337, SNCAIP, SMOC2, PYGO2, FLJ12770, FLJ40432, BMF, SLC27A4, C1orf19, SLC5A1, CHRM1,

FLJ14457，DKFZp434F054，SES2，MGC45474，BTC，APOA5，DKFZP434P106，KIAA1522，ZNF317，a1/3GTP，PCDHB3，FLJ14457, DKFZp434F054, SES2, MGC45474, BTC, APOA5, DKFZP434P106, KIAA1522, ZNF317, a1/3GTP, PCDHB3,

MGC26963，HSPC182，SNX9，NFAT5，C4orf7，NCAG1，KIAA1363，TAF6L，NAV1，KIAA1361，ZDHHC9，MGC2615，MGC26963, HSPC182, SNX9, NFAT5, C4orf7, NCAG1, KIAA1363, TAF6L, NAV1, KIAA1361, ZDHHC9, MGC2615,

PHLDA1，AD-003，LOC90268，FLJ10101，PCDHB16，SLC2A12，CKLFSF2，FLJ23518，SEMA6D，PS1D，SLC31A1，PHLDA1, AD-003, LOC90268, FLJ10101, PCDHB16, SLC2A12, CKLFSF2, FLJ23518, SEMA6D, PS1D, SLC31A1,

MGC10485，SLC5A2，ARHGAP9，NKD2，ETS1，FLJ90586，REN，FLJ14981，DKFZp761H0421，DKFZp434F2322，MUM2，MGC10485, SLC5A2, ARHGAP9, NKD2, ETS1, FLJ90586, REN, FLJ14981, DKFZp761H0421, DKFZp434F2322, MUM2,

SPP2，MGC4734，FLJ13687，BANK，CNTN3，TLR8，HM13，FLJ36525，SLC12A6，DAPP1，VANGL1，MSH5，P5CR2，SPP2, MGC4734, FLJ13687, BANK, CNTN3, TLR8, HM13, FLJ36525, SLC12A6, DAPP1, VANGL1, MSH5, P5CR2,

HAVCR2，CXCL14，GALNT5，ANKH，MGC29463，FLJ00028，TMPRSS6，AMOTL1，ODF3，MGC4604，ARG2，FLJ10052，HAVCR2, CXCL14, GALNT5, ANKH, MGC29463, FLJ00028, TMPRSS6, AMOTL1, ODF3, MGC4604, ARG2, FLJ10052,

FLJ13881，PP2135，SLC12A4，MGC10500，MAP1B，DKFZp5471094，FLJ30473，FLJ12886，ST6GALNAC6，ESDN，SEC15B，FLJ13881, PP2135, SLC12A4, MGC10500, MAP1B, DKFZp5471094, FLJ30473, FLJ12886, ST6GALNAC6, ESDN, SEC15B,

FLJ33903，LATS2，ZNFN1A1，SLC16A10，DSCRIL2，PSMB5，GPR34，FLJ20557，CGI-85，HCA127，DKFZp434I1930，FLJ33903, LATS2, ZNFN1A1, SLC16A10, DSCRIL2, PSMB5, GPR34, FLJ20557, CGI-85, HCA127, DKFZp434I1930,

FLJ90811，LOC113026，FBXO18，MGC8721，BLVRA，MGC10974，PRO1635，MAP4K1，HKE2，FLJ32122，FLJ35867，FLJ90811, LOC113026, FBXO18, MGC8721, BLVRA, MGC10974, PRO1635, MAP4K1, HKE2, FLJ32122, FLJ35867,

FLJ10392，WFDC3，C21orf6，FLJ23654，DKFZP586D0824，C21orf91，ENTPD2，RGNEF，GPRC5C，RALBP1，FLJ31052，FLJ10392, WFDC3, C21orf6, FLJ23654, DKFZP586D0824, C21orf91, ENTPD2, RGNEF, GPRC5C, RALBP1, FLJ31052,

C11ORF30，FLJ30803，ITGA11，KIAA1053，AGTRAP，NDUFS2，FLJ32069，ACTR1A，SLC2A4RG，PPARBP，FLJ10055，C11ORF30, FLJ30803, ITGA11, KIAA1053, AGTRAP, NDUFS2, FLJ32069, ACTR1A, SLC2A4RG, PPARBP, FLJ10055,

C20orf67，FLJ12649，KLAA1909，IFIT2，EMR2，CD5，HT036，SERPINB9，MAP1LC3A，IGKC，ZD52F10，FLJ32028，C20orf67, FLJ12649, KLAA1909, IFIT2, EMR2, CD5, HT036, SERPINB9, MAP1LC3A, IGKC, ZD52F10, FLJ32028,

BTEB1，FLJ20539，CCL28，MGC21621，KIAA1130，KIAA1554，FLJ31937，RPL29，GSA7，FLJ25067，FLJ20989，LOC92689，BTEB1, FLJ20539, CCL28, MGC21621, KIAA1130, KIAA1554, FLJ31937, RPL29, GSA7, FLJ25067, FLJ20989, LOC92689,

FLJ12604，MS4A6A，ELA1，SMOC1，CIQG，MGC14421，KIAA1576，FLJ20245，LOC155066，PRDM6，DAP10，PCDHB14，FLJ12604, MS4A6A, ELA1, SMOC1, CIQG, MGC14421, KIAA1576, FLJ20245, LOC155066, PRDM6, DAP10, PCDHB14,

FLJ25124，SNRK，ADAMTS16，SES2，SECP43，EPST11，KIAA1948，NOL6，PALMD，PAG，MGC39807，TTY7，NUDE1，FLJ25124, SNRK, ADAMTS16, SES2, SECP43, EPST11, KIAA1948, NOL6, PALMD, PAG, MGC39807, TTY7, NUDE1,

KIAA1210，HRB2，USP21，C9orf19，LOC93589，DKFZp434EI822，MGC10561，RNO2，GLCC11，MGC3234，AMOTL1，KIAA1210, HRB2, USP21, C9orf19, LOC93589, DKFZp434EI822, MGC10561, RNO2, GLCC11, MGC3234, AMOTL1,

FLJ33868，B3GNT5，FAM11A，SBBI31，FLJ23654，SLT，CPM，DKFZp762K222，NSE1，KIAA1817，NYD-SP21，LUC7L，FLJ33868, B3GNT5, FAM11A, SBBI31, FLJ23654, SLT, CPM, DKFZp762K222, NSE1, KIAA1817, NYD-SP21, LUC7L,

FLJ13063，SIAT6，CASP14，FLJ11896，GPR92，FLJ25027，EVC，HOXA3，HTGN29，MGC4281，MGC15548，GSN，AD023，FLJ13063, SIAT6, CASP14, FLJ11896, GPR92, FLJ25027, EVC, HOXA3, HTGN29, MGC4281, MGC15548, GSN, AD023,

FLJ14311，TAGAP，KIAA1276，CGN，ZDHHC12，FLJ21736，FGFR2，LOC91461，GNG2，BACH1，KIAA1921，KIAA1957，FLJ14311, TAGAP, KIAA1276, CGN, ZDHHC12, FLJ21736, FGFR2, LOC91461, GNG2, BACH1, KIAA1921, KIAA1957,

FLJ10111，KIAA1145，ARHGEF7，STARD4，retSDR3，HBXAP，ARFGAP1，NY-REN-60，RIG-1，X102，AFIQ，SYTL4，FLJ10111, KIAA1145, ARHGEF7, STARD4, retSDR3, HBXAP, ARFGAP1, NY-REN-60, RIG-1, X102, AFIQ, SYTL4,

ICAP-1A，KIAA0872，LOC148932，SCML1，NOL6，Hes4，LOC57038，TRPM6，ABCC13，CGI-85，DRLM，BCAR1，NR0B1，ICAP-1A, KIAA0872, LOC148932, SCML1, NOL6, Hes4, LOC57038, TRPM6, ABCC13, CGI-85, DRLM, BCAR1, NR0B1,

MCOLN2，KIAA1836，MGC35048，VIL1，LOC124245，MRP63，TTYH2，FLJ14735，PRIC285，KIAA1999，GALNT7，EGR4，MCOLN2, KIAA1836, MGC35048, VIL1, LOC124245, MRP63, TTYH2, FLJ14735, PRIC285, KIAA1999, GALNT7, EGR4,

DKFZp434F2322，PHACS，LOC51219，LOC132158，PRO0971，SU11，SKD3，RNF26，TTY6，TTRC18，CTXL，FLJ12666，DKFZp434F2322, PHACS, LOC51219, LOC132158, PRO0971, SU11, SKD3, RNF26, TTY6, TTRC18, CTXL, FLJ12666,

FLJ39957，FACL5，POLK，SLC25A13，FLJ31318，ZFP91，MGC19825，TPM2，PPPIR14C，LOC142820，ALDOA，EGFR-RS，FLJ39957, FACL5, POLK, SLC25A13, FLJ31318, ZFP91, MGC19825, TPM2, PPPIR14C, LOC142820, ALDOA, EGFR-RS,

FBXO27，PRO0038，MGC10992，NPCR，HCMOGT-1，RSP3，PPPIR9A，KCNMB3，GPR55，ZFP28，PRO1635，C20orf154，FBXO27, PRO0038, MGC10992, NPCR, HCMOGT-1, RSP3, PPPIR9A, KCNMB3, GPR55, ZFP28, PRO1635, C20orf154,

FLJ32203，MS4A6A，KIAA1647，KIAA1607，BAZ2B，FLJ32752，ZNF216，PP2135，KIAA1357，MGC16207，KIAA1694，FLJ32203, MS4A6A, KIAA1647, KIAA1607, BAZ2B, FLJ32752, ZNF216, PP2135, KIAA1357, MGC16207, KIAA1694,

GBP1，FLJ10474，FLJ10826，ELAVL3，LOC90668，CPXM，MGC2452，FLJ20273，MIC2L1，FAD104，GPR107，MGC15419，GBP1, FLJ10474, FLJ10826, ELAVL3, LOC90668, CPXM, MGC2452, FLJ20273, MIC2L1, FAD104, GPR107, MGC15419,

SORCS2，ST6GalNAc1，RP4-622L5，DKFZP434F011，TNKS2，DKFZp761K2222，EIIs1，SLC4A11，KIAA1163，CALN1，SORCS2, ST6GalNAc1, RP4-622L5, DKFZP434F011, TNKS2, DKFZp761K2222, EIIs1, SLC4A11, KIAA1163, CALN1,

KIAA1828，MEGF10，GRIN3A，REVIL，BHLHB5，ADMP，DKFZp6671133，MGC13275，KIAA1889，DKFZP434A236，KIAA1828, MEGF10, GRIN3A, REVIL, BHLHB5, ADMP, DKFZp6671133, MGC13275, KIAA1889, DKFZP434A236,

GPS2，FLJ20309，NAVI，MGC2603，ARHU，FLJ33071，NUMBL，CDGAP，FLJ35713，DKFZp761A132，FLJ10300，GPS2, FLJ20309, NAVI, MGC2603, ARHU, FLJ33071, NUMBL, CDGAP, FLJ35713, DKFZp761A132, FLJ10300,

FLJ12634，GTF3A，NEO1，RRAD，MGC10966，PTPN2，FLJ10292，ACPP，CISH，DOTIL，POLRMT，CGI-149，KIAA1202，FLJ12634, GTF3A, NEO1, RRAD, MGC10966, PTPN2, FLJ10292, ACPP, CISH, DOTIL, POLRMT, CGI-149, KIAA1202,

DKFZp761J139，MGC40178，GATA4，EVIN2，MS4A8B，FLJ10057，NDUFV3，SF3b10，RP2，FLJ21032，CLG，MGC3040，DKFZp761J139, MGC40178, GATA4, EVIN2, MS4A8B, FLJ10057, NDUFV3, SF3b10, RP2, FLJ21032, CLG, MGC3040,

ODZ2，AQPI，DKFZp566F0947，CCL27，TARD9，MGC40222，DKFZp564C236，SDS-RS1，SNCAIP，ENDOGLYX1，CGI-30，ODZ2, AQPI, DKFZp566F0947, CCL27, TARD9, MGC40222, DKFZp564C236, SDS-RS1, SNCAIP, ENDOGLYX1, CGI-30,

FLJ10314，MGC20470，KL11L6，KIAA0212，PRO0899，KIAA1894，FLN29，FLJ20373，GTF21，GJC1，BHLHB3，CPNE5，FLJ10314, MGC20470, KL11L6, KIAA0212, PRO0899, KIAA1894, FLN29, FLJ20373, GTF21, GJC1, BHLHB3, CPNE5,

GPC6，IL6R，RRN3，DKFZP564J047，C20orf99，CED-6，DKFZP434P1735，TGIF2LY，LOC83690，GPR110，FLJ34922，GPC6, IL6R, RRN3, DKFZP564J047, C20orf99, CED-6, DKFZP434P1735, TGIF2LY, LOC83690, GPR110, FLJ34922,

FLJ20211，FREQ，USP26，MGC15634，ZSIG11，ZFHX2，C7，UNKL，LOC151835，MGC21854，FLJ25410，EGLN2，KIF9，FLJ20211, FREQ, USP26, MGC15634, ZSIG11, ZFHX2, C7, UNKL, LOC151835, MGC21854, FLJ25410, EGLN2, KIF9,

KIAA1550，CIPI，DNAJC9，FLJ14768，MGC2599，LOC57018，DDX12，MGC33993，SLC22A3，KIAA1399，DKFZP434F091，KIAA1550, CIPI, DNAJC9, FLJ14768, MGC2599, LOC57018, DDX12, MGC33993, SLC22A3, KIAA1399, DKFZP434F091,

EG1，SE70-2，DKFZP56411171，CDH26，TRPC7，DKFZP566K1924，C20orf60，ROR2，KLHL5，SCARA3，PRO1580，EG1, SE70-2, DKFZP56411171, CDH26, TRPC7, DKFZP566K1924, C20orf60, ROR2, KLHL5, SCARA3, PRO1580,

MGC15523，DKFZp434C0328，FLJ31528，CR1L，FLJ32734，NXF3，MGC41906，CLECSF9，SSBP4，ZNFN1A4，FBXO22，MGC15523, DKFZp434C0328, FLJ31528, CR1L, FLJ32734, NXF3, MGC41906, CLECSF9, SSBP4, ZNFN1A4, FBXO22,

NCAG1，MAP2，KIAA1529，TIGD5，SNX9，FLJ32001，RPC5，AK2，KIAA1887，ACK1，FLJ373l2，ARSD，FLJ31564，NCAG1, MAP2, KIAA1529, TIGD5, SNX9, FLJ32001, RPC5, AK2, KIAA1887, ACK1, FLJ373l2, ARSD, FLJ31564,

LOC51136，MYEOV，GNA11，MGC12335，FLJ20356，KIAA1617，HNT，C21orf59，LOC221468，ENAM，PB1，TBXAS1，LOC51136, MYEOV, GNA11, MGC12335, FLJ20356, KIAA1617, HNT, C21orf59, LOC221468, ENAM, PB1, TBXAS1,

NMNAT，MGC10204，TNKS1BP1，LOC57401，FLJ32194，ENTH，APOA1，ITGA6，MGC12458，FLJ23403，BCL10，H19，NMNAT, MGC10204, TNKS1BP1, LOC57401, FLJ32194, ENTH, APOA1, ITGA6, MGC12458, FLJ23403, BCL10, H19,

C7orf2，DNER，PDE11A，MAF，FLJ10378，MGC14276，TLE1，SH3GLB2，TTTY8，KCNH3，LOC90693，ENDOGLYX1，C7orf2, DNER, PDE11A, MAF, FLJ10378, MGC14276, TLE1, SH3GLB2, TTTY8, KCNH3, LOC90693, ENDOGLYX1,

LOC144402，CG1-105，LOC153222，ASAH2，MGC4415，KIAA1495，SFRS12，and AGPAT3.LOC144402, CG1-105, LOC153222, ASAH2, MGC4415, KIAA1495, SFRS12, and AGPAT3.

                                    表5 table 5

                          UPTG和HSC中相比上调的Up-regulated in UPTG compared with HSC

CFL1，S100A8，SERPINA3，UBC，MUC1，SFN，ANXA2，ANXA2，COX7A2，HSPA1A，KRT18，ANXA2，OAZ1，TMSB10，CFL1, S100A8, SERPINA3, UBC, MUC1, SFN, ANXA2, ANXA2, COX7A2, HSPA1A, KRT18, ANXA2, OAZ1, TMSB10,

CA12，DNCL1，CEACAM6，ASAH1，RAC1，ARF4，TACSTD2，MYL6，MSF，JTB，CKAP4，TFF1，IER3，GATA3，IFITM2，CA12, DNCL1, CEACAM6, ASAH1, RAC1, ARF4, TACSTD2, MYL6, MSF, JTB, CKAP4, TFF1, IER3, GATA3, IFITM2,

SFN，MTCH1，TPM1，CD24，NET-6，MLC-B，MLPH，QP-C，SCGB2A2，S100P，S100A9，COX6A1，CAPN2，COX5B，CD24，SFN, MTCH1, TPM1, CD24, NET-6, MLC-B, MLPH, QP-C, SCGB2A2, S100P, S100A9, COX6A1, CAPN2, COX5B, CD24,

H2BFT，XBP1，FXYD3，RNP24，PTS，GSPT1，COX6C，TIP-1，HIG1，RPS16，SAT，HSPCA，TPD52L1，TMSB4X，S100A10，H2BFT, XBP1, FXYD3, RNP24, PTS, GSPT1, COX6C, TIP-1, HIG1, RPS16, SAT, HSPCA, TPD52L1, TMSB4X, S100A10,

JTB，RBPMS，KRT19，FLJ10830，TUBB，JTB，ITGB1，CEACAM5，MT2A，LIV-1，HN1L，LCN2，LOC51142，LGALS3，JTB, RBPMS, KRT19, FLJ10830, TUBB, JTB, ITGB1, CEACAM5, MT2A, LIV-1, HN1L, LCN2, LOC51142, LGALS3,

RAB13，FTH1，TCTEL1，IFITM2，S100A7，PSMB4，MAGED1，FLJ20151，DBI，COX6B，C20orf24，ARHA，NFIB，PTP4A2，RAB13, FTH1, TCTEL1, IFITM2, S100A7, PSMB4, MAGED1, FLJ20151, DBI, COX6B, C20orf24, ARHA, NFIB, PTP4A2,

NDUFB2，CALM1，ATP1B1，GNG5，CD63，NAT1，S100A6，E1F4B，ESR1，HSPB1，TAGLN2，ALCAM，NDUFS6，AGR2，NDUFB2, CALM1, ATP1B1, GNG5, CD63, NAT1, S100A6, E1F4B, ESR1, HSPB1, TAGLN2, ALCAM, NDUFS6, AGR2,

C8FW，TXN，HDLBP，NDUFA4，PPIC，GLO1，RAB11A，LPP，HDGF，CALM1，MGLL，PTS，ARF1，DC12，SNRPD2，C4A，C8FW, TXN, HDLBP, NDUFA4, PPIC, GLO1, RAB11A, LPP, HDGF, CALM1, MGLL, PTS, ARF1, DC12, SNRPD2, C4A,

RA13，NDUFA6，ATP6V1D，MLCB，TEGT，DSP，PNN，ACTN1，NIFIE14，NDUFB4，DAF，VAV3，UBC，SSR2，MKNK2，RA13, NDUFA6, ATP6V1D, MLCB, TEGT, DSP, PNN, ACTN1, NIFIE14, NDUFB4, DAF, VAV3, UBC, SSR2, MKNK2,

HSPC014，KDELR3，TACSTD1，DKFZP564A2416，ASAH1，DDR1，ENAH，KDELR2，DNC12，PPPIR11，PP，SERF2，CTSB，HSPC014, KDELR3, TACSTD1, DKFZP564A2416, ASAH1, DDR1, ENAH, KDELR2, DNC12, PPPIR11, PP, SERF2, CTSB,

SSR4，GNAS，PGM1，CEACAM6，PDLIM1，GATA3，MGC3178，SHC1，GOLPH2，GNAS，VAMP3，S100A14，GABARAP，SSR4, GNAS, PGM1, CEACAM6, PDLIM1, GATA3, MGC3178, SHC1, GOLPH2, GNAS, VAMP3, S100A14, GABARAP,

ALDOA，TAXIBP1，LASP1，NFIB，CCT3，AQP3，DB1，VCL，GNAS，ALDOA，COL3A1，ATP5J2，MGC16723，USP9X，ALDOA, TAXIBP1, LASP1, NFIB, CCT3, AQP3, DB1, VCL, GNAS, ALDOA, COL3A1, ATP5J2, MGC16723, USP9X,

TMEM4，MTX1，HSPC134，ZMPSTE24，UQCR，AHCYL1，GOCAP1，HTO11，EDF1，CRIP1，FXYD3，MRPL9，RIP60，TMEM4, MTX1, HSPC134, ZMPSTE24, UQCR, AHCYL1, GOCAP1, HTO11, EDF1, CRIP1, FXYD3, MRPL9, RIP60,

TIMM17A，BF，RER1，DC50，CTBP2，HEBP2，YIF1P，LOC54499，APMCF1，UGDH，PSAP，SPEC1，FLJ12619，TUFT1，TIMM17A, BF, RER1, DC50, CTBP2, HEBP2, YIF1P, LOC54499, APMCF1, UGDH, PSAP, SPEC1, FLJ12619, TUFT1,

COX5B，LRP10，ATP6V0E，CYP27A1，PON2，NQO1，PTPRK，EIF4EL3，GNAS，CLTA，MDH2，TCEB2UBE3A，TM9SF2，COX5B, LRP10, ATP6V0E, CYP27A1, PON2, NQO1, PTPRK, EIF4EL3, GNAS, CLTA, MDH2, TCEB2UBE3A, TM9SF2,

MUC1，RARRES1，PRDX4，MIF，TPD52，CD81，DSTN，HRY，HSPC051，SMBP，HDGF，C14orf2，BRD3，NHP2L1，PPP2CB，MUC1, RARRES1, PRDX4, MIF, TPD52, CD81, DSTN, HRY, HSPC051, SMBP, HDGF, C14orf2, BRD3, NHP2L1, PPP2CB,

DLG5，ASS，ENSA，MAGED1，CD59，SHAPY，CAST，JDP1，HK1FBXO9，RPL38，INHBA，EMS1，HRI，APP，HAX1，DLG5, ASS, ENSA, MAGED1, CD59, SHAPY, CAST, JDP1, HK1FBXO9, RPL38, INHBA, EMS1, HRI, APP, HAX1,

FKBP11，GOLGB1，SPINT2，GORASP2，CD24，HSPA1B，FLJ13593，MGC5466，E2F4，PRO1855，UBE2V1，KIAA0882，FKBP11, GOLGB1, SPINT2, GORASP2, CD24, HSPA1B, FLJ13593, MGC5466, E2F4, PRO1855, UBE2V1, KIAA0882,

RPL36AL，CSTB，ATP51，OASIS，DKFZP564K0822，RCP，MAGED1，PSMB5，NDUFS2，YWHAZ，KIAA0310，RPL38，RPL36AL, CSTB, ATP51, OASIS, DKFZP564K0822, RCP, MAGED1, PSMB5, NDUFS2, YWHAZ, KIAA0310, RPL38,

FLJ20273，RAB3-GAP150，PSMA5，ATP2A2，C20orf97，TUBB2，RAB31，C9orf7，HIG1，INSR，TPM1，GSPT1，PSME2，FLJ20273, RAB3-GAP150, PSMA5, ATP2A2, C20orf97, TUBB2, RAB31, C9orf7, HIG1, INSR, TPM1, GSPT1, PSME2,

CSNKIA1，P4HB，EIF2S1，LOC92689，NDUFA3，KIF5B，PAM，MT1H，SHAPY，FLJ10898，GUSB，BNIP3，KIAA0992，CSNKIA1, P4HB, EIF2S1, LOC92689, NDUFA3, KIF5B, PAM, MT1H, SHAPY, FLJ10898, GUSB, BNIP3, KIAA0992,

FLOT1，PSMB7，TAF10，CSNK2B，EPRS，PIG7，DAP3，ECHS1，AP3D1，COX8，PMP22，LOC54499，ALDH3B2，MGST3，FLOT1, PSMB7, TAF10, CSNK2B, EPRS, PIG7, DAP3, ECHS1, AP3D1, COX8, PMP22, LOC54499, ALDH3B2, MGST3,

PRDX2，PTD011，COX5B，CAST，LASS2，PSMB2，MT1X，MYD88，DKFZp56411922，FLJ20719，C4B，H2AFL，FLOT1，PRDX2, PTD011, COX5B, CAST, LASS2, PSMB2, MT1X, MYD88, DKFZp56411922, FLJ20719, C4B, H2AFL, FLOT1,

PIN4，TCEB1，WFDC2，SQRDL，CSTA，PTD009，PTPRF，DAD1，PDEF，FN1，GPX4，DDR1，ARHD，COL1A2，PDEF，PIN4, TCEB1, WFDC2, SQRDL, CSTA, PTD009, PTPRF, DAD1, PDEF, FN1, GPX4, DDR1, ARHD, COL1A2, PDEF,

HSPC009，MEA，ABCD3，CYB5，MLCB，PRO1489，PDEF，RPS11，IDH1，SLC12A7，H2BFB，SH3BP4，CD24，SLC38A1，HSPC009, MEA, ABCD3, CYB5, MLCB, PRO1489, PDEF, RPS11, IDH1, SLC12A7, H2BFB, SH3BP4, CD24, SLC38A1,

RAB31，LTF，TIMP1，SH3YL1，SEMA3F，TSPAN-1，K1AA0852，NDUFA8，COL1A2，SLPI，PSMD4，RPL27A，GNAS，RAB31, LTF, TIMP1, SH3YL1, SEMA3F, TSPAN-1, K1AA0852, NDUFA8, COL1A2, SLPI, PSMD4, RPL27A, GNAS,

KIAA0876，DP1，CEBPD，CIB1，IQGAP1，TSG101，MGC3077，CYB5，FN1，LOC51128，EMP2，CETN2，PACSIN2，PBEF，KIAA0876, DP1, CEBPD, CIB1, IQGAP1, TSG101, MGC3077, CYB5, FN1, LOC51128, EMP2, CETN2, PACSIN2, PBEF,

MRPL24，CTSB，SDFR1，MLP，TM4SF1，C20orf3，PRKAR2A，MGC5178，FN1，FLJ20054，MMP24，SEPX1，GFPT1，MRPL24, CTSB, SDFR1, MLP, TM4SF1, C20orf3, PRKAR2A, MGC5178, FN1, FLJ20054, MMP24, SEPX1, GFPT1,

ANXA11，ADFP，GMFB，AP3S2，PTBP1，BAG1，FLJ10496，CYB5，CXADR，RAB25，FH，APP，CDR2，PSEN1，RFP，ANXA11, ADFP, GMFB, AP3S2, PTBP1, BAG1, FLJ10496, CYB5, CXADR, RAB25, FH, APP, CDR2, PSEN1, RFP,

SEC22L1，GGPS1，ARMET，USP7，FLJ20847，EFA6R，HSPA4，RDBP，TNFSF10，DDR1，KIAA0429，PLP2，RABGGTB，SEC22L1, GGPS1, ARMET, USP7, FLJ20847, EFA6R, HSPA4, RDBP, TNFSF10, DDR1, KIAA0429, PLP2, RABGGTB,

BAG3，IFI27，GATA3，LAMP2，CD24，MRPS14，FHL2，CGI-130，CPB1，SCAMP3，NESCA，BACE2，PSMD8，LGALS1，BAG3, IFI27, GATA3, LAMP2, CD24, MRPS14, FHL2, CGI-130, CPB1, SCAMP3, NESCA, BACE2, PSMD8, LGALS1,

MPHOSPH6，FLJ14154，COPZI，CALR，HK2，WIRE，PTP4A1，TRA1，DKFZP564G2022，CTSH，CRAT，PLAT，ANXA2P2，MPHOSPH6, FLJ14154, COPZI, CALR, HK2, WIRE, PTP4A1, TRA1, DKFZP564G2022, CTSH, CRAT, PLAT, ANXA2P2,

YME1L1，P1LB，ITGB5，KIAA1026，FKBP4，TBL2，PIGT，WSB2，IFI30，TUBB2，E21G5，YME1L1，ATP6V0E，RAB4A，YME1L1, P1LB, ITGB5, KIAA1026, FKBP4, TBL2, PIGT, WSB2, IFI30, TUBB2, E21G5, YME1L1, ATP6V0E, RAB4A,

LOH11CR2A，PLU-1，K1AA0483，SLC2A1，LBP，MGC11256，FMOD，TLE1，POLR2H，TOB1，NSF，TACC2，OPN3，USP3，LOH11CR2A, PLU-1, K1AA0483, SLC2A1, LBP, MGC11256, FMOD, TLE1, POLR2H, TOB1, NSF, TACC2, OPN3, USP3,

PSMB1，TMP21，DUSP4，RAB2，SVIL，FDFT1，NFE2L1，PTGIS，RPP20，PGLS，ORMDL2，NR2F6，P1G7，ERBB3，TRAP1，PSMB1, TMP21, DUSP4, RAB2, SVIL, FDFT1, NFE2L1, PTGIS, RPP20, PGLS, ORMDL2, NR2F6, P1G7, ERBB3, TRAP1,

DDR1，SDC4，HSA243666，PLU-1，ATP6V1E1，DAAM1，GSN，MCP，KIAA0143，P17.3，P1N4，WARS，FN1，TFG，COPB2，DDR1, SDC4, HSA243666, PLU-1, ATP6V1E1, DAAM1, GSN, MCP, KIAA0143, P17.3, P1N4, WARS, FN1, TFG, COPB2,

ERP70，MRPS18A，C22orf5，LYSAL1，POLR21，SAR1，ATP6V0B，TUFM，NDUFB2，BCL6，PDCD61P，TRIM33，UBE2N，ERP70, MRPS18A, C22orf5, LYSAL1, POLR21, SAR1, ATP6V0B, TUFM, NDUFB2, BCL6, PDCD61P, TRIM33, UBE2N,

WBSCR21，NEDD5，LOC51123，GMFB，PFN2，KRTHB1，NANS，CLU，TOMM20-PENDING，NDUFS8，MT1G，ANK3，WBSCR21, NEDD5, LOC51123, GMFB, PFN2, KRTHB1, NANS, CLU, TOMM20-PENDING, NDUFS8, MT1G, ANK3,

PIK3R3，IL13RA1，TNFSF10，DNPEP，TNRC9，NIPSNAP1，BRP44L，PEX11B，FLJ13612，FLJ22028，POLB，ANXA4，PIK3R3, IL13RA1, TNFSF10, DNPEP, TNRC9, NIPSNAP1, BRP44L, PEX11B, FLJ13612, FLJ22028, POLB, ANXA4,

SEC61G，PRE13，CDKN1A，MT1L，SAS，PSMD5，COBL，CARD10，UBE2D3，RABAC1，CPD，C21orf97，PAM，MRPS10，SEC61G, PRE13, CDKN1A, MT1L, SAS, PSMD5, COBL, CARD10, UBE2D3, RABAC1, CPD, C21orf97, PAM, MRPS10,

CGI-109，GBP2，TC10，NMA，FASTK，P4HA1，GTF21，COG2，MYO6，LMNA，TCF3，C14orf3，PEA15，PRKCBP1，GALNT3，CGI-109, GBP2, TC10, NMA, FASTK, P4HA1, GTF21, COG2, MYO6, LMNA, TCF3, C14orf3, PEA15, PRKCBP1, GALNT3,

IRS1，ACP1，GUK1，MBD2，PTD008，RBM4，TNFRSF10B，KIAA0266，NQO1，DNAJA1，FACL3，FER1L3，CD59，PPAP2A，IRS1, ACP1, GUK1, MBD2, PTD008, RBM4, TNFRSF10B, KIAA0266, NQO1, DNAJA1, FACL3, FER1L3, CD59, PPAP2A,

FACL3，KIAA1598，TGM2，MTMR9，LOC51760，TST，TM9SF1，LGALS3BP，P24B，D2S448，RPL27，KDELR2，TJP1，FACL3, KIAA1598, TGM2, MTMR9, LOC51760, TST, TM9SF1, LGALS3BP, P24B, D2S448, RPL27, KDELR2, TJP1,

OPTN，NME2，HRI，F12，RABIF，TJP2，ATP1B1，GGPS1，FLJ10116，PTGES，SCO2，PEN-2，PSMB3，CDS2，RAD23B，OPTN, NME2, HRI, F12, RABIF, TJP2, ATP1B1, GGPS1, FLJ10116, PTGES, SCO2, PEN-2, PSMB3, CDS2, RAD23B,

PPM1A，ARL3，TXNDC4，GOLGA5DDX32，DAG1，VIL2，TPBG，GM2A，EIF2S2，NEUGRIN，DKFZP564G2022，PPM1A, ARL3, TXNDC4, GOLGA5DDX32, DAG1, VIL2, TPBG, GM2A, EIF2S2, NEUGRIN, DKFZP564G2022,

KIAA0934，ADM，CSRP1，GR1M19，FAT，SLC21A11，ACADVL，NDUFA2，GALNAC4S-6ST，EIF5，RAB1B，NME1，ASPH，KIAA0934, ADM, CSRP1, GR1M19, FAT, SLC21A11, ACADVL, NDUFA2, GALNAC4S-6ST, EIF5, RAB1B, NME1, ASPH,

MUT，ARF4，FBXL11，COPA，UBL5，CSNK1E，ATP51，CCND1，HT021，PPP1R7，LOC56851，SRP54，DAF，CTBP2，TLE2，MUT, ARF4, FBXL11, COPA, UBL5, CSNK1E, ATP51, CCND1, HT021, PPP1R7, LOC56851, SRP54, DAF, CTBP2, TLE2,

HSD17B1，SRD5A1，SLC9A3R1，MUC16，PPL，MGC10765，EPB41L4B，SECTM1，CHPPR，SORD，VT11B，CRABP2，HSD17B1, SRD5A1, SLC9A3R1, MUC16, PPL, MGC10765, EPB41L4B, SECTM1, CHPPR, SORD, VT11B, CRABP2,

EFNA1，HERPUD1，CDYL，MRPS17，SGPL1，DUSP14，SSBP1，C20orf35，C3，HSPC163，ATP6V1G1，YF13H12，FLJ13052，EFNA1, HERPUD1, CDYL, MRPS17, SGPL1, DUSP14, SSBP1, C20orf35, C3, HSPC163, ATP6V1G1, YF13H12, FLJ13052,

ABCC10，STUB1，NNMT，RAB20，CALU，PLCB1，NR2F2，HSPE1，TM4SF1，RSN，FLJ208l3，TPARL，SEPW1，H1F2，ABCC10, STUB1, NNMT, RAB20, CALU, PLCB1, NR2F2, HSPE1, TM4SF1, RSN, FLJ208l3, TPARL, SEPW1, H1F2,

GRHPR，HSPA1A，RAB2L，SARS，FIBP，PSMB6，RER1，BCL10，ATP9A，IDS，PPIB，RAB2，Cab45，PYCR1，GSTM3，GRHPR, HSPA1A, RAB2L, SARS, FIBP, PSMB6, RER1, BCL10, ATP9A, IDS, PPIB, RAB2, Cab45, PYCR1, GSTM3,

SEC24A，MAPT，FLJ10579，ADAM9，FLJ21603，DNAJB1，C20orf116，DKFZP564G0222，RDGBB，RRAS2，AKAP9，SEC24A, MAPT, FLJ10579, ADAM9, FLJ21603, DNAJB1, C20orf116, DKFZP564G0222, RDGBB, RRAS2, AKAP9,

K1AA1243，DC1，ELF3，PDE4A，CRIM1，CORO1B，PXMP4，S100A13，DPP3，GTF2H2，PSMB8，TUBB4，MRPL33，STK39，K1AA1243, DC1, ELF3, PDE4A, CRIM1, CORO1B, PXMP4, S100A13, DPP3, GTF2H2, PSMB8, TUBB4, MRPL33, STK39,

VCAM1，MAOB，DKFZP566C134，CSNK1A1，FLJ20761，EGFL6，ATP1A1，APH-1A，FLJ22055，TOP1，RCL，SMT3H2，VCAM1, MAOB, DKFZP566C134, CSNK1A1, FLJ20761, EGFL6, ATP1A1, APH-1A, FLJ22055, TOP1, RCL, SMT3H2,

POLR2K，LMNA，ID4，JTV1，CLN5，AKIP，TGFB1，LLGL2，ITGAVPPP2R5A，IFNGR1，JAG1，DD96，PGRMC2，SNRPE，POLR2K, LMNA, ID4, JTV1, CLN5, AKIP, TGFB1, LLGL2, ITGAVPPP2R5A, IFNGR1, JAG1, DD96, PGRMC2, SNRPE,

MGC19606，DJ97IN18.2，CKAP1，MGC3180，HYOU1，PACE-1，FLJ22662，KIAA0674，ALS2CR3，EPLIN，MYOIC，CD164，MGC19606, DJ97IN18.2, CKAP1, MGC3180, HYOU1, PACE-1, FLJ22662, KIAA0674, ALS2CR3, EPLIN, MYOIC, CD164,

PCMT1，IL1R1，SERPINB2，HSD17B4，FOLR1，HRIHFB2122，FLJ22457，MX11，TCFLI，POR1，FLJ20375，H4FD，KRT7，PCMT1, IL1R1, SERPINB2, HSD17B4, FOLR1, HRIHFB2122, FLJ22457, MX11, TCFLI, POR1, FLJ20375, H4FD, KRT7,

TFAP2B，MRPL15，SLC5A6，RGS16，TNFAIP1，FLJ14146，HOXB7，PIK4CB，RPS20，C11orf24，SYNGR2，NCKAP1，APG3，TFAP2B, MRPL15, SLC5A6, RGS16, TNFAIP1, FLJ14146, HOXB7, PIK4CB, RPS20, C11orf24, SYNGR2, NCKAP1, APG3,

RHBDL2，ASC，C1orf9，KIAA0247，HRB，PAFAH1B3，SNK，ASB13，LSM1，GP1，MCJ，CASK，HOXB7，RBBP6，PKIG，RHBDL2, ASC, C1orf9, KIAA0247, HRB, PAFAH1B3, SNK, ASB13, LSM1, GP1, MCJ, CASK, HOXB7, RBBP6, PKIG,

SMARCA4，BLVRB，HYPK，SUCLG2，KIAA0494，SLC2A10，HIG2，TSTA3，TNRC9，SEC23B，SELENBP1，RAB6C，SMARCA4, BLVRB, HYPK, SUCLG2, KIAA0494, SLC2A10, HIG2, TSTA3, TNRC9, SEC23B, SELENBP1, RAB6C,

VAPB，ZNF144，PCNP，SULT1A3，NQO2，SMP1，FLJ30656，NUBP2，FLJ20152，ATP5H，FLJ22418，DCN，SOD2，FLJ20958，VAPB, ZNF144, PCNP, SULT1A3, NQO2, SMP1, FLJ30656, NUBP2, FLJ20152, ATP5H, FLJ22418, DCN, SOD2, FLJ20958,

YWHAZ，TRPS1，CYP51，SUCLG2，CGI-45，ZFP103，MID2，CPD，TFAP2C，Clorf37，dJ222E13.1，ICMT，UNC84A，YWHAZ, TRPS1, CYP51, SUCLG2, CGI-45, ZFP103, MID2, CPD, TFAP2C, Clorf37, dJ222E13.1, ICMT, UNC84A,

CALM1，DF，SUPT16H，BZRP，SLC9A1，FLJ13110，ATIP1，MUC5B，CTSB，GJA1，SDHC，SUCLG2，MGC3067，PBEF，CALM1, DF, SUPT16H, BZRP, SLC9A1, FLJ13110, ATIP1, MUC5B, CTSB, GJA1, SDHC, SUCLG2, MGC3067, PBEF,

IL27w，HSD17B7，GRSF1，CD9，H11，FLJ10099，NIT1，LAMC1，HBX1P，NDUFV2，STX12，SDHA，D123，Z391G，RPL5，IL27w, HSD17B7, GRSF1, CD9, H11, FLJ10099, NIT1, LAMC1, HBX1P, NDUFV2, STX12, SDHA, D123, Z391G, RPL5,

PA200，SC4MOL，HSPC171，STXBP1，CACNG4，MAGED2，MGC4368，MPZL1，ZDHHC7，RPA40，IGSF3，FLJ22638，PA200, SC4MOL, HSPC171, STXBP1, CACNG4, MAGED2, MGC4368, MPZL1, ZDHHC7, RPA40, IGSF3, FLJ22638,

SPTLC2，MTVR1，FLJ21016，SGK，NCOA1，MAP4，GLRX2，P4HA2，JAG1，MTVR1，FLJ22940，NDUFB8，ISGF3G，SPTLC2, MTVR1, FLJ21016, SGK, NCOA1, MAP4, GLRX2, P4HA2, JAG1, MTVR1, FLJ22940, NDUFB8, ISGF3G,

B4GALT5，EMS1，C22orf2，LRPAP1，PON3，EIF5A，ENSADKFZP564F0522，FLJ11273，EPS8R1，EDF1，ISG20，EPS8R1，B4GALT5, EMS1, C22orf2, LRPAP1, PON3, EIF5A, ENSADKFZP564F0522, FLJ11273, EPS8R1, EDF1, ISG20, EPS8R1,

FLJ10525，PSMD4，NINJ1，TSSC3，FDPS，RGS3，CREB3，UBE2D1，ProSAPiP1，CAST，WBSCR20A，MAPKAPK2，RPP38，FLJ10525, PSMD4, NINJ1, TSSC3, FDPS, RGS3, CREB3, UBE2D1, ProSAPiP1, CAST, WBSCR20A, MAPKAPK2, RPP38,

YWHAB，A2M，RBX1，PDGFRA，EFS2，RAB9A，RAD23B，BAZ1A，BCL3，SNX4，CLMN，HRY，INHBB，NPD009，YWHAB, A2M, RBX1, PDGFRA, EFS2, RAB9A, RAD23B, BAZ1A, BCL3, SNX4, CLMN, HRY, INHBB, NPD009,

AHNAK，TNRC9，S100A11，MYO1C，LDLR，KIAA0102SCYE1，LARP，GNA11，NDUFA7，CKAP1，KPNA1，NDUFS7，AHNAK, TNRC9, S100A11, MYO1C, LDLR, KIAA0102SCYE1, LARP, GNA11, NDUFA7, CKAP1, KPNA1, NDUFS7,

RDH11，RAP140，MTCH2，HPGD，ITGB4BP，CLDN7，CGI-147，GTF21RD1，LRRFIP1，DAB2，DKFZp667G2110，LGALS8，RDH11, RAP140, MTCH2, HPGD, ITGB4BP, CLDN7, CGI-147, GTF21RD1, LRRFIP1, DAB2, DKFZp667G2110, LGALS8,

MARS，MGC14480，MGC3038，PLXNB2，ZFP36L1，DBI，AP2B1，PLS1，CYC1，PPIF，COL3A1，PDHB，NSAP1，PFDN2，MARS, MGC14480, MGC3038, PLXNB2, ZFP36L1, DBI, AP2B1, PLS1, CYC1, PPIF, COL3A1, PDHB, NSAP1, PFDN2,

GAS2L1，DMBT1，FZD1，GBA，DNCL2A，VCP，MYO1B，ANXA8，C11orf13，DSS1，KIF13B，CECR5，GARS，COPB，GAS2L1, DMBT1, FZD1, GBA, DNCL2A, VCP, MYO1B, ANXA8, C11orf13, DSS1, KIF13B, CECR5, GARS, COPB,

NFE2L1，DLG3，FLJ12443，NALP2，APM2，KIAA0790，CIS，HNI，GALNT6，CLPP，STK24，PP3111，MTA1，CAMTA2，NFE2L1, DLG3, FLJ12443, NALP2, APM2, KIAA0790, CIS, HNI, GALNT6, CLPP, STK24, PP3111, MTA1, CAMTA2,

BAT3，FADD，BC-2，CLOCK，UAP1，AAK1，MGC3121，CD14，CDC2L5，FYCO1，SQSTM1，UBE3B，CSPG2，EIF5，DEFB1，BAT3, FADD, BC-2, CLOCK, UAP1, AAK1, MGC3121, CD14, CDC2L5, FYCO1, SQSTM1, UBE3B, CSPG2, EIF5, DEFB1,

MTMR6，KIAA0643，101F6，SLC35A2，TNKS2，TPMT，WWP1，LHFPL2，NEDD8，PC326，PTK2，FLJ20748，FOXA1，IDE，MTMR6, KIAA0643, 101F6, SLC35A2, TNKS2, TPMT, WWP1, LHFPL2, NEDD8, PC326, PTK2, FLJ20748, FOXA1, IDE,

FLJ20275，CACNB3，CDC42，TEX27，KIF3B，PP3501，CDCP1，HNRPU，TULIP1，SPARC，DVL1，GMDS，EZF-2，AP2S1，FLJ20275, CACNB3, CDC42, TEX27, KIF3B, PP3501, CDCP1, HNRPU, TULIP1, SPARC, DVL1, GMDS, EZF-2, AP2S1,

GNA11，SEMA4C，WT1，KIAA0010，LAMA5，PTDSR，ETFB，K1AA0284，TFF3，GRHPR，RPL37A，G1P2，MGC11242，GNA11, SEMA4C, WT1, KIAA0010, LAMA5, PTDSR, ETFB, K1AA0284, TFF3, GRHPR, RPL37A, G1P2, MGC11242,

FLJ23189，FKBP9，MGC35048，RTN1，ASL，PTK9，THBS2，SDHC，H1S1，DSTN，MGC3047，PAFAH1B1，AGPAT1，PGM3，FLJ23189, FKBP9, MGC35048, RTN1, ASL, PTK9, THBS2, SDHC, H1S1, DSTN, MGC3047, PAFAH1B1, AGPAT1, PGM3,

AKR7A3，COL1A1，KIAA0436，GD11，CYR61，RNPEP，SGPL1，APBA3，GNB2，SOCS5，FGFR3，RGS19IP1，ORC5L，AKR7A3, COL1A1, KIAA0436, GD11, CYR61, RNPEP, SGPL1, APBA3, GNB2, SOCS5, FGFR3, RGS19IP1, ORC5L,

SLC6A14，KI1AA0229，FLJ22028，LAMP1，SNRPD3，MAPK13，DNAJA3，FLJ22471，CKMT1，PSMB4，CCL22，CLU，SLC6A14, KI1AA0229, FLJ22028, LAMP1, SNRPD3, MAPK13, DNAJA3, FLJ22471, CKMT1, PSMB4, CCL22, CLU,

CD163，ANXA3，ATOX1，GTF2E2，ANXA6，FLJ21127，BMPR1A，WBSCR20C，MBLL39，IL4R，SEC24D，SLC19A2，CD163, ANXA3, ATOX1, GTF2E2, ANXA6, FLJ21127, BMPR1A, WBSCR20C, MBLL39, IL4R, SEC24D, SLC19A2,

RNASEHIALAS1，ACAA1，DPM3，ABL1，TUBB4，EFNB2，CALR，ARPC1B，MCP，SH3GL1，ECT2，LOC51619，NEK11，RNASEHIALAS1, ACAA1, DPM3, ABL1, TUBB4, EFNB2, CALR, ARPC1B, MCP, SH3GL1, ECT2, LOC51619, NEK11,

MAFB，EFEMP1，G10，DPP7，FUT2，ATP6V0E，SLC22A5，SSH-3，SYNE-2，PH-4，CTBP2，BATF，PDE4DIP，TRIP6，P2Y5，MAFB, EFEMP1, G10, DPP7, FUT2, ATP6V0E, SLC22A5, SSH-3, SYNE-2, PH-4, CTBP2, BATF, PDE4DIP, TRIP6, P2Y5,

RNASE4，CANX，CD2AP，HIP1R，FH，ADCY2，SPUVE，FLJ10462，QSCN6，CLTA，SLC31A1，DEPP，CLTB，K1AA0544，RNASE4, CANX, CD2AP, HIP1R, FH, ADCY2, SPUVE, FLJ10462, QSCN6, CLTA, SLC31A1, DEPP, CLTB, K1AA0544,

CTSB，MARS，PAK4，PHIP，HIP2，FLJ23375，ARHGAP8，TNFRSF12A，KRT8，UBE2V1，PDPK1，KIAA0251，PPGB，GAS1，CTSB, MARS, PAK4, PHIP, HIP2, FLJ23375, ARHGAP8, TNFRSF12A, KRT8, UBE2V1, PDPK1, KIAA0251, PPGB, GAS1,

RAD17，PIAS3，37872.00，ABCA1，FLJ10375，KIAA0217，SPR，GRN，EIF2B4，ITGB5，RPN1，APLP2，WDR1，SDC1，RAD17, PIAS3, 37872.00, ABCA1, FLJ10375, KIAA0217, SPR, GRN, EIF2B4, ITGB5, RPN1, APLP2, WDR1, SDC1,

MGC2963，PM5，MGC5178，TBCE，EEF1D，SGP28，FEM1B，FLJ10829，FLRT2，KIAA0934，PCDHGC3，COPS6，PART1，MGC2963, PM5, MGC5178, TBCE, EEF1D, SGP28, FEM1B, FLJ10829, FLRT2, KIAA0934, PCDHGC3, COPS6, PART1,

ACACA，AMPH，LUM，FLJ23338，EPHB4，FBP1，WSB2，HBP1，EVA1，MUS81，POLR2K，KIAA0103，HPS1，LOC55831，ACACA, AMPH, LUM, FLJ23338, EPHB4, FBP1, WSB2, HBP1, EVA1, MUS81, POLR2K, KIAA0103, HPS1, LOC55831,

FEM1C，RIN2，DKFZP564O092，ENDOFIN，DHCR24，FLJ20604，LOC90141，PCDH7，SLC7A7，SLC12A2，FLJ21047，FEM1C, RIN2, DKFZP564O092, ENDOFIN, DHCR24, FLJ20604, LOC90141, PCDH7, SLC7A7, SLC12A2, FLJ21047,

S100A11P，CG1-115，TOM1L1，C1orf34，SOX9，MB，EIF4EL3，S100A8，APLP2，TDP1，FGF13，URG4，RARRES3，S100A11P, CG1-115, TOM1L1, C1orf34, SOX9, MB, EIF4EL3, S100A8, APLP2, TDP1, FGF13, URG4, RARRES3,

FLJ12910，DAP，RFX5，MVP，FLJ21749，PAXIP1L，FLJ20152，ATF71P，GPSN2，RIL，VEGF，TM4SF6，SPP1，NVL，CALR，FLJ12910, DAP, RFX5, MVP, FLJ21749, PAXIP1L, FLJ20152, ATF71P, GPSN2, RIL, VEGF, TM4SF6, SPP1, NVL, CALR,

CKAP1，AKAP1，HSPC166，TMPRSS3，TM9SF1，LOC56902，ENT3，GRB2，COG5，DOC1，COL5A2，RLN2，GRN，ADCY9，CKAP1, AKAP1, HSPC166, TMPRSS3, TM9SF1, LOC56902, ENT3, GRB2, COG5, DOC1, COL5A2, RLN2, GRN, ADCY9,

KIAA0690，ENPP2，ILF1，SLC35A3，SLC39A1，C20orf11，PCDHGA1，CGI-148，WBSCR20A，CSGlcA-T，KIAA0937，KIAA0690, ENPP2, ILF1, SLC35A3, SLC39A1, C20orf11, PCDHGA1, CGI-148, WBSCR20A, CSGlcA-T, KIAA0937,

KIAA0674，LTBP1，H2BFT，SEMA3C，SULT1A1，ERP70，KIAA1078，KIAA0869，PLA2G12，PACE-1，KIAA0984，AUP1，KIAA0674, LTBP1, H2BFT, SEMA3C, SULT1A1, ERP70, KIAA1078, KIAA0869, PLA2G12, PACE-1, KIAA0984, AUP1,

RBSK，AMOTL2，SULT1A3，LANCL2，PAIP1，JUP，PPP3CB，KYNU，SH120，PRKCI，ARG2，OSBPL2，APOL6，GATM，RBSK, AMOTL2, SULT1A3, LANCL2, PAIP1, JUP, PPP3CB, KYNU, SH120, PRKCI, ARG2, OSBPL2, APOL6, GATM,

LOC113251，GM2A，FLJ12436，CD24，SYNGR3，HSPA1A，CTNND1，SEC61A1，IFRD2，PCK2，PSMA3，COL6A1，LOC113251, GM2A, FLJ12436, CD24, SYNGR3, HSPA1A, CTNND1, SEC61A1, IFRD2, PCK2, PSMA3, COL6A1,

ARHGEF5，RAI，VPS45A，BECN1，GNPI，PA200，PXF，BZW1，KIAA0876，KIAA0471，ATP6VID，CRYM，KCNS3，FARP1，ARHGEF5, RAI, VPS45A, BECN1, GNPI, PA200, PXF, BZW1, KIAA0876, KIAA0471, ATP6VID, CRYM, KCNS3, FARP1,

ANK1，FLJ20234，PLU-1，NPCI，ZNF339，RNF14，RBPMS，SEC13L1，KIAA1630，SIX2，SGSH，RPA3，VLDLR，ENPP1，ANK1, FLJ20234, PLU-1, NPCI, ZNF339, RNF14, RBPMS, SEC13L1, KIAA1630, SIX2, SGSH, RPA3, VLDLR, ENPP1,

ITSN1，AP2B1，ARHC，SWAP2，UBE1，MARK4，MK-STYX，HDLBP，ZNF185，KIAA0227，GOLGA3，KIAA0033，RAB26，ITSN1, AP2B1, ARHC, SWAP2, UBE1, MARK4, MK-STYX, HDLBP, ZNF185, KIAA0227, GOLGA3, KIAA0033, RAB26,

SHANK2，ALDH3A2，DCN，HT008，PLAB，IMPDH1，GRIT，FARP1，MAPK13，ERBB2，TGOLN2，RALA，ARHE，ABCF2，SHANK2, ALDH3A2, DCN, HT008, PLAB, IMPDH1, GRIT, FARP1, MAPK13, ERBB2, TGOLN2, RALA, ARHE, ABCF2,

PRSS11，PLCD1，HSPC111，TRIM29，ARL1，ACTN4，MUC1，DJ434O14.5，FLJ11619，SH3GLB1，TCN1，FLJ11149，BIK，PRSS11, PLCD1, HSPC111, TRIM29, ARL1, ACTN4, MUC1, DJ434O14.5, FLJ11619, SH3GLB1, TCN1, FLJ11149, BIK,

ZNF91，PRSS8，CYB5R1，TRIM16，EPS15R，NARF，SLC11A2，AUTS2，LIM，SLC1A1，ALDH7A1，TC10，SC65，IRF7，ZNF91, PRSS8, CYB5R1, TRIM16, EPS15R, NARF, SLC11A2, AUTS2, LIM, SLC1A1, ALDH7A1, TC10, SC65, IRF7,

HLXB9，RAB17，KIAA0746，PCDHGC3，APOC1，AKAP1，EPS8R1，TBCC，DDAH2，TYROBP，N33，FLNB，HLXB9, RAB17, KIAA0746, PCDHGC3, APOC1, AKAP1, EPS8R1, TBCC, DDAH2, TYROBP, N33, FLNB,

DKFZp564A176，PRE13，JAG2，UGCG，OSR2，KRT6B，CDc42EP4，TPD52，C20of149，FLJ12975，MAN2A1，GCN5L1，DKFZp564A176, PRE13, JAG2, UGCG, OSR2, KRT6B, CDc42EP4, TPD52, C20of149, FLJ12975, MAN2A1, GCN5L1,

MCF2L，FLJ22386，STHM，RAB26，AP1S1，GMPPB，CYP2B6，F-LAN-1，PRKCZ，DC-TM4F2，KIAA0556，FLJ12619，MCF2L, FLJ22386, STHM, RAB26, AP1S1, GMPPB, CYP2B6, F-LAN-1, PRKCZ, DC-TM4F2, KIAA0556, FLJ12619,

CD163，DAZAP1，TIMM13，MADH2，COL4A5，POGK，FXC1，POP4，NET1，ARHGEF5，NS，KMO，PTP4A2，LOC57228，CD163, DAZAP1, TIMM13, MADH2, COL4A5, POGK, FXC1, POP4, NET1, ARHGEF5, NS, KMO, PTP4A2, LOC57228,

MUC5B，AUH，BAIAP3，SFMBT，CD44，BYSL，FLJ20085，PARG1，C4.4A，PSMD4，GSK3B，PSMD12，EIF2AK3，SCARB1，MUC5B, AUH, BAIAP3, SFMBT, CD44, BYSL, FLJ20085, PARG1, C4.4A, PSMD4, GSK3B, PSMD12, EIF2AK3, SCARB1,

DP1，STRN3，FLJ23263，CTSD，HSGP25L2G，TFIP11，MPZL1，SNAPC3，RBM3，PP591，TGFB1I1，GRHPR，AHR，DP1, STRN3, FLJ23263, CTSD, HSGP25L2G, TFIP11, MPZL1, SNAPC3, RBM3, PP591, TGFB1I1, GRHPR, AHR,

FLJ12389，SORT1，KDELR3，ATP6V0C，MD-1，D8S2298E，XAP135，HSPC023，C9orf7，C21orf97，DNCH1，ZNF36，FLJ12389, SORT1, KDELR3, ATP6V0C, MD-1, D8S2298E, XAP135, HSPC023, C9orf7, C21orf97, DNCH1, ZNF36,

PPP1R7，VIL2，RAB2，MYH9，TRIM14，UGTREL1，CTSL，KIAA0977，RPC62，UBE2N，DCAMKL1，FUCA1，ATP7B，PPP1R7, VIL2, RAB2, MYH9, TRIM14, UGTREL1, CTSL, KIAA0977, RPC62, UBE2N, DCAMKL1, FUCA1, ATP7B,

RBSK，ST5，CGI-90，NOH61，FLJ10925，RAB22A，RTN2，KIAA0089，SH3GLB1，CDS1，MGC5466，WFS1，AMMECR1，RBSK, ST5, CGI-90, NOH61, FLJ10925, RAB22A, RTN2, KIAA0089, SH3GLB1, CDS1, MGC5466, WFS1, AMMECR1,

COX17，ACOX2，FLJ10101，HT012，LMNA，PRDX2，SULF1，KIAA0923，FLJ22637，SCA1，PAIP1，CAP2，CMT2，ZNF217，COX17, ACOX2, FLJ10101, HT012, LMNA, PRDX2, SULF1, KIAA0923, FLJ22637, SCA1, PAIP1, CAP2, CMT2, ZNF217,

CYB561，PAPSS2，STX18，FZD4，DDXx，UBAP1，ITPKC，PTS，PGLS，LAD1，DSC2，STOML1，DDX16，PTP4A1，CYB561, PAPSS2, STX18, FZD4, DDXx, UBAP1, ITPKC, PTS, PGLS, LAD1, DSC2, STOML1, DDX16, PTP4A1,

FLJ10901，SLC12A8，NME3，TEM7，NPR2L，ACYI，GNB1，GRN，PLEK2，KRAS2，ARHGAP8，FLJ11856，DCN，FLJ10901, SLC12A8, NME3, TEM7, NPR2L, ACYI, GNB1, GRN, PLEK2, KRAS2, ARHGAP8, FLJ11856, DCN,

LOC55871，NAGK，FLJ14154，FLJ22709，TP53TG1，STK6，COX5B，MICA，EPPK1，EPS8R2，MMP19，WWP1，TUBG1，LOC55871, NAGK, FLJ14154, FLJ22709, TP53TG1, STK6, COX5B, MICA, EPPK1, EPS8R2, MMP19, WWP1, TUBG1,

LBP，ATP10B，CLN3，UBE2G1，SULF1，FLJ30002，SYN47，CSPG2，CACNB3，IGFBP3ELOVL1，DTNA，ANK1，C12orf22，LBP, ATP10B, CLN3, UBE2G1, SULF1, FLJ30002, SYN47, CSPG2, CACNB3, IGFBP3ELOVL1, DTNA, ANK1, C12orf22,

EPN3，IDE，DKFZp761F2014，SEC22L1，ILF2，ACTR1A，FLJ10052，STAT3，CED-6，FLJ10359，SOX9，PIASY，KIAA1169，EPN3, IDE, DKFZp761F2014, SEC22L1, ILF2, ACTR1A, FLJ10052, STAT3, CED-6, FLJ10359, SOX9, PIASY, KIAA1169,

CAV1，HOXB2，FLJ22191，LOC57117，PMVK，BLNK，TREM1，HSRTSBETA，EIF4EBPI，SIGIRR，TSLRP，C20orf44，CAV1, HOXB2, FLJ22191, LOC57117, PMVK, BLNK, TREM1, HSRTSBETA, EIF4EBPI, SIGIRR, TSLRP, C20orf44,

PTD009，PP1665，HMG20B，RTCD1，PDE8A，CNNM2，GNA11，GPX2，KIAA0599，FLJ13868，DBN1，GEMIN6，PMM2，PTD009, PP1665, HMG20B, RTCD1, PDE8A, CNNM2, GNA11, GPX2, KIAA0599, FLJ13868, DBN1, GEMIN6, PMM2,

SPTAN1，PFN1，DCTN1，UBE2A，GPR107，MRPS2，SNARK，SSA1，SH120，UBPH，CPD，HOXC6，DXS9928E，TEAD3，SPTAN1, PFN1, DCTN1, UBE2A, GPR107, MRPS2, SNARK, SSA1, SH120, UBPH, CPD, HOXC6, DXS9928E, TEAD3,

PGBD5，ST14，CNN3，KIAA0256，MGC3262，FLJ13840，CLDN4，FLJ11939，ABCA3，OAZIN，MRPL17，PPP2R4，CGI-135，PGBD5, ST14, CNN3, KIAA0256, MGC3262, FLJ13840, CLDN4, FLJ11939, ABCA3, OAZIN, MRPL17, PPP2R4, CGI-135,

KIAA0802，AP1M2，SCN10A，PPIB，MRPL40，ZK1，FLJ12517，CDH11，CDC42EP2，CLN3，CG1-152，FLJ10815，C11orf13，KIAA0802, AP1M2, SCN10A, PPIB, MRPL40, ZK1, FLJ12517, CDH11, CDC42EP2, CLN3, CG1-152, FLJ10815, C11orf13,

MADH1，FLJ20539，HMGE，KIAA0923，LAP1B，PTGDS，FLJ20559，SFXN1，KRTHB6，UNC13，MUC4，FUT8，NET1，MADH1, FLJ20539, HMGE, KIAA0923, LAP1B, PTGDS, FLJ20559, SFXN1, KRTHB6, UNC13, MUC4, FUT8, NET1,

NEBL，BCS1L，RAI16，CAV2，FAAH，CEACAM1，LEF1，GALNT10，NAGA，ABHD3，STOML2，C1orf27，OSTF1，NEBL, BCS1L, RAI16, CAV2, FAAH, CEACAM1, LEF1, GALNT10, NAGA, ABHD3, STOML2, C1orf27, OSTF1,

KIAA0227，PCLO，MYO10，THBS1，LANO，HMCS，H3FK，SPS，C9orf9，PITPN，SCR1B，PAM，NPDC1，ASNS，SLC33A1，KIAA0227, PCLO, MYO10, THBS1, LANO, HMCS, H3FK, SPS, C9orf9, PITPN, SCR1B, PAM, NPDC1, ASNS, SLC33A1,

HSPA6，HMBS，FLJ21918，FLJ11939，C6orf29，PRSS15，ENC1，HTR4，SSH-3，RECK，NAV2，TRN-SR，MRS2L，FLJ20366，HSPA6, HMBS, FLJ21918, FLJ11939, C6orf29, PRSS15, ENC1, HTR4, SSH-3, RECK, NAV2, TRN-SR, MRS2L, FLJ20366,

LOC51754，LGALS8，KIAA1040，B4GALT1，FLJ21841，KIAA0237，IL8RA，MLF1，ANXA9，VRP，LOXL2，MIR，ATP5D，LOC51754, LGALS8, KIAA1040, B4GALT1, FLJ21841, KIAA0237, IL8RA, MLF1, ANXA9, VRP, LOXL2, MIR, ATP5D,

KIAA0632，FLJ20174，FRAT2，DDX26，BCKDK，ATP6V0A4，KIF1B，ENTPD3，RAB1A，EGLN1，KIAA0268，LGMN，KIAA0632, FLJ20174, FRAT2, DDX26, BCKDK, ATP6V0A4, KIF1B, ENTPD3, RAB1A, EGLN1, KIAA0268, LGMN,

PTPRH，KMO，UGCGL1，AKR7A3，RIG-1，CYB5R2，FLJ11773，RPS6KA2，CLCN3，PTPN18，GNG12，PKP3，ALDH1A2，PTPRH, KMO, UGCGL1, AKR7A3, RIG-1, CYB5R2, FLJ11773, RPS6KA2, CLCN3, PTPN18, GNG12, PKP3, ALDH1A2,

NEK3，UQCRC1，ZNF236，RASAL1，RPL14，FLJ12287，AP1M2，C4BPA，MAF，FLJ10815，FLJ90798，TRAM，POLR2J，NEK3, UQCRC1, ZNF236, RASAL1, RPL14, FLJ12287, AP1M2, C4BPA, MAF, FLJ10815, FLJ90798, TRAM, POLR2J,

TLN2，DNASE2，PEX11A，KJAA0790，TM4SF3，HPGD，TRIP10，THY1，CGI-143，TPR，AQR，CTNND1，HOXC10，TLN2, DNASE2, PEX11A, KJAA0790, TM4SF3, HPGD, TRIP10, THY1, CGI-143, TPR, AQR, CTNND1, HOXC10,

CDC42EP4，PLEC1，PSFL，PTP4A1，FLJ22353，NCALD，INPP5E，MKRN4，PAD12，SMARCA1，KIAA0317，EHD1，AZGP1，CDC42EP4, PLEC1, PSFL, PTP4A1, FLJ22353, NCALD, INPP5E, MKRN4, PAD12, SMARCA1, KIAA0317, EHD1, AZGP1,

SMARCA1，NOVA1，MRPS11，FLJ23091，HOXC4，OCRL，CKAP4，CD44，CD2BP2，FLJ10055，TM7SF1，PVRL2，1D4，SMARCA1, NOVA1, MRPS11, FLJ23091, HOXC4, OCRL, CKAP4, CD44, CD2BP2, FLJ10055, TM7SF1, PVRL2, 1D4,

DJ434O14.5，SLC7A8，DKFZP5641122，MIPEP，PLA2G4C，KPNB2，DAXX，NOS1，ID3，MRC2，SSSCA1，PPPIR14B，DJ434O14.5, SLC7A8, DKFZP5641122, MIPEP, PLA2G4C, KPNB2, DAXX, NOS1, ID3, MRC2, SSSCA1, PPPIR14B,

MTHFS，HSPA5，ELF5，MARCKS，KIAA0514，RRAS2，ADRM1，ANK1，KIAA1324，PSEN2，UBXD2，CALU，DOK5，MTHFS, HSPA5, ELF5, MARCKS, KIAA0514, RRAS2, ADRM1, ANK1, KIAA1324, PSEN2, UBXD2, CALU, DOK5,

KCNMA1，COL9A2，ATP2C1，FGFR2，DPM2，KIAA0895，DPH2L1，MUC5B，SSR1，LOC113146，KIAA0644，LOC51042，KCNMA1, COL9A2, ATP2C1, FGFR2, DPM2, KIAA0895, DPH2L1, MUC5B, SSR1, LOC113146, KIAA0644, LOC51042,

DNAL4，PIG3，GPS2，CX3CL1，INHBC，CIQB，PDPK1，RPLP2，HRI，MGC4825，TGFBR3，LAMC2，PEX7，HFE，DNAL4, PIG3, GPS2, CX3CL1, INHBC, CIQB, PDPK1, RPLP2, HRI, MGC4825, TGFBR3, LAMC2, PEX7, HFE,

DJ434O14.5，FLJ20296，MGC5347，FLJ10521，RARA，KLC2，SLC21A2，SPTAN1，APOC1，LARGE，STK38，GCC1，SNX13，DJ434O14.5, FLJ20296, MGC5347, FLJ10521, RARA, KLC2, SLC21A2, SPTAN1, APOC1, LARGE, STK38, GCC1, SNX13,

TNNT1，NTRK3，TGIF，H3FH，KIAA0485，KIAA1416，EFEMP2，SMARCE1，KREMEN2，UMPK，KIAA0268，DDEF2，TNNT1, NTRK3, TGIF, H3FH, KIAA0485, KIAA1416, EFEMP2, SMARCE1, KREMEN2, UMPK, KIAA0268, DDEF2,

VAMP3，CGTHBA，OSBPL10，CG1-96，MGC3248，TUBB-5，PXMP3，RBM9，LOC51257，LAMC1，SLC30A5，PPARD，VAMP3, CGTHBA, OSBPL10, CG1-96, MGC3248, TUBB-5, PXMP3, RBM9, LOC51257, LAMC1, SLC30A5, PPARD,

KIAA0349，MAP4K4，GNG4，CCL3，GPRC5C，CCRIDKFZP586B0923，RNF10，SCGB1D2，VIPR1，RGL，TESK1，AK3，KIAA0349, MAP4K4, GNG4, CCL3, GPRC5C, CCRIDKFZP586B0923, RNF10, SCGB1D2, VIPR1, RGL, TESK1, AK3,

KIAA0649，SCARB2，MGC2494，FLJ20048，EPS8，DNAJC1，MOB，FLJ11200，CDIC，AGPAT1，FBLN1，GW112，ICT1，KIAA0649, SCARB2, MGC2494, FLJ20048, EPS8, DNAJC1, MOB, FLJ11200, CDIC, AGPAT1, FBLN1, GW112, ICT1,

CG1-141，DSCR1，PIP5K1C，PRY，ALP，PRDM4，PLAC1，ISG20，FLJ20457，TCF-3，PTE1，TNK1，MAGED1，FLJ13782，CG1-141, DSCR1, PIP5K1C, PRY, ALP, PRDM4, PLAC1, ISG20, FLJ20457, TCF-3, PTE1, TNK1, MAGED1, FLJ13782,

NPD009，UCHL3，PRELP，LOC55893，KIAA0451，AK1，LMCD1，NET-7，AP3B1，OS4，AB1-2，NOTCH3，KRT9，COPZ2，NPD009, UCHL3, PRELP, LOC55893, KIAA0451, AK1, LMCD1, NET-7, AP3B1, OS4, AB1-2, NOTCH3, KRT9, COPZ2,

CG1-58，RISC，DKFZP566C243，ATP6V1C1，TRIM38，PTOV1，PDGFB，PIP，IDN3，FLJ10199，BCAT2，HOXA11，PDXK，CG1-58, RISC, DKFZP566C243, ATP6V1C1, TRIM38, PTOV1, PDGFB, PIP, IDN3, FLJ10199, BCAT2, HOXA11, PDXK,

NEDD4L，MGC29816，TPD52，TMPRSS4，HAIK1，SUPT4H1，WNT5A，PCSK7，ANK1，FCERIG，FLJ13397，EROIL，NEDD4L, MGC29816, TPD52, TMPRSS4, HAIK1, SUPT4H1, WNT5A, PCSK7, ANK1, FCERIG, FLJ13397, EROIL,

BPGM，HLA-DQA1，DCXR，KIAA1094，NEO1，FKBP4，SMARCD3，TPSG1，FLJ21940，APBA2BP，TMPRSS6，TBC1D1，BPGM, HLA-DQA1, DCXR, KIAA1094, NEO1, FKBP4, SMARCD3, TPSG1, FLJ21940, APBA2BP, TMPRSS6, TBC1D1,

MS4A6A，U2AF1RS2，MGC11308，MRPL23，PCDHA12，SMA3，CELSR3，SLC22A4，MGEA6，ICAI，STX4A，EFS2，MS4A6A, U2AF1RS2, MGC11308, MRPL23, PCDHA12, SMA3, CELSR3, SLC22A4, MGEA6, ICAI, STX4A, EFS2,

RRP22，X123，GBA，DNAJB1，TGFB3，CRAT，FLJ11159，TMEM8，GALE，FLJ20555，DDX3，TULP3，TACC2，SLC6A8，RRP22, X123, GBA, DNAJB1, TGFB3, CRAT, FLJ11159, TMEM8, GALE, FLJ20555, DDX3, TULP3, TACC2, SLC6A8,

C3AR1，BSCL2，TRIM2，ELF3，SPTBN5，SERPINB8，FLJ23259，TNFRSF6，MIPEP，CELSR2，LDB1，MOG1，PXF，HPIP，C3AR1, BSCL2, TRIM2, ELF3, SPTBN5, SERPINB8, FLJ23259, TNFRSF6, MIPEP, CELSR2, LDB1, MOG1, PXF, HPIP,

HMOX2，SURB7，HRIHFB2122，FLJ22056，CLASP2，IF，HSKM-B，UPKIB，WDR10，IQGAP1，PSPHL，DUSP4，FLJ10856，HMOX2, SURB7, HRIHFB2122, FLJ22056, CLASP2, IF, HSKM-B, UPKIB, WDR10, IQGAP1, PSPHL, DUSP4, FLJ10856,

RARRES1，ALAD，PARVA，KIAA0608，DNPEP，GMPPA，PLJ20254，IDE，COL5A1，GFER，PSMA7，FLJ11017，ZNF144，RARRES1, ALAD, PARVA, KIAA0608, DNPEP, GMPPA, PLJ20254, IDE, COL5A1, GFER, PSMA7, FLJ11017, ZNF144,

MYC，PEX14，CCR5，ARL1，NME5，NDUFB7，PPAP2B，C21orf80，CAPG，MRPL52，MIG2，HSPC039，DPH2L2，SRD5A1，MYC, PEX14, CCR5, ARL1, NME5, NDUFB7, PPAP2B, C21orf80, CAPG, MRPL52, MIG2, HSPC039, DPH2L2, SRD5A1,

SDR1，RAB36，SCGB2A1，PRDM4，ASM3A，FRA，GLUD1，FLJ13187，CARM1，RPS6KB2，LOC55565，B3GALT4，SDR1, RAB36, SCGB2A1, PRDM4, ASM3A, FRA, GLUD1, FLJ13187, CARM1, RPS6KB2, LOC55565, B3GALT4,

ALOX5AP，PLAU，DMN，DFNA5，CGI-36，TC10，SLC38A6，KIAA0852，CRJP2，HSPC003，NSFLIC，FLJ20605，GPC1，ALOX5AP, PLAU, DMN, DFNA5, CGI-36, TC10, SLC38A6, KIAA0852, CRJP2, HSPC003, NSFLIC, FLJ20605, GPC1,

FLJ10504，MKLN1，TIP-1，SCAM-1，IL13RA1，UPLC1，FLJ20171，LOC88523，HSD17B2，MYOIB，ZNF364，CDK7，MAP7，FLJ10504, MKLN1, TIP-1, SCAM-1, IL13RA1, UPLC1, FLJ20171, LOC88523, HSD17B2, MYOIB, ZNF364, CDK7, MAP7,

PCOLCE，IL13RA1，SSNA1，ESRRA，CPS1，APOE，MY014，CHK，THBS3，DAB2，PCMT1，MAP7，SLC7A4，APPD，ITCH，PCOLCE, IL13RA1, SSNA1, ESRRA, CPS1, APOE, MY014, CHK, THBS3, DAB2, PCMT1, MAP7, SLC7A4, APPD, ITCH,

KIAA0255，BCMP1，AKAP9，SNCAIP，MRPS7，PIGPC1，HIVEP1，SLC6A8，DKFZP564O0823，CRK，BAIAP2，SLC7A11，KIAA0255, BCMP1, AKAP9, SNCAIP, MRPS7, PIGPC1, HIVEP1, SLC6A8, DKFZP564O0823, CRK, BAIAP2, SLC7A11,

CPE，MPZL1，TDO2，FUT1，STAB2，CDKN2A，CG1-12，TPM4，IL1RN，MGC4504，K1AA1395，COQ7，CARHSP1，PARVA，CPE, MPZL1, TDO2, FUT1, STAB2, CDKN2A, CG1-12, TPM4, IL1RN, MGC4504, K1AA1395, COQ7, CARHSP1, PARVA,

FLNC，C11orf24，NPR2L，GFPT1，ARVCF，CAPN9，SRRM2，NBL1，KIAA1078，SURF5，ARHGEF4，F23149_1，FKBP11，FLNC, C11orf24, NPR2L, GFPT1, ARVCF, CAPN9, SRRM2, NBL1, KIAA1078, SURF5, ARHGEF4, F23149_1, FKBP11,

K1AA1102，IGF1，RBT1，HNOEL-iso，LAMB2，DKFZp566O084，FGB，GPNMB，TLR5，CX3CR1，THBS1，GORASP1，K1AA1102, IGF1, RBT1, HNOEL-iso, LAMB2, DKFZp566O084, FGB, GPNMB, TLR5, CX3CR1, THBS1, GORASP1,

HCA112，AQP3，BDKRB2，SLC4A7，CLTB，MRPS18A，CTSK，CELSR2，KIAA0652，NKX3-1，MXD4，ALDH4A1，DYSF，HCA112, AQP3, BDKRB2, SLC4A7, CLTB, MRPS18A, CTSK, CELSR2, KIAA0652, NKX3-1, MXD4, ALDH4A1, DYSF,

ECGF1，DCN，PSME3，TIMP2，HOXB6，EGFR-RS，EPS8R1，ECM1，LTBP2，PRPS1，CDA08，HUMAUANTIG，MGC955，ECGF1, DCN, PSME3, TIMP2, HOXB6, EGFR-RS, EPS8R1, ECM1, LTBP2, PRPS1, CDA08, HUMAUANTIG, MGC955,

FLJ22678，LAMA4，GLUL，MAGED2，HES2，FASN，CYB561，IDH3A，MPPE1，PRKARIA，KDR，DICER1，PROCR，FLJ22678, LAMA4, GLUL, MAGED2, HES2, FASN, CYB561, IDH3A, MPPE1, PRKARIA, KDR, DICER1, PROCR,

TNFSF10，HAGH，FBXO3，TC10，PRKARIA，ZNF20，AK1，ALDH3A2，FSTL3，ZNF408，PTP4A1，PMS2L9，BAG1，TNFSF10, HAGH, FBXO3, TC10, PRKARIA, ZNF20, AK1, ALDH3A2, FSTL3, ZNF408, PTP4A1, PMS2L9, BAG1,

DKFZp667G2110，MUC2，KIAA0265，ZFP100，KCNK1，IF135，THY1，FLJ23186，H2BFG，ARSA，KRT15，ICA1，FLNA，DKFZp667G2110, MUC2, KIAA0265, ZFP100, KCNK1, IF135, THY1, FLJ23186, H2BFG, ARSA, KRT15, ICA1, FLNA,

BPHL，PCTK1，TUBA2，KRT17，SHANK2，CEACAMIGAK，VARS2，AGTR1，ASB8，MPZL1，RFPL3，DNMIL，SPUF，BPHL, PCTK1, TUBA2, KRT17, SHANK2, CEACAMIGAK, VARS2, AGTR1, ASB8, MPZL1, RFPL3, DNMIL, SPUF,

KIAA0792，NUCKS，C1R，HRASLS3，TM4SF6，SPINT1，XT3，SLC16A5，FLJ21079，MST1，MMP9，DKFZP434B044，NY-KIAA0792, NUCKS, C1R, HRASLS3, TM4SF6, SPINT1, XT3, SLC16A5, FLJ21079, MST1, MMP9, DKFZP434B044, NY-

REN-24，ALDH1A3，NID2，KIAA0409，ANKRD5，KIAA0513，U2AF1RS2，IGF2R，H2BFL，FUT3，LEC2，LY6E，CSH2，REN-24, ALDH1A3, NID2, KIAA0409, ANKRD5, KIAA0513, U2AF1RS2, IGF2R, H2BFL, FUT3, LEC2, LY6E, CSH2,

SRCAP，DKFZp434G2311，CHST4，PPP2R1B，PVALB，FLJ12960，ITPR3，PODXL，PARD3，PRSS22，FLJ10697，MGC2376，SRCAP, DKFZp434G2311, CHST4, PPP2R1B, PVALB, FLJ12960, ITPR3, PODXL, PARD3, PRSS22, FLJ10697, MGC2376,

SLC39A4，MRPS16，QPRT，GFRA1，BRD2，CNGB3，LAK，C5orf8，PPP2R3A，HCGH-7，ANK1，OAZ3，PSMC4，ACATE2，SLC39A4, MRPS16, QPRT, GFRA1, BRD2, CNGB3, LAK, C5orf8, PPP2R3A, HCGH-7, ANK1, OAZ3, PSMC4, ACATE2,

DKFZP434L0117，EDAR，PPF1A3，GRB7，MCM3AP，CALB2，APXL，ABI-2，TTR，CSNKID，DJ1042K10.2，TRM38，DKFZP434L0117, EDAR, PPF1A3, GRB7, MCM3AP, CALB2, APXL, ABI-2, TTR, CSNKID, DJ1042K10.2, TRM38,

PSCD2，HSPC134，SREBF1，HUS1，PSK，C12orf5，SPOCK，EDG4，FLJ10769，ANKRD3，FLJ21135，PPP2R4，CED-6，PSCD2, HSPC134, SREBF1, HUS1, PSK, C12orf5, SPOCK, EDG4, FLJ10769, ANKRD3, FLJ21135, PPP2R4, CED-6,

GATA6，MGC10963，ZNF14，CPR2，KIAA1199，HIPIR，NOL3，ZNF306，FLJ14298，RAGE，IDH3A，GPR107，KIAA0368，GATA6, MGC10963, ZNF14, CPR2, KIAA1199, HIPIR, NOL3, ZNF306, FLJ14298, RAGE, IDH3A, GPR107, KIAA0368,

RPA40，ME1S2，PHLDA1，CELSR1，N33，BLZF1，FLJ22637，IL1RL1，GOLGA1，SAR1，FGFR2，FL11，ANK3，SIRT7，RPA40, ME1S2, PHLDA1, CELSR1, N33, BLZF1, FLJ22637, IL1RL1, GOLGA1, SAR1, FGFR2, FL11, ANK3, SIRT7,

BAP29，EFEMP1，FLJ20277，DXS1283E，LAMB1，TLE2，TJP1，PDE8A，RCV1，HYAL2，ERdj5，KIAA0350，CLSTN2，MDK，BAP29, EFEMP1, FLJ20277, DXS1283E, LAMB1, TLE2, TJP1, PDE8A, RCV1, HYAL2, ERdj5, KIAA0350, CLSTN2, MDK,

LOC51762，APOE，KIAA0964，SSH-3，TJP3，ZNF193，PRDX2，PTGDS，TEM7，DNAJB4，POLR2D，DKFZP586J1624，LOC51762, APOE, KIAA0964, SSH-3, TJP3, ZNF193, PRDX2, PTGDS, TEM7, DNAJB4, POLR2D, DKFZP586J1624,

JAM1，LHX3，FLJ10252，K1AA0451，INE2，WIT-1，FLJ23209，CXCL1，RAI2，KIAA0857，FLJ21062，KIAA1096，ARF4L，JAM1, LHX3, FLJ10252, K1AA0451, INE2, WIT-1, FLJ23209, CXCL1, RAI2, KIAA0857, FLJ21062, KIAA1096, ARF4L,

THBS1，RAB31，SS18，NDRG3，TGOLN2，FLJ10665，COL6A3，TAZ，AGRN，PGC，SOX11，MCP，EXTL3，ACRV1，NELL2，THBS1, RAB31, SS18, NDRG3, TGOLN2, FLJ10665, COL6A3, TAZ, AGRN, PGC, SOX11, MCP, EXTL3, ACRV1, NELL2,

MGC4309，LOC114990，KYNU，SNX11，ANGPTL2，CYP2J2，SMURF1，SDCCAG16，BRAF，NFYA，ADD1，LIG3，CAV1，MGC4309, LOC114990, KYNU, SNX11, ANGPTL2, CYP2J2, SMURF1, SDCCAG16, BRAF, NFYA, ADD1, LIG3, CAV1,

BIRC1，TJP3，STEAP，NDUFA2，MYBPC3，C1NP，KIAA1096，ACLY，TUBB，GREB1，MARK3，TEAD4，CG11，UNG2，BIRC1, TJP3, STEAP, NDUFA2, MYBPC3, C1NP, KIAA1096, ACLY, TUBB, GREB1, MARK3, TEAD4, CG11, UNG2,

SLC30A5，FLJ20920，ACAA1，EIF3S10，SEC5，SLC31A2，MGC10993，VEGF，P4HB，TFP12，DKK1，ARPC1A，CHST1，SLC30A5, FLJ20920, ACAA1, EIF3S10, SEC5, SLC31A2, MGC10993, VEGF, P4HB, TFP12, DKK1, ARPC1A, CHST1,

MAF，FLJ90798，K1AA0682，GRP58，CACNA2D2，MAPKAP1，GPR27，ICAM1，RPL39L，CYP1B1，PIGO，KIF5B，MAF, FLJ90798, K1AA0682, GRP58, CACNA2D2, MAPKAP1, GPR27, ICAM1, RPL39L, CYP1B1, PIGO, KIF5B,

HSD11B2，CLDN3，FLJ20255，SNX16，FKBP10，STK23，DRD2，SPA17，FOLR1，WNT16，KIAA1010，FLJ11467，EFNA4，HSD11B2, CLDN3, FLJ20255, SNX16, FKBP10, STK23, DRD2, SPA17, FOLR1, WNT16, KIAA1010, FLJ11467, EFNA4,

H3FB，RAB5C，EHD1，SLC7A11，RHOBTB3，COQ7，SLC21A11，FLJ14827，SPRR1A，PVR，MAST205，CFLAR，PAX6，H3FB, RAB5C, EHD1, SLC7A11, RHOBTB3, COQ7, SLC21A11, FLJ14827, SPRR1A, PVR, MAST205, CFLAR, PAX6,

N33，ADAM10，GNA11，ZFP26，GPR48，KRT4，C2，CRIM1，MGC3121，FLJ23471，GGCX，PPP4C，PAWWR，PTHLH，N33, ADAM10, GNA11, ZFP26, GPR48, KRT4, C2, CRIM1, MGC3121, FLJ23471, GGCX, PPP4C, PAWWR, PTHLH,

KIAA1219，SRP72，ETV6，ALOX15B，SLC24A3，SLC25A4，RDS，DAXX，ICAM1，LOXL1，GMDS，TRAF4，NTHL1，KIAA1219, SRP72, ETV6, ALOX15B, SLC24A3, SLC25A4, RDS, DAXX, ICAM1, LOXL1, GMDS, TRAF4, NTHL1,

LISCH7，GAS2L1，TRIM10，S1AT4A，FLJ22584，SL1，ITGB5，TFPT，CD8A，DSCR1L1，KIAA0779，GPRC5B，PP591，LISCH7, GAS2L1, TRIM10, S1AT4A, FLJ22584, SL1, ITGB5, TFPT, CD8A, DSCR1L1, KIAA0779, GPRC5B, PP591,

SEC31B-1，PPFIBP2，CYP27B1，DOC-1R，COP9，KIAA1193，MSTIR，HBS1L，RARG-1，FZD7，KIAA0626，SMT3H1，SEC31B-1, PPFIBP2, CYP27B1, DOC-1R, COP9, KIAA1193, MSTIR, HBS1L, RARG-1, FZD7, KIAA0626, SMT3H1,

RALGDS，SOX13，FLJ22612，NFE2L1，CST7，KCNJ5，PALMD，KIAA0644，MRPL9，ERCC1，MSTP9，PTPN3，SUPV3L1，RALGDS, SOX13, FLJ22612, NFE2L1, CST7, KCNJ5, PALMD, KIAA0644, MRPL9, ERCC1, MSTP9, PTPN3, SUPV3L1,

GAL3ST-4，SUHW1，PRSS16，C6orf9，PTPRT，CGI-112，TBX3，ARD1，KDELR3，CGA，TSPY，SPAG1，CRELD1，FLJ20967，GAL3ST-4, SUHW1, PRSS16, C6orf9, PTPRT, CGI-112, TBX3, ARD1, KDELR3, CGA, TSPY, SPAG1, CRELD1, FLJ20967,

RNASE1，LRP3，LARP，SOX11，TUL1P1，RORC，HARC，RPL5，FLJ13544，MAP3K12，KIAA1096，PLA2G10，RAB2，RNASE1, LRP3, LARP, SOX11, TUL1P1, RORC, HARC, RPL5, FLJ13544, MAP3K12, KIAA1096, PLA2G10, RAB2,

FLJ12681，FLJ23469，PP1057，MAPT，TMEM4，pSME3，FLJ21963，SGCB，GL13，PRRG2，MYL9，GFR，HOMER-3，FLJ12681, FLJ23469, PP1057, MAPT, TMEM4, pSME3, FLJ21963, SGCB, GL13, PRRG2, MYL9, GFR, HOMER-3,

PDGF：RA，DPP4，D15Wsu75e，KPNA1，SGCD，RABGGTB，MMP24，FGL2，ATF6，STX10，ARHGEF12，UPK1B，EGFR，PDGF: RA, DPP4, D15Wsu75e, KPNA1, SGCD, RABGGTB, MMP24, FGL2, ATF6, STX10, ARHGEF12, UPK1B, EGFR,

MCAM，CYP3A43，FCGR3A，FLJ10534，FLJ12571，FLJ20422，CD80，KIAA1023，C21orf18，H4FH，TEL2，MSCP，PEX10，MCAM, CYP3A43, FCGR3A, FLJ10534, FLJ12571, FLJ20422, CD80, KIAA1023, C21orf18, H4FH, TEL2, MSCP, PEX10,

B4GALT2，ADAMTS5，CSG1cA-T，TNFAIP6，PRKCDBP，TR1P11，PTN，FGD1，NPEPPS，CAPN1，H2BFH，LOC51337，B4GALT2, ADAMTS5, CSG1cA-T, TNFAIP6, PRKCDBP, TR1P11, PTN, FGD1, NPEPPS, CAPN1, H2BFH, LOC51337,

FLJ21736，VAV3，FLJ11198，KIAA0923，NONO，ALDOB，AQP6，FLJ20315，PHLDA1，VDR，KIR3DL7，YBX2，DUSP3，FLJ21736, VAV3, FLJ11198, KIAA0923, NONO, ALDOB, AQP6, FLJ20315, PHLDA1, VDR, KIR3DL7, YBX2, DUSP3,

MGC11271，CHST6，MGC4171，PL6，SH3BGR，SPPL2B，EPHA2，CRYAB，MST1，RGS16，CLPTM1，MD-2，KIAA0152，MGC11271, CHST6, MGC4171, PL6, SH3BGR, SPPL2B, EPHA2, CRYAB, MST1, RGS16, CLPTM1, MD-2, KIAA0152,

PACE4，DKFZp564K142，RALGPS1A，DKFZP564A022，RTN1，LAMB3，PLDI，SERPINB5，ENSA，DKFZP586N0721，PACE4, DKFZp564K142, RALGPS1A, DKFZP564A022, RTN1, LAMB3, PLDI, SERPINB5, ENSA, DKFZP586N0721,

PLAA，FKBP14，LR1G1，RARA，BN51T，PTHR2，PPP1R3C，HSPC002，CNTNAP2，HNF4A，CHI3L2，TGFB2，CGI-58，PLAA, FKBP14, LR1G1, RARA, BN51T, PTHR2, PPP1R3C, HSPC002, CNTNAP2, HNF4A, CHI3L2, TGFB2, CGI-58,

PPF1A1，K1AA0440，PLAUR，SNTB2，ID1，ALOX5，IGF1，OPCML，TAGLN2，UBXD2，M11S1，REPS2，BCHE，SRD5A1，PPF1A1, K1AA0440, PLAUR, SNTB2, ID1, ALOX5, IGF1, OPCML, TAGLN2, UBXD2, M11S1, REPS2, BCHE, SRD5A1,

TED，EIF5，K1AA0595，BA1AP1，K1AA1718，TRA@，STS，C11orf17，ASNA1，MAOA，PTGER3，NPY1R，SMARCA4，TED, EIF5, K1AA0595, BA1AP1, K1AA1718, TRA@, STS, C11orf17, ASNA1, MAOA, PTGER3, NPY1R, SMARCA4,

PGM3，PCTK1，MATN2，FLJ23393，MGC2821，MGC2376，FZD2，SLC7A6，PPAP2C，PHKA1，GOLGA1，WARS，PGM3, PCTK1, MATN2, FLJ23393, MGC2821, MGC2376, FZD2, SLC7A6, PPAP2C, PHKA1, GOLGA1, WARS,

GADD45G，L1V-1，NEK1，C22orf3，VAMP4，C18B11，MGP，KIAA0040，IGLJ3，FLJ21125，BTD，G3BP，CLEC1，NUP98，GADD45G, L1V-1, NEK1, C22orf3, VAMP4, C18B11, MGP, KIAA0040, IGLJ3, FLJ21125, BTD, G3BP, CLEC1, NUP98,

MLN，NRXN3，FBXL7，DLG1，PLA2G5，CYP26A1，OR52A1，DSC3，PPAP2A，C20orf121，UBE2H，EEF1A2，ATP10A，MLN, NRXN3, FBXL7, DLG1, PLA2G5, CYP26A1, OR52A1, DSC3, PPAP2A, C20orf121, UBE2H, EEF1A2, ATP10A,

TFEB，GABRQ，GFPT2，WIG1，FBLNI，PTPRF，MEPE，RAMP3，COL13A1，SLC6A8，PPP1R10，COL18A1，GAC1，EPHX1，TFEB, GABRQ, GFPT2, WIG1, FBLNI, PTPRF, MEPE, RAMP3, COL13A1, SLC6A8, PPP1R10, COL18A1, GAC1, EPHX1,

C11orf9，OSF-2，ETSI，INSIG1，FLJ10111，CEACAM7，DCX，C14orf58，MIRO-2，SRPX，EPHA1，CRK，CPE，TIMM17A，C11orf9, OSF-2, ETSI, INSIG1, FLJ10111, CEACAM7, DCX, C14orf58, MIRO-2, SRPX, EPHA1, CRK, CPE, TIMM17A,

LCN7，CENTG2，FLJ10534，C6orf18，FLJ12671，VEGF，SPANXA1，MECP2，EPHB3，TSTA3，ILVBL，F7，BAZIB，MGEA5，LCN7, CENTG2, FLJ10534, C6orf18, FLJ12671, VEGF, SPANXA1, MECP2, EPHB3, TSTA3, ILVBL, F7, BAZIB, MGEA5,

E4F1，PPP1R13B，PZP，KIAA0913，CSRP2，DKFZP564K2062，CA2，SLC7A8，BNC，ADAMTS1，PIASY，MGC11061，E4F1, PPP1R13B, PZP, KIAA0913, CSRP2, DKFZP564K2062, CA2, SLC7A8, BNC, ADAMTS1, PIASY, MGC11061,

FERIL4，FKSG28，ZA P128，FLJ21610，ATRN，NEU1，H2AFA，IL10RA，BNIP3，NRP1，WISP3，C8orf4，TGFA，FLJ11526，FERIL4, FKSG28, ZA P128, FLJ21610, ATRN, NEU1, H2AFA, IL10RA, BNIP3, NRP1, WISP3, C8orf4, TGFA, FLJ11526,

MRPL2，HP，DHPS，SLC7A8，GPX5，PLXN3，CDC34，POLR3K，FLJ11506，KIAA0980，PDCD8，EV15，CST3，KIAA0752，MRPL2, HP, DHPS, SLC7A8, GPX5, PLXN3, CDC34, POLR3K, FLJ11506, KIAA0980, PDCD8, EV15, CST3, KIAA0752,

C1orf16，CYP4F3，ROR1，MAP3K9，HSPC121CDKN2A，CAPN9，DUSP8，APOD，CCRK，DDX26，USP21，PP35，ABCA1，C1orf16, CYP4F3, ROR1, MAP3K9, HSPC121CDKN2A, CAPN9, DUSP8, APOD, CCRK, DDX26, USP21, PP35, ABCA1,

IGHG3，IL1RL1，ELOVL1，HPIP，FLJ12650，KIAA1078，IL17R，H2AFN，FLJ13352，ELK1，TPM1，TLN2，PPIC，SLC16A3，IGHG3, IL1RL1, ELOVL1, HPIP, FLJ12650, KIAA1078, IL17R, H2AFN, FLJ13352, ELK1, TPM1, TLN2, PPIC, SLC16A3,

FZD3，CARS，TNFSF8，zizimin1，GALGT，DSCR6，TP53TG1，SPTAN1，FBXL2，H2AFX，HMGE，TCEB3，PLN，FLJ10847，FZD3, CARS, TNFSF8, zizimin1, GALGT, DSCR6, TP53TG1, SPTAN1, FBXL2, H2AFX, HMGE, TCEB3, PLN, FLJ10847,

SNA12，STC2，MACF1，ARF1，UGT1A9，PCDH7，MAN1C1，NESG1，EVIN1，FKBPL，KIAAO417，VDR，SPUF，SCGN，SNA12, STC2, MACF1, ARF1, UGT1A9, PCDH7, MAN1C1, NESG1, EVIN1, FKBPL, KIAAO417, VDR, SPUF, SCGN,

IGSF4，ARK5，F5，LIMK2，POP3，RGS5，LOX，ADORA2A，PEX14，VAX2，RANGAP1，MSF，TNFA1P1，C6.1A，ARHGEF7，IGSF4, ARK5, F5, LIMK2, POP3, RGS5, LOX, ADORA2A, PEX14, VAX2, RANGAP1, MSF, TNFA1P1, C6.1A, ARHGEF7,

LP1N1，KIAA0876，ZFX，PLJ22635，PL1N，TRIM2，EDG2，POF1B，IF2，PPPIR9A，ANG，STC1，DNAJB2，ODAG，LP1N1, KIAA0876, ZFX, PLJ22635, PL1N, TRIM2, EDG2, POF1B, IF2, PPPIR9A, ANG, STC1, DNAJB2, ODAG,

KIAA0763，FLJ11274，FLJ20151，MARcKS，ECGP，MFNG，COG7，KIAA0429，NEDD4L，ATP61P2，DONSON，MUC6，KIAA0763, FLJ11274, FLJ20151, MARcKS, ECGP, MFNG, COG7, KIAA0429, NEDD4L, ATP61P2, DONSON, MUC6,

PTGES，SOAT1，MAN1B1，TNFRSF9，SEC61A2，KIAA0500，AP3S2，KIAA1089，B4GALT4，PTGER3，TLR2，FCGBP，PTGES, SOAT1, MAN1B1, TNFRSF9, SEC61A2, KIAA0500, AP3S2, KIAA1089, B4GALT4, PTGER3, TLR2, FCGBP,

ZDHHC3，KIAA0716，MMP12，CYP2A6，GRAF，LOC54499，NNMT，COL8A2，OXTR，NOL3，ZNF79，HRASLS，HAMP，ZDHHC3, KIAA0716, MMP12, CYP2A6, GRAF, LOC54499, NNMT, COL8A2, OXTR, NOL3, ZNF79, HRASLS, HAMP,

AIF1，CGI-38，SPUF，BAZ2A，FLRT3，PDEF，PDK3，SLC4A7，HMOX1，IFNA21，HKE4，CA5B，KLK8，PLUNC，NCBP2，AIF1, CGI-38, SPUF, BAZ2A, FLRT3, PDEF, PDK3, SLC4A7, HMOX1, IFNA21, HKE4, CA5B, KLK8, PLUNC, NCBP2,

KIAA0703，T1A-2，MSX2，FLJ20374，ANXA2P3，DLG3，PON2，IL17BR，AGRN，PRDM11，TNFRSF6B，STXBP2，PTGDS，KIAA0703, T1A-2, MSX2, FLJ20374, ANXA2P3, DLG3, PON2, IL17BR, AGRN, PRDM11, TNFRSF6B, STXBP2, PTGDS,

MARCO，UBE2G2，EPB41L1，PDGFA，IL13RA2，CXCL6，CGI-96，APOA1，MRF-1，NPAS2，MRPL41，LENG4，FGF1，MARCO, UBE2G2, EPB41L1, PDGFA, IL13RA2, CXCL6, CGI-96, APOA1, MRF-1, NPAS2, MRPL41, LENG4, FGF1,

TRAM，AMBP，GPLD1，CH13L1，AQP1，SSB1，K1AA1608，MEIS3，FLJ13385，IL1RAPL2，NQO1，MINK，KIAA0843，TRAM, AMBP, GPLD1, CH13L1, AQP1, SSB1, K1AA1608, MEIS3, FLJ13385, IL1RAPL2, NQO1, MINK, KIAA0843,

DKFZp564A176，MOP3，BGN，B1G1，FLJ13110，dJ222E13.1，SWAP70，DKFZP586L151，TBC1D2，MAGEA3，ARF3，DKFZp564A176, MOP3, BGN, B1G1, FLJ13110, dJ222E13.1, SWAP70, DKFZP586L151, TBC1D2, MAGEA3, ARF3,

CSNK1A1，KRTHA6，FLJ21034，GPR58，KIAA1735，MGAT4A，GNA11，SLC4A2，H41，HAP1，CYBB，MARK1，GRIT，CSNK1A1, KRTHA6, FLJ21034, GPR58, KIAA1735, MGAT4A, GNA11, SLC4A2, H41, HAP1, CYBB, MARK1, GRIT,

ETFDH，FUS1，PTN，FUT2，CDSN，MAP3K6，CHST8，BENE，ATF5，ENPP2，PEX13，PAK4，CUBN，SLC39A2，MYO6，ETFDH, FUS1, PTN, FUT2, CDSN, MAP3K6, CHST8, BENE, ATF5, ENPP2, PEX13, PAK4, CUBN, SLC39A2, MYO6,

DRIL1，SELT，SLC25A22，HFE，KIAA0237，PKD1，NPAS2，ZNF3，FLJ23516，SIX2，LIMR，STAM2，NE1L1，VIL2，MATN3，DRIL1, SELT, SLC25A22, HFE, KIAA0237, PKD1, NPAS2, ZNF3, FLJ23516, SIX2, LIMR, STAM2, NE1L1, VIL2, MATN3,

FLJ23537，AADAC，MCAM，GPR65，TP53TG1，CAP350，CYP17，EMSI，DKFZp547O146，TNS，MGC13523，ASTN2，FLJ23537, AADAC, MCAM, GPR65, TP53TG1, CAP350, CYP17, EMSI, DKFZp547O146, TNS, MGC13523, ASTN2,

TRA1，NPY，CEBPD，PNLIPRP1，PNMT，TM7SF2，NCF2，AP4M1，ITGB4，SLC11A1，LIM，CBFA2T1，FLJ20184，RA114，TRA1, NPY, CEBPD, PNLIPRP1, PNMT, TM7SF2, NCF2, AP4M1, ITGB4, SLC11A1, LIM, CBFA2T1, FLJ20184, RA114,

WBSCR20B，BAIAP2，COPS7A，PNMA2，KIAA0923，PACE4，FLJ10261，KIAA1395，EDNI，ADAMDEC1，LTBR，WBSCR20B, BAIAP2, COPS7A, PNMA2, KIAA0923, PACE4, FLJ10261, KIAA1395, EDNI, ADAMDEC1, LTBR,

KIAA0509，RIL，LPPCALD1，MCRS1，HML2，FLJ22965，FLJ21870，ME1，FLJ22405，RIT1，FLJ11565，KIAA0481，KIAA0509, RIL, LPPCALD1, MCRS1, HML2, FLJ22965, FLJ21870, ME1, FLJ22405, RIT1, FLJ11565, KIAA0481,

FLJ20627，XLKD1，RAB5C，AMPD1，PDCD4，BMPR1A，SLC26A6，KIAA0939，FLJ10874，KCNK15，ARHGEF9，HDLBP，FLJ20627, XLKD1, RAB5C, AMPD1, PDCD4, BMPR1A, SLC26A6, KIAA0939, FLJ10874, KCNK15, ARHGEF9, HDLBP,

MCF2L，AQP1，FLJ1305S，PVRL3，RNPEPL1，GPC4，ADCY9，PTPN13，MGC2656，TSNAXIP1，ACO2，IRX5，IF2，CIC，MCF2L, AQP1, FLJ1305S, PVRL3, RNPEPL1, GPC4, ADCY9, PTPN13, MGC2656, TSNAXIP1, ACO2, IRX5, IF2, CIC,

KIAA0976，BDH，ZFPM2，PSEN2，C20orf46，NDUFS8，GGA2，FLJ10490，TPD52L1，HLALS，ALFY，FLJ20699，UEV3，KIAA0976, BDH, ZFPM2, PSEN2, C20orf46, NDUFS8, GGA2, FLJ10490, TPD52L1, HLALS, ALFY, FLJ20699, UEV3,

AES，DKFZp761K1423，JAG2FLJ13195，DDX8，G0S2，ITPK1，SEMA6B，SLC16A3，CCL18，HUMPPA，EIF4G1，HRH1，AES, DKFZp761K1423, JAG2FLJ13195, DDX8, G0S2, ITPK1, SEMA6B, SLC16A3, CCL18, HUMPPA, EIF4G1, HRH1,

GSA7，FASTK，HBP17，FLJ14117，LOC146542，APPBP2，TNRC15，CLDN11，SCARA3，H2BFJ，APEG1，PPP5C，TDRD1，GSA7, FASTK, HBP17, FLJ14117, LOC146542, APPBP2, TNRC15, CLDN11, SCARA3, H2BFJ, APEG1, PPP5C, TDRD1,

IRS3L，IGF1，PDGFRL，MUC13，DUSP10，KPNA6，FLJ22795，OASL，HRMT1L3，MOS，SCGB1A1，PEX11A，ARHD，IRS3L, IGF1, PDGFRL, MUC13, DUSP10, KPNA6, FLJ22795, OASL, HRMT1L3, MOS, SCGB1A1, PEX11A, ARHD,

KIAA0977，MMP24，FCN1，ACP1，LAMP3，AKAP6，ALDH3B1，TNXB，NF1，APOA1，RBP4，CLTB，GP2，FBXO2，DRG2，KIAA0977, MMP24, FCN1, ACP1, LAMP3, AKAP6, ALDH3B1, TNXB, NF1, APOA1, RBP4, CLTB, GP2, FBXO2, DRG2,

DLG3，PCDHB3，FOLR2，NCBPI，SOX13，HOXD4，FGR，EFEMP2，KIAA0625，TULP2，GPRK5，EVIN1，CHODL，CDH8，DLG3, PCDHB3, FOLR2, NCBPI, SOX13, HOXD4, FGR, EFEMP2, KIAA0625, TULP2, GPRK5, EVIN1, CHODL, CDH8,

FLJ22173，OR10J1，IFNGR1，PRO1787，ACADSB，LAMP1，HSPB7，PCSK2，KRT6A，C5R1，DUSP5，MGC1136，TPSD1，FLJ22173, OR10J1, IFNGR1, PRO1787, ACADSB, LAMP1, HSPB7, PCSK2, KRT6A, C5R1, DUSP5, MGC1136, TPSD1,

HMGCS2，BCAR3，MOCS2，KIAA1233，VSNL1，UBD，ANGPTL2，GENX-3414，FLJ12547，HMGCSI，KDELR1，CPT1A，HMGCS2, BCAR3, MOCS2, KIAA1233, VSNL1, UBD, ANGPTL2, GENX-3414, FLJ12547, HMGCSI, KDELR1, CPT1A,

VAMP2，GSTZ1，GJB3，MRPS12，PCBD，FLJ23322，PASK，ARGBP2，SELIL，FST，FARP2，HSF2BP，CGI-96，MGC2601，VAMP2, GSTZ1, GJB3, MRPS12, PCBD, FLJ23322, PASK, ARGBP2, SELIL, FST, FARP2, HSF2BP, CGI-96, MGC2601,

PBX2，FZD1，ABAT，TSHB，KIAA0874，RHEB2，FMO1，NCDN，CSPG2，KIAA0844，FLJ22531，COL4A3BP，ACE2，NAV3，PBX2, FZD1, ABAT, TSHB, KIAA0874, RHEB2, FMO1, NCDN, CSPG2, KIAA0844, FLJ22531, COL4A3BP, ACE2, NAV3,

SULT2B1，TETRAN，RODH-4，MADHIP，HT009，ACR，CLECSF12，SULT1B1，ELMO3，NICE-1，HSA243396，NDRG2，SULT2B1, TETRAN, RODH-4, MADHIP, HT009, ACR, CLECSF12, SULT1B1, ELMO3, NICE-1, HSA243396, NDRG2,

GSTT1，BLJAM E，TAPBP-R，SERPINA1，CNNM4，TCF3，SSX5，MPDU1，CHP，FLJ11183，NOL6，FIJ23129，FLJ11196，GSTT1, BLJAM E, TAPBP-R, SERPINA1, CNNM4, TCF3, SSX5, MPDU1, CHP, FLJ11183, NOL6, FIJ23129, FLJ11196,

DKFZP76112123，KNSL3，DTNA，BDKRB1，CSNK2A1，1D4，OCLN，CLN2，SLIT3，MAPK7，EZF-2，GYG2，K6HF，DKFZP76112123, KNSL3, DTNA, BDKRB1, CSNK2A1, 1D4, OCLN, CLN2, SLIT3, MAPK7, EZF-2, GYG2, K6HF,

ALS2CR3，TMEM2，NPAS2，HOXB9，MAN1B1，APOBEC2，HFSE-1，DNAJC7，POU5F1，PSMB1，PAFAH2，FLJ13852，ALS2CR3, TMEM2, NPAS2, HOXB9, MAN1B1, APOBEC2, HFSE-1, DNAJC7, POU5F1, PSMB1, PAFAH2, FLJ13852,

CCK，PITX1，NTE，ABL2，CLN8，KIAA0819，GALNT10，FLJ13841，NEFL，ARHGAP12，APOC2，PTPRO，HSPA6，NMB，CCK, PITX1, NTE, ABL2, CLN8, KIAA0819, GALNT10, FLJ13841, NEFL, ARHGAP12, APOC2, PTPRO, HSPA6, NMB,

OR2F1，MPP2，HPGD，CALB1，ADRBK2，AMBP，PPP1R1A，CCR7，C20orf28，TRA@，EFNA3，CX3CL1，F25965，CD2BP2，OR2F1, MPP2, HPGD, CALB1, ADRBK2, AMBP, PPP1R1A, CCR7, C20orf28, TRA@, EFNA3, CX3CL1, F25965, CD2BP2,

CDC42EP1，OLFM1，C20orf31，SNAPC3，MIRO-2CALBI，PIK4CB，FOXA2，CI1ORF4，RRAS，HUNK，TGFB2，RBMS2，CDC42EP1, OLFM1, C20orf31, SNAPC3, MIRO-2CALBI, PIK4CB, FOXA2, CI1ORF4, RRAS, HUNK, TGFB2, RBMS2,

MASP1，ATP6V1C1，NMU，PCDHGA1，SLC29A2，PPIE，GGA2，FLJ20535，POU5F1，MGC5509，CITED1，ATP6V0E，LIPE，MASP1, ATP6V1C1, NMU, PCDHGA1, SLC29A2, PPIE, GGA2, FLJ20535, POU5F1, MGC5509, CITED1, ATP6V0E, LIPE,

ACTN1，SLC26A10，SLC21A9，WNT4，RBMS2，MRPS15，P8，KIAA1609，FBXL11，TGM2，CHRNA1，TSSC4，SBB131，ACTN1, SLC26A10, SLC21A9, WNT4, RBMS2, MRPS15, P8, KIAA1609, FBXL11, TGM2, CHRNA1, TSSC4, SBB131,

KIAA0356，OLFM1，SEMACAP3，CD6，ITGA2，GTF2H1，FAIM2，FLJ21313，STAT5B，TBX2，GABRD，AVIL，KIAA0356, OLFM1, SEMACAP3, CD6, ITGA2, GTF2H1, FAIM2, FLJ21313, STAT5B, TBX2, GABRD, AVIL,

MGC2615FJX1，FLJ14675，IL1RL2，AK3，ZNFN1A3，SSPN，RELN，SIGLEC7，COL5A2，HLA-DOB，SLC12A3，HFE，MGC2615FJX1, FLJ14675, IL1RL2, AK3, ZNFN1A3, SSPN, RELN, SIGLEC7, COL5A2, HLA-DOB, SLC12A3, HFE,

PLINP-1，Apg4B，MGC39851，HIPK2，HSPC159，PSK-1，ABCA12，MMP15，PKP3，HERC3，RECQL4，DKFZp434C0923，PLINP-1, Apg4B, MGC39851, HIPK2, HSPC159, PSK-1, ABCA12, MMP15, PKP3, HERC3, RECQL4, DKFZp434C0923,

UNC84A，FTS，AZGP1，FASTK，ARFGEF2，DSCAM，MED8，SPP2，P2RY6，RP1P8，DHPS，ST14，SAMHD1，MGC32043，UNC84A, FTS, AZGP1, FASTK, ARFGEF2, DSCAM, MED8, SPP2, P2RY6, RP1P8, DHPS, ST14, SAMHD1, MGC32043,

SPARCL1，FLJ22160，GHR，YAP1，MTMR3，SLC20A2，PART1，PTPN14，BAIAP3，EPPB9，ED1，TPM4，TEK，PRO1942，SPARCL1, FLJ22160, GHR, YAP1, MTMR3, SLC20A2, PART1, PTPN14, BAIAP3, EPPB9, ED1, TPM4, TEK, PRO1942,

H2BFE，LEPR，NAPG，MGC29761，SLC34A2，ZNF358，GRB14，CMKLR1，KIR-023GB，MET，PBX1，CYP2D6，SLC7A8，H2BFE, LEPR, NAPG, MGC29761, SLC34A2, ZNF358, GRB14, CMKLR1, KIR-023GB, MET, PBX1, CYP2D6, SLC7A8,

IL13RA1，ARNT2，GTF2H4，CD86，BM88，CEACAM1，B1RC1，CAMTA1，PDZK1，MOCS1，GLYAT，ChGn，RQCD1，CRA，IL13RA1, ARNT2, GTF2H4, CD86, BM88, CEACAM1, B1RC1, CAMTA1, PDZK1, MOCS1, GLYAT, ChGn, RQCD1, CRA,

BA1AP2，PTX3，CYR61，VAMP4，HSPA4，HUG1，GBL，EPS8R3，PTPRU，DLGAP1，GEMIN7，MADH6，PTPRG，NFX1，BA1AP2, PTX3, CYR61, VAMP4, HSPA4, HUG1, GBL, EPS8R3, PTPRU, DLGAP1, GEMIN7, MADH6, PTPRG, NFX1,

KIAA1028，RNASE6，AD037，PI15，SNA11，LOC157542，ACTG2，SLC35A3，SIRT3，NPR2，NPC1L1，HCK，DDR2，SLC5A2，KIAA1028, RNASE6, AD037, PI15, SNA11, LOC157542, ACTG2, SLC35A3, SIRT3, NPR2, NPC1L1, HCK, DDR2, SLC5A2,

OASIS，FLJ21511，LRP2，RGS10，ALDH8A1，COL4A3，GS3955，CLECSF6，UP，MKL1，MADH6，PRDM5，WNT1，SPAG4，OASIS, FLJ21511, LRP2, RGS10, ALDH8A1, COL4A3, GS3955, CLECSF6, UP, MKL1, MADH6, PRDM5, WNT1, SPAG4,

SORBS1，ASPH，PLK，IGSF1，ARHF，CAPN2，LIG3，SULF1，CCKBR，TEAD4，C8A，MGC10771，FCGR2A，SEC14L1，SORBS1, ASPH, PLK, IGSF1, ARHF, CAPN2, LIG3, SULF1, CCKBR, TEAD4, C8A, MGC10771, FCGR2A, SEC14L1,

KLK11，SPIN2，C8orf17，THBD，FKSG28，NEURL，FLJ10647，LTB4R，CHRM4，C3orf4，ALLC，SLC3A1，SLC1A1，KLK11, SPIN2, C8orf17, THBD, FKSG28, NEURL, FLJ10647, LTB4R, CHRM4, C3orf4, ALLC, SLC3A1, SLC1A1,

MS4A4A，EDNRA，ILT11，IGHMBP2，MGC4276，1GF2R，FLJ20421，PBX2，37872.00，FLJ23604，FOXI1，LUC7L，CD86，MS4A4A, EDNRA, ILT11, IGHMBP2, MGC4276, 1GF2R, FLJ20421, PBX2, 37872.00, FLJ23604, FOXI1, LUC7L, CD86,

PVR，SCD，GPR37，UNC119，NXPH4，FCGR2B，S100A2，MORF，BMPR2，AKT1，FLJ11715，IL13，TADA3L，NFATC4，PVR, SCD, GPR37, UNC119, NXPH4, FCGR2B, S100A2, MORF, BMPR2, AKT1, FLJ11715, IL13, TADA3L, NFATC4,

PPP3CC，CARM1，PTGIS，PLOD，CD36，BBOX1，VNN3，AKR1B10，SEMA6A，E21G4，HOXC13，RNASE4，PPP3CC, CARM1, PTGIS, PLOD, CD36, BBOX1, VNN3, AKR1B10, SEMA6A, E21G4, HOXC13, RNASE4,

DKFZp434H2215，EK11，MGC5356，KIAA0752，RUNX2，ACCN2，GALNS，CABYR，PCDHA3，SSX2，GOTINPAT，DKFZp434H2215, EK11, MGC5356, KIAA0752, RUNX2, ACCN2, GALNS, CABYR, PCDHA3, SSX2, GOTINPAT,

CORO2A，DGCR13，CAPN5，GPM6A，GLRB，NPEPPS，RIPK1，CYP-M，GLRA3，BIGM103，UTX，NY-REN-45，ATP1A3，CORO2A, DGCR13, CAPN5, GPM6A, GLRB, NPEPPS, RIPK1, CYP-M, GLRA3, BIGM103, UTX, NY-REN-45, ATP1A3,

ANXA2P1，IL1RAP，PRO1600，WNT2，HYAL1，SH2D1A，TREM2，TUB，KIAA1036，KCNB1，CNN1，BLAME，P1TX1，ANXA2P1, IL1RAP, PRO1600, WNT2, HYAL1, SH2D1A, TREM2, TUB, KIAA1036, KCNB1, CNN1, BLAME, P1TX1,

DXS542，ADORA1，TNXB，GABRE，FABP3，PGRMC1，FLJ20513，SC1N，FLJ13052，CP，LIMK1，MSF，EDN2，FLJ20623，DXS542, ADORA1, TNXB, GABRE, FABP3, PGRMC1, FLJ20513, SC1N, FLJ13052, CP, LIMK1, MSF, EDN2, FLJ20623,

ESRRG，KIAA1237，INADL，KIAA0889，HS3ST3A1，FLJ22593，AS1C4，FLJ21144，FLJ11827，TAT，FLJ20584，SMA5，ESRRG, KIAA1237, INADL, KIAA0889, HS3ST3A1, FLJ22593, AS1C4, FLJ21144, FLJ11827, TAT, FLJ20584, SMA5,

NCOA3，GLP1R，PRODH，FABP3，FDXR，DEFA4，SORBS1，MRPS12，HSF1，EEF1E1，CTLA4，WDR4，ASB7，ABCA8，NCOA3, GLP1R, PRODH, FABP3, FDXR, DEFA4, SORBS1, MRPS12, HSF1, EEF1E1, CTLA4, WDR4, ASB7, ABCA8,

CLPS，PSMA7，ARHN，PEG10，AKAP12，MGC12904，FLJ10312，FLJ11539，RAD1，SERPINF1，MGAM，PVTI，PTHLH，CLPS, PSMA7, ARHN, PEG10, AKAP12, MGC12904, FLJ10312, FLJ11539, RAD1, SERPINF1, MGAM, PVTI, PTHLH,

STS，PRG4，SYNCOILIN，CASP2，FLJ12168，MARCKS，HTR3B，RECQL，COL4A2，CD97，TRIM36，MGAT3，GRIN1，STS, PRG4, SYNCOILIN, CASP2, FLJ12168, MARCKS, HTR3B, RECQL, COL4A2, CD97, TRIM36, MGAT3, GRIN1,

SOX4，K1AA0475，DKFZP586M1120，SLC2A4RG，CTSZ，SQV7L，PLD3，OR7E24P，CDK5，GRIA2，PRLR，MHC2TA，SOX4, K1AA0475, DKFZP586M1120, SLC2A4RG, CTSZ, SQV7L, PLD3, OR7E24P, CDK5, GRIA2, PRLR, MHC2TA,

CST6，LOC56920，NUP214，BETIL，FIGF，THBS4，HLA-DRB4，CAPN6，TLR7，MBTPS1，KIAA0992，BG1，FLJ12681，CST6, LOC56920, NUP214, BETIL, FIGF, THBS4, HLA-DRB4, CAPN6, TLR7, MBTPS1, KIAA0992, BG1, FLJ12681,

MAK，APOH，TNFA1P6，CRYAA，PKD2，IGFBP2，TSPAN-3，ATP6V0E，KIAA1579，MGC20727，KIAA1093，LOC55565，MAK, APOH, TNFA1P6, CRYAA, PKD2, IGFBP2, TSPAN-3, ATP6V0E, KIAA1579, MGC20727, KIAA1093, LOC55565,

HS322B1A，LOC51285，STC1，KIAA0992，CGI-01，TRGC2，EPHB4，DES，CNOT4，MAP4，CDC42EP2，HSD3B1，RDH5，HS322B1A, LOC51285, STC1, KIAA0992, CGI-01, TRGC2, EPHB4, DES, CNOT4, MAP4, CDC42EP2, HSD3B1, RDH5,

XYLT2，CHRD，SPBPBP，PDP，MYBL1，HPN，GOLGA2，LOC63929，EXO70，PCDHB11，KIAA1036，ANGPTL4，XYLT2, CHRD, SPBPBP, PDP, MYBL1, HPN, GOLGA2, LOC63929, EXO70, PCDHB11, KIAA1036, ANGPTL4,

TNFRSF10C，EVPL，TEAD1，SIAH2，PMM1，DPYSL3，FLJ14297，TACSTD2，BSN，FAP，SEMA3A，RER1，AXL，PROL4，TNFRSF10C, EVPL, TEAD1, SIAH2, PMM1, DPYSL3, FLJ14297, TACSTD2, BSN, FAP, SEMA3A, RER1, AXL, PROL4,

CASKIN2，RENT1，CLDN3，DRAP1，ADAMTS7，TCEB2，EPB41L1，GUCA1A，FLJ22659，PAPPA，CBLN1，FRCP1，IL1F9，CASKIN2, RENT1, CLDN3, DRAP1, ADAMTS7, TCEB2, EPB41L1, GUCA1A, FLJ22659, PAPPA, CBLN1, FRCP1, IL1F9,

ITCH，MMP26，STRN3，CEBPD，COL21A1，BTD，KIAA1034，MIG2，FLJ20591，FGG，ASCL1，CXCL14，PDE1A，OR7C1，ITCH, MMP26, STRN3, CEBPD, COL21A1, BTD, KIAA1034, MIG2, FLJ20591, FGG, ASCL1, CXCL14, PDE1A, OR7C1,

HLCS，PTPN21，HUMMLC2B，SECP43，BCAT1，DRD2，TAT，MSR1，OMD，IGFBP4，C13orf1，FLJ21919，FLJ11807，HLCS, PTPN21, HUMMLC2B, SECP43, BCAT1, DRD2, TAT, MSR1, OMD, IGFBP4, C13orf1, FLJ21919, FLJ11807,

AMELX，KIAA0346，FLJ21916，OL1G2，L1CAM，TAPBP-R，Cab45，NRIH2，TCP10，KRTHB5，PCDHA9，TNC，AMELX, KIAA0346, FLJ21916, OL1G2, L1CAM, TAPBP-R, Cab45, NRIH2, TCP10, KRTHB5, PCDHA9, TNC,

DKFZp434L0850，FLJ11011，SKD3，SPINK4，DZ1P1，FLJ23548，FLJ23420，TFEB，PCDHA6，LOC160313，FLJ10496，DKFZp434L0850, FLJ11011, SKD3, SPINK4, DZ1P1, FLJ23548, FLJ23420, TFEB, PCDHA6, LOC160313, FLJ10496,

R291241，THPO，AQP6，KIR3DL2，MGC10848，C21orf18，ACCN2，TBL1X，RAB6B，BHMT2，APOB，IGSF4，PAPSS2，R291241, THPO, AQP6, KIR3DL2, MGC10848, C21orf18, ACCN2, TBL1X, RAB6B, BHMT2, APOB, IGSF4, PAPSS2,

RBP1，TCF2，R309531，CD3G，ZXDA，TNFRSF10C，FLJ21665，CYSLTR2，IL6ST，ZNF214，AICDA，PTAFR，FLJ12806，RBP1, TCF2, R309531, CD3G, ZXDA, TNFRSF10C, FLJ21665, CYSLTR2, IL6ST, ZNF214, AICDA, PTAFR, FLJ12806,

BA526D8.4，CYP2C9，TWIST，PPP2R5C，MASP2，DUSP9，CGEF2，GABRB1，CDC42BPB，TNFRSF5，CCR4，PYY，BA526D8.4, CYP2C9, TWIST, PPP2R5C, MASP2, DUSP9, CGEF2, GABRB1, CDC42BPB, TNFRSF5, CCR4, PYY,

PILR(ALPHA)，B1RC7，LANGERIN，H2AFI，PLCE1，OGG1，TAZ，PDCD5，SE57-1，FKBP2，FBLN2，RBM9，384D8-2，PILR(ALPHA), B1RC7, LANGERIN, H2AFI, PLCE1, OGG1, TAZ, PDCD5, SE57-1, FKBP2, FBLN2, RBM9, 384D8-2,

WNT2B，NRBP，CDH6，G6PD，C1orf22，LSM4，STX6，ZIC4，FPRL1，CALCB，AGPAT3，SHB，TOM1，AGA，ZIC1，S1AT9，WNT2B, NRBP, CDH6, G6PD, C1orf22, LSM4, STX6, ZIC4, FPRL1, CALCB, AGPAT3, SHB, TOM1, AGA, ZIC1, S1AT9,

PTPRZ1，MSC，DKFZP566F0546，FLJ32069，CD28，PPP2R3A，ASTN2，ARHGEF11，JPH3，FLJ21477，GH1，HOXD3，PTPRZ1, MSC, DKFZP566F0546, FLJ32069, CD28, PPP2R3A, ASTN2, ARHGEF11, JPH3, FLJ21477, GH1, HOXD3,

MS4A2，SV1L，DPYS，F2RL1，ECGF1，PRCC，POLD4，OAZ1N，CHRNA3，KIAA1000，DKFZP586D2223，DAZ4，WNT7B，MS4A2, SV1L, DPYS, F2RL1, ECGF1, PRCC, POLD4, OAZ1N, CHRNA3, KIAA1000, DKFZP586D2223, DAZ4, WNT7B,

MUC4，GCNT3，OR1E1，CLSP，CD1D，CCR1，ORCTL3，EEA1，SIX3，FLJ10140，FL10884，HNRNPG-THSD3B2，MUC4, GCNT3, OR1E1, CLSP, CD1D, CCR1, ORCTL3, EEA1, SIX3, FLJ10140, FL10884, HNRNPG-THSD3B2,

SERPINE1，RHO，MUC4，PTN，DNCL12，TNFRSF10B，LOC90326，NR6A1，NCYM，SCGB1D1，EPHB1，NOX4，DJ122O8.2，SERPINE1, RHO, MUC4, PTN, DNCL12, TNFRSF10B, LOC90326, NR6A1, NCYM, SCGB1D1, EPHB1, NOX4, DJ122O8.2,

PLAUR，PDE4C，PIP5K1A，MGC14799，IGFBP1，IDUA，IGHM，NAPA，PARD3，LIM2，ADD2，HSF4，CABP5，TF，TNXB，PLAUR, PDE4C, PIP5K1A, MGC14799, IGFBP1, IDUA, IGHM, NAPA, PARD3, LIM2, ADD2, HSF4, CABP5, TF, TNXB,

NET-5，ITGA3，IGFBP3，GDF10，PRB4，KCNF1，ATP11A，KIR2DL2，SMARCB1，MBP，IGL@，NFATC1，CDH16，RHO6，NET-5, ITGA3, IGFBP3, GDF10, PRB4, KCNF1, ATP11A, KIR2DL2, SMARCB1, MBP, IGL@, NFATC1, CDH16, RHO6,

CCL20，FLJ20605，ASIP，LDB2，HCRTR2，HOXD3，GPR87，VCX-8rLOC116150，TPM3，LRP1B，MAGEA6，FLJ20701，CCL20, FLJ20605, ASIP, LDB2, HCRTR2, HOXD3, GPR87, VCX-8rLOC116150, TPM3, LRP1B, MAGEA6, FLJ20701,

PAX3，IGSF6，TOMM22，GALNT3，CHML，COL6A1，FAAH，B7，RANBP1，KIAA0876，CYP2A13，CD5L，C21orf2，RYBP，PAX3, IGSF6, TOMM22, GALNT3, CHML, COL6A1, FAAH, B7, RANBP1, KIAA0876, CYP2A13, CD5L, C21orf2, RYBP,

GJA10，COL15A1，TEX13A，SCNN1B，TRD@，RIL，ITGB8，PLEKHA1，GRIN2A，FSHB，PDK2，SAST，PRPF18，FLJ13479，GJA10, COL15A1, TEX13A, SCNN1B, TRD@, RIL, ITGB8, PLEKHA1, GRIN2A, FSHB, PDK2, SAST, PRPF18, FLJ13479,

GRP，SLC4A8，SMURF1，GK2，INSL4，FLJ20311，GLRA3，KIAA0828，DLX2，EPOR，RRBP1，SDC2，zizimin1，CCND1，GRP, SLC4A8, SMURF1, GK2, INSL4, FLJ20311, GLRA3, KIAA0828, DLX2, EPOR, RRBP1, SDC2, zizimin1, CCND1,

P2RY2，CD28，B4GALT4，ARHGDIG，TBL3，IL17，FLJ20519，FAT2，UPK1A，SERPINA2，CD209L，NRP1，ACINUS，P2RY2, CD28, B4GALT4, ARHGDIG, TBL3, IL17, FLJ20519, FAT2, UPK1A, SERPINA2, CD209L, NRP1, ACINUS,

RREB1，TNFRSF4，PRO2214，DKFZp761O0113MAP3K7，SPRR2B，DNA11，NOVA1，DEPP，LOC51725，SCAMP-4，TLR4，RREB1, TNFRSF4, PRO2214, DKFZp761O0113MAP3K7, SPRR2B, DNA11, NOVA1, DEPP, LOC51725, SCAMP-4, TLR4,

MAX，PRDM16，KRTHA5，PCDHB1，GNAL，P37NB，ISL1，SH2D3A，TFP12，CREBBP，ACTA1，ALP，OR1A2，CG1-58，MAX, PRDM16, KRTHA5, PCDHB1, GNAL, P37NB, ISL1, SH2D3A, TFP12, CREBBP, ACTA1, ALP, OR1A2, CG1-58,

SH3BP2，APAF1，CD209，DKK4，IL18RAP，ESM1，PAX2，EV15，MFNG，ATF5，CUGBP1，FLJ10376，CMKLR1，SLC23A1，SH3BP2, APAF1, CD209, DKK4, IL18RAP, ESM1, PAX2, EV15, MFNG, ATF5, CUGBP1, FLJ10376, CMKLR1, SLC23A1,

MGC34772，FLJ23033，IGLJ3，AMACR，SIN3B，CCL18，CSPG4，FLJ20241，DNMI，FHR-4，GNS，GDF11，PAL，PPFIA2，MGC34772, FLJ23033, IGLJ3, AMACR, SIN3B, CCL18, CSPG4, FLJ20241, DNMI, FHR-4, GNS, GDF11, PAL, PPFIA2,

CASP10，ORM2，SPTAN1，SPUF，CALCRL，USH1C，ALK，FLJ11850，FOXD1，SH3BGRL3，MNDA，EPB41L4A，MMP16，CASP10, ORM2, SPTAN1, SPUF, CALCRL, USH1C, ALK, FLJ11850, FOXD1, SH3BGRL3, MNDA, EPB41L4A, MMP16,

ANK1，WISP2，GSTAl，FER1L3，MGC33190，DAZ2，CHST3，DRF1，TM4SF9，CDC25C，ACVR1B，LU，SGCE，POP2，ANK1, WISP2, GSTAl, FER1L3, MGC33190, DAZ2, CHST3, DRF1, TM4SF9, CDC25C, ACVR1B, LU, SGCE, POP2,

PCLO，COL18A1，TSHR，Eu-HMTase1，MSR1，GPD2，CLDN17，KIAA1069，CYLC1，ABCB11，MIG2，LY6H，ARFRP1，PCLO, COL18A1, TSHR, Eu-HMTase1, MSR1, GPD2, CLDN17, KIAA1069, CYLC1, ABCB11, MIG2, LY6H, ARFRP1,

BMP2，ACOX1，FZR1，CAMK2B，HUMCYT2A，LILRB5，ENPP3，IL4，SCN11A，CALU，IGKC，THEA，OPRL1，KIAA1053，BMP2, ACOX1, FZR1, CAMK2B, HUMCYT2A, LILRB5, ENPP3, IL4, SCN11A, CALU, IGKC, THEA, OPRL1, KIAA1053,

SIXICABIN1，SCN7A，THOP1，NR2C2，FLJ23462TRPM1，RAB3D，CREBL1，ABCD2，VDU1，GAL，CPN2，FLJ10408，SIXICABIN1, SCN7A, THOP1, NR2C2, FLJ23462TRPM1, RAB3D, CREBL1, ABCD2, VDU1, GAL, CPN2, FLJ10408,

PHLDA1，RAB1A，HAND1，MGC5347，BAI2，EDG8，GPR30，PCDHB8，TYRO3，PRO0618，PRKC1，UCP3，GSG1，PHLDA1, RAB1A, HAND1, MGC5347, BAI2, EDG8, GPR30, PCDHB8, TYRO3, PRO0618, PRKC1, UCP3, GSG1,

PRO1048，HRH3，SARDH，FLJ10803，WISP1，PRLR，RIPX，NNAT，SFN，APBB2，TLL1，PCNX，KYNU，MKRN3，PRO1048, HRH3, SARDH, FLJ10803, WISP1, PRLR, RIPX, NNAT, SFN, APBB2, TLL1, PCNX, KYNU, MKRN3,

HGC6.1.1，PLN，RIPX，CDC2L5，ATP11A，SP11，RIGPDK3，AFAP，KIAA0427，CYP4F12，EFNA5，FLJ11125，DUOX1，HGC6.1.1, PLN, RIPX, CDC2L5, ATP11A, SP11, RIGPDK3, AFAP, KIAA0427, CYP4F12, EFNA5, FLJ11125, DUOX1,

FLJ21240，DNAJC9，RQCD1，DLG5，PIGO，ABCB8KCNA5，KIAA0409，FLJ12891，SHMT1，DNALI1，POLYDOM，FLJ21240, DNAJC9, RQCD1, DLG5, PIGO, ABCB8KCNA5, KIAA0409, FLJ12891, SHMT1, DNALI1, POLYDOM,

PFKFB4，SHOX2，DGKE，ELF2，MUC5B，WHN，SCAND2，LOC160313，FLJ23510，AK5，FLJ11871，ITGB5，CPS1，DBT，PFKFB4, SHOX2, DGKE, ELF2, MUC5B, WHN, SCAND2, LOC160313, FLJ23510, AK5, FLJ11871, ITGB5, CPS1, DBT,

CDH17，FCGR2B，PCK1，PLXNA2，ACE2，CD7，FLJ11619，ZDHHC11，FLJ21562，FLJ20211，MGC2821，FLJ20624，ICK，CDH17, FCGR2B, PCK1, PLXNA2, ACE2, CD7, FLJ11619, ZDHHC11, FLJ21562, FLJ20211, MGC2821, FLJ20624, ICK,

PARK2，PNAS-4，CLECSF6，PCDH11XFGFR3，PTGER3，PROX1，HRC，EPB41L2，KIAA1117，ATSV，LAMC2，ITGB1，PARK2, PNAS-4, CLECSF6, PCDH11XFGFR3, PTGER3, PROX1, HRC, EPB41L2, KIAA1117, ATSV, LAMC2, ITGB1,

TRA@，PAK2，DKFZp762C186，OCM，HNF4A，AVPR2，FTCD，TNN13，HR，SLC35A2，PP1665，GA，RGS5，OPLAH，GDF1，TRA@, PAK2, DKFZp762C186, OCM, HNF4A, AVPR2, FTCD, TNN13, HR, SLC35A2, PP1665, GA, RGS5, OPLAH, GDF1,

OR3A2，FOXO3A，TNRC21ABO，ITSN1，PVR，CNGA1，UPK3B，PCDHB12，ALCAM，HFE，KCNJ15，KIAA0997，RGS11，OR3A2, FOXO3A, TNRC21ABO, ITSN1, PVR, CNGA1, UPK3B, PCDHB12, ALCAM, HFE, KCNJ15, KIAA0997, RGS11,

NDUFB7，ADAM28，FLJ13055，PRO2176，CACNB4，R1N3，SLC5A7，FOXH1，PKDREJ，FLJ10232，DGKA，retSDR4，EDG2，NDUFB7, ADAM28, FLJ13055, PRO2176, CACNB4, R1N3, SLC5A7, FOXH1, PKDREJ, FLJ10232, DGKA, retSDR4, EDG2,

SEMA3E，SARCOSIN，THPO，PTPN21，POU2F3，MAP1A，ZFP37，SUPT6H，ADAMTS6，ASMT，DKFZp434C0328，ROR1，SEMA3E, SARCOSIN, THPO, PTPN21, POU2F3, MAP1A, ZFP37, SUPT6H, ADAMTS6, ASMT, DKFZp434C0328, ROR1,

FLJ22800，VAMP1，KIAA1654，RBM8A，EPAG，TNIP3，INSM1，XRCC4，IL6ST，UNC84A，UBE4B，CAPN11，NPEPL1，FLJ22800, VAMP1, KIAA1654, RBM8A, EPAG, TNIP3, INSM1, XRCC4, IL6ST, UNC84A, UBE4B, CAPN11, NPEPL1,

TAS2R10，FLJ23093，NPPC，PTPN21，SLC22A8GAD2，LOC51063，OGN，MAGEA8，GUCY2C，NT5E，SGCG，C8orf1，TAS2R10, FLJ23093, NPPC, PTPN21, SLC22A8GAD2, LOC51063, OGN, MAGEA8, GUCY2C, NT5E, SGCG, C8orf1,

LGALS2，PRKAR1B，DEDD，PPARG，PDGFB，PRO0461，ALFY，TNFRSF11A，DNAJC9，KCND2，PEG10，SPINK1，GCM1，LGALS2, PRKAR1B, DEDD, PPARG, PDGFB, PRO0461, ALFY, TNFRSF11A, DNAJC9, KCND2, PEG10, SPINK1, GCM1,

VHL，CLDN1，PRSS7，H4F2，D21S2056E，CXCR6，LIFR，KIAA0599，TNXB，EHD1，ARNTL2，CGR11，SOCS1，PKLR，VHL, CLDN1, PRSS7, H4F2, D21S2056E, CXCR6, LIFR, KIAA0599, TNXB, EHD1, ARNTL2, CGR11, SOCS1, PKLR,

ZFP318，ZF，CHRNA1，DKFZp434M0331，DES，TMOD3，SP140，KSR，BS69，IREB2，PAWR，CACNA2D1，C21orf62，GeneZFP318, ZF, CHRNA1, DKFZp434M0331, DES, TMOD3, SP140, KSR, BS69, IREB2, PAWR, CACNA2D1, C21orf62, Gene

Symbol，OAZ1，CFL1，RPL28，JAM1，CG1-119，N1CE-3，RNP24，JTBFLJ12806，ARHA，FLJ13352，SYNE-1，TRPS1CGI-119，Symbol, OAZ1, CFL1, RPL28, JAM1, CG1-119, N1CE-3, RNP24, JTBFLJ12806, ARHA, FLJ13352, SYNE-1, TRPS1CGI-119,

NDUFB9C20orf114，JAM1，RALA，FLJ30532，PIGR，MRPS24，MYO5B，LOC155465STUB1，MGC14353，ARF1，C20orf24，NDUFB9C20orf114, JAM1, RALA, FLJ30532, PIGR, MRPS24, MYO5B, LOC155465STUB1, MGC14353, ARF1, C20orf24,

EGR1，ANAPC11，MRPS15，MIR，PIGPC1，MRPS21，CL25084，H41LOC124220，RAB10，B4GALT1，PPP1CB，MGST1，EGR1, ANAPC11, MRPS15, MIR, PIGPC1, MRPS21, CL25084, H41LOC124220, RAB10, B4GALT1, PPP1CB, MGST1,

TCEB2，MGC19825，HSPC163BACE2，BRI3BP，FLJ14511，MRPL47，NMES1，FLJ14735，DAD1，KIAA1324，ENAH，TCEB2, MGC19825, HSPC163BACE2, BRI3BP, FLJ14511, MRPL47, NMES1, FLJ14735, DAD1, KIAA1324, ENAH,

PSMB2，RHPN2，HTPAP，DKFZp761P0423，C20of108，MGC45416，TMEM9，UBQLN1STK35，APOA1BP，GRLF1，PSMB2, RHPN2, HTPAP, DKFZp761P0423, C20of108, MGC45416, TMEM9, UBQLN1STK35, APOA1BP, GRLF1,

SPEC1INSR，LOC150678，SMP1，FLJ32115STUBl，HLA-C，ORF1-FL49，TAF10，RAB40C，DPP3，AIBZIP，LOC55971，SPEC1INSR, LOC150678, SMP1, FLJ32115STUB1, HLA-C, ORF1-FL49, TAF10, RAB40C, DPP3, AIBZIP, LOC55971,

SSR3，ATP6V0E，SNX6，SNAPAP，ALS2CR9，KPNB2，EPC1，NTN4，C20orf52，H2AFJ，UGCG，IMAGE3451454，EEF2K，SSR3, ATP6V0E, SNX6, SNAPAP, ALS2CR9, KPNB2, EPC1, NTN4, C20orf52, H2AFJ, UGCG, IMAGE3451454, EEF2K,

MRPL14，E2IG5，MRPL36，GPCR1，E21G5，MGC14151，RASD1，CGI-141，AGR2，KIAA1437，HSPC210，BTBD6.H2AFJ，MRPL14, E2IG5, MRPL36, GPCR1, E21G5, MGC14151, RASD1, CGI-141, AGR2, KIAA1437, HSPC210, BTBD6.H2AFJ,

MGC14151，FLJ20048PSMB4，MGST1，FLJ31364，EGLN1，MRRPL53，LOC88745，IRX3NFKBIEUNC5H2，TAF13，RDH-E2，MGC14151, FLJ20048PSMB4, MGST1, FLJ31364, EGLN1, MRRPL53, LOC88745, IRX3NFKBIEUNC5H2, TAF13, RDH-E2,

MGC12966，DKFZp434G171，GUK1，FL120671，FLJ20623，CAPNS1，PFN1，KIAA1671，FGG，H19，C20orf149，CAPZA1，MGC12966, DKFZp434G171, GUK1, FL120671, FLJ20623, CAPNS1, PFN1, KIAA1671, FGG, H19, C20orf149, CAPZA1,

RAB18，FLJ23153，CGI-19ABCF1，TCEA3，NDUFB10，NDUFB10，RNF7MAL2，NUCKS，RPL23A，LOC51290，TMEPA1，RAB18, FLJ23153, CGI-19ABCF1, TCEA3, NDUFB10, NDUFB10, RNF7MAL2, NUCKS, RPL23A, LOC51290, TMEPA1,

APH2，FLJ13593ATP6V0B，TLP19，SLC17A5，ENPP5，C20orf24，AKIP，D1S155E，FLJ20171，MGC39329，MRPL41，APH2, FLJ13593ATP6V0B, TLP19, SLC17A5, ENPP5, C20orf24, AKIP, D1S155E, FLJ20171, MGC39329, MRPL41,

NDUFV3，KIAA1096，LRG，BPNT1，LOC51255，CISHPGK1，PLEKHA1，HSPCA，COPZ1，DKFZP434L1435，TMEPA1.NDUFV3, KIAA1096, LRG, BPNT1, LOC51255, CISHPGK1, PLEKHA1, HSPCA, COPZ1, DKFZP434L1435, TMEPA1.

BR13，AKIP，KIAA1191，LOC92840，CLDN12，FLJ14525，C20orf149，CDC42，TMPRSS3，LOC199692，FLJ22174，BR13, AKIP, KIAA1191, LOC92840, CLDN12, FLJ14525, C20orf149, CDC42, TMPRSS3, LOC199692, FLJ22174,

LOC113246PKIB，RAP2B，HIBADH，LOC57038，FLJ14117，EDG3，MBC3205MGC2550，RCP，NUDT5，LOC51260，SIPL，LOC113246PKIB, RAP2B, HIBADH, LOC57038, FLJ14117, EDG3, MBC3205MGC2550, RCP, NUDT5, LOC51260, SIPL,

KIAA1223，HINT2，HN1，ERdj5，PHP14，MRPS36MRPL32，C6orf49，CAPN13，MIR，RNF19，ATP11A，LOC51128，FLVCR，KIAA1223, HINT2, HN1, ERdj5, PHP14, MRPS36MRPL32, C6orf49, CAPN13, MIR, RNF19, ATP11A, LOC51128, FLVCR,

ADCY4，KIF5B，ARV1，RABSEP，PX19，RREB1，MIR16，LOC51248SMAP-5，SYTL2，FLJ11320，MSTP028，OCLN，ADCY4, KIF5B, ARV1, RABSEP, PX19, RREB1, MIR16, LOC51248SMAP-5, SYTL2, FLJ11320, MSTP028, OCLN,

MGC14833，SMBPRDH13，MGC40107，KIAA1165，SPPL2A，Cab45，MGC20781，LOC51241，MGC11266，DKFZP566J2046，MGC14833, SMBPRDH13, MGC40107, KIAA1165, SPPL2A, Cab45, MGC20781, LOC51241, MGC11266, DKFZP566J2046,

FLJ14624，CKLFSF6，LOC147184，DKFZP566F084，FLJ20203，FLJ10856，MGC110341MUP，CAMK2D，MK-STYX，FLJ14624, CKLFSF6, LOC147184, DKFZP566F084, FLJ20203, FLJ10856, MGC110341MUP, CAMK2D, MK-STYX,

RAB3D，C20orf142，DNAJB11，MGC23908，FLJ10074SURF4MGC11102HSCARG，MGC14327，HYPK，HSPC121，RAB3D, C20orf142, DNAJB11, MGC23908, FLJ10074SURF4MGC11102HSCARG, MGC14327, HYPK, HSPC121,

TOBISA1，MGC14832，JAM1，MGC27385，PX19，FNTB，MIR，LOC56932，POSH，MPP5，MRP152，MIG-6，LTB4DH，TOBISA1, MGC14832, JAM1, MGC27385, PX19, FNTB, MIR, LOC56932, POSH, MPP5, MRP152, MIG-6, LTB4DH,

ZAK，FLJ22649，SCGB3A1，MGC33974，FLJ21016MGAT4B，KIAA1404RBMS1，DKFZp761H0421，ARHU，FLJ12697，ZAK, FLJ22649, SCGB3A1, MGC33974, FLJ21016MGAT4B, KIAA1404RBMS1, DKFZp761H0421, ARHU, FLJ12697,

CGI-149，SPUVE，TINF2，RPL17，LOC54516，WTAP，MAGI-3SAMHD1，FLJ11011，FLJ10052FLJ23751UCK1，LOC170394，CGI-149, SPUVE, TINF2, RPL17, LOC54516, WTAP, MAGI-3SAMHD1, FLJ11011, FLJ10052FLJ23751UCK1, LOC170394,

TP53INP1，HOXD8，XPR1，MGC10540，SORBS1，BCCIPFLRT3，FLJ22558，FLJ11200，SAMHD1，PIGR，FAM3B，CYP4X1，TP53INP1, HOXD8, XPR1, MGC10540, SORBS1, BCCIPFLRT3, FLJ22558, FLJ11200, SAMHD1, PIGR, FAM3B, CYP4X1,

NFIA，KIAA1715，FLJ20160，CTHRC1，DKFZp547A023HSPC121，LOC84661，LOC113386SH120，GNPNAT1，FLJ32499，NFIA, KIAA1715, FLJ20160, CTHRC1, DKFZp547A023HSPC121, LOC84661, LOC113386SH120, GNPNAT1, FLJ32499,

UBXD1，LOC90120，HBLD1，MGC13186，SPEC1，MYBBP1A，MGC4248，DKFZP43411735，LOC127018，FLJ37318，UBXD1, LOC90120, HBLD1, MGC13186, SPEC1, MYBBP1A, MGC4248, DKFZP43411735, LOC127018, FLJ37318,

FLJ20421，PTGFRN，p25，PIGM，MGC43399，ERdj5，SYT13，IHPK2TH1L，FLJ20727，POLE4ASH1，KIAA1130，LOC55829，FLJ20421, PTGFRN, p25, PIGM, MGC43399, ERdj5, SYT13, IHPK2TH1L, FLJ20727, POLE4ASH1, KIAA1130, LOC55829,

MGC10084，ZPR9，KIAA1458，CNN3，WASLFLJ20097，SURF4，HSPC163YAP1，H4FH，MGC40214KIAA1200，C20orf139，MGC10084, ZPR9, KIAA1458, CNN3, WASLFLJ20097, SURF4, HSPC163YAP1, H4FH, MGC40214KIAA1200, C20orf139,

PKIB，CGI-36，CLMN，SET7，SEC10L1，MGC22825，FLJ10525，LOC113386SELENBP1，SLMAP，VPS29，KIAA1972，PKIB, CGI-36, CLMN, SET7, SEC10L1, MGC22825, FLJ10525, LOC113386SELENBP1, SLMAP, VPS29, KIAA1972,

MTCH2，NPD007，OLD35DNCL11MGC14839，SH120UBPH，APOAIBPLANPL，UBQLN1，FLJ11101，C8orf13，MTCH2, NPD007, OLD35DNCL11MGC14839, SH120UBPH, APOAIBPLANPL, UBQLN1, FLJ11101, C8orf13,

DKFZp434A2417，C14orf31，C14orf100，MMP24，CRIM1，FLJ23393，MGC45714，INADL，SEI1，OPN3，CGI-97，MGC21874，DKFZp434A2417, C14orf31, C14orf100, MMP24, CRIM1, FLJ23393, MGC45714, INADL, SEI1, OPN3, CGI-97, MGC21874,

C14orf47，KIF3B，FLJ11046，C(27)-3BETA-HSD，RAB18，IR1899308，MGC17299KIAA1223，KIAA1322，RAB23FLJ32205，C14orf47, KIF3B, FLJ11046, C(27)-3BETA-HSD, RAB18, IR1899308, MGC17299KIAA1223, KIAA1322, RAB23FLJ32205,

DKFZp434K114，EHF，ShrmL，KIAA1434，KIF1B，ERO1L，MGC15397，BAT5，C20orf45，FLJ31235，LOXL4，FLJ20707，DKFZp434K114, EHF, ShrmL, KIAA1434, KIF1B, ERO1L, MGC15397, BAT5, C20orf45, FLJ31235, LOXL4, FLJ20707,

Cab45RNF7，MGC2803，FLJ36445，CLDN1，DKFZp761N0624FLJ20308，MGC33338，MYO5BRBM8A，MGC10765，Cab45RNF7, MGC2803, FLJ36445, CLDN1, DKFZp761N0624FLJ20308, MGC33338, MYO5BRBM8A, MGC10765,

C14orf9，FLJ32642，ATP1B1，MGC4309，KIAA1272，LOC154467KIAA1483，UBE2H，EHD4，UBE212，FLJ20085，C14orf9, FLJ32642, ATP1B1, MGC4309, KIAA1272, LOC154467KIAA1483, UBE2H, EHD4, UBE212, FLJ20085,

DKFZp762H185，MGC20486，MGC26847，MGC15854，LOC115265，NEK6，SPR2AMGC13045，MGC4604，LOC51256，DKFZp762H185, MGC20486, MGC26847, MGC15854, LOC115265, NEK6, SPR2AMGC13045, MGC4604, LOC51256,

ANKRD9FLJ31208TRIM47，AP1G1DNAJC1DKFZP4341116，LNX，SDCBP2MacGAP，FLJ14957，C20orf10，SURF4，ANKRD9FLJ31208TRIM47, AP1G1DNAJC1DKFZP4341116, LNX, SDCBP2MacGAP, FLJ14957, C20orf10, SURF4,

RAB5EPC12orf4，GL004，DC-TM4F2，SAT，DKFZP434A0225，GK003，dj55C23.6，JUB，LOC89894，LOC115294，RAB5EPC12orf4, GL004, DC-TM4F2, SAT, DKFZP434A0225, GK003, dj55C23.6, JUB, LOC89894, LOC115294,

C20orf129，PCDHA10，HSPC242RAB18，COX15，MGC11115，MRPL27，MGC15397，FLJ11752，LOC116238，C9orf25，C20orf129, PCDHA10, HSPC242RAB18, COX15, MGC11115, MRPL27, MGC15397, FLJ11752, LOC116238, C9orf25,

LOC51760，MGC45408TBX3，HSZFP36，TRIM8MGC22793，BAL，FLJ25157，C20orf155，RPL35A，ZNF2651LF2，LOC51760, MGC45408TBX3, HSZFP36, TRIM8MGC22793, BAL, FLJ25157, C20orf155, RPL35A, ZNF2651LF2,

MGC23166，FBXO6，KIAA1870，DKFZp761D0614，ZNF398，ALS2CR9，MGC26818，EMS1，FLJ90119，GALNT4，MGC23166, FBXO6, KIAA1870, DKFZp761D0614, ZNF398, ALS2CR9, MGC26818, EMS1, FLJ90119, GALNT4,

LOC54516，BR13，HSCARG，PPP1RlB，GPR54，FLJ14299，PPP2R2A，MGC5391，SDCCAG28，PHP14，TGFBR3，MGC1842，LOC54516, BR13, HSCARG, PPP1RlB, GPR54, FLJ14299, PPP2R2A, MGC5391, SDCCAG28, PHP14, TGFBR3, MGC1842,

MLLT4，DFFA，SELM，MAPKAP1，MGC10974，AD-003，FLJ10902，MEF-2，MURR1，MGC2541，GSR，MGC19825，MAFB，MLLT4, DFFA, SELM, MAPKAP1, MGC10974, AD-003, FLJ10902, MEF-2, MURR1, MGC2541, GSR, MGC19825, MAFB,

LOC139231，FLJ23091TEM8，RERGKIAA1553，CFL2，CEBPG，KIAA1554，SEMA4BPDCD4，PNAS-131，MGC31963，LOC139231, FLJ23091TEM8, RERGKIAA1553, CFL2, CEBPG, KIAA1554, SEMA4BPDCD4, PNAS-131, MGC31963,

HT002，HRD1，MESDC2，PRO2605，PTGFRN，KIAA1244，MGC10999，MGC10715，CGI-85，KIAA0779，NUCKS，HT002, HRD1, MESDC2, PRO2605, PTGFRN, KIAA1244, MGC10999, MGC10715, CGI-85, KIAA0779, NUCKS,

FLJ13881，LOC127829，HR，KIAA1538，KIAA1255，STUB1，KIAA1841，CALM2，RIG-1，HOXB8N4WBP5，HTPAP，FLJ13881, LOC127829, HR, KIAA1538, KIAA1255, STUB1, KIAA1841, CALM2, RIG-1, HOXB8N4WBP5, HTPAP,

CXCL16NAC1，TRABID，LOC135154，TRIM56，MK-STYX，Eu-HMTase1FLJ30794，DIRC2PTPN23，GBP2，TRIM11，CXCL16NAC1, TRABID, LOC135154, TRIM56, MK-STYX, Eu-HMTase1FLJ30794, DIRC2PTPN23, GBP2, TRIM11,

KIAA1976，MRPS26，TMEM9，FLJ23420，MGC14817，MK-STYX，IDS，EP164，KIAA1724，MGC2477，FAD104MGC32065，KIAA1976, MRPS26, TMEM9, FLJ23420, MGC14817, MK-STYX, IDS, EP164, KIAA1724, MGC2477, FAD104MGC32065,

MRAS，DKFZP761L0424MGC4840，FLJ20739，GFRA1，FLJ23867，MGC40555，FLJ14251，FLJ38628，MGC2941，MRAS, DKFZP761L0424MGC4840, FLJ20739, GFRA1, FLJ23867, MGC40555, FLJ14251, FLJ38628, MGC2941,

MGC22805，NOL6，MESDC1，FLJ22865，FLJ25357，DLG5ARHGEF5，HYPK，DHRSX，PCDHB2，FLJ90165，MGC22805, NOL6, MESDC1, FLJ22865, FLJ25357, DLG5ARHGEF5, HYPK, DHRSX, PCDHB2, FLJ90165,

C17orf26PVRL2，DKFZP564D166，NOR1，GLJS2，SPPL3，TTC8，FLJ14502CED-6，MGC14141，MLZE，LOC57168，C17orf26PVRL2, DKFZP564D166, NOR1, GLJS2, SPPL3, TTC8, FLJ14502CED-6, MGC14141, MLZE, LOC57168,

KIAA1337，KIAA0217，CRB3，KIAA1350，PPM1AFLJ20273CCL28，PDP，MGC14859，GJB2，GPR，ECGF1LOC92399，KIAA1337, KIAA0217, CRB3, KIAA1350, PPM1AFLJ20273CCL28, PDP, MGC14859, GJB2, GPR, ECGF1LOC92399,

HOXB9，LOC90522，KIAA1951，MANBAL，MGC11386，RIPK1，NLNHCC8LOC115548NUP88，TMEM8，CHDH，HOXB9, LOC90522, KIAA1951, MANBAL, MGC11386, RIPK1, NLNHCC8LOC115548NUP88, TMEM8, CHDH,

FLJ20507FGFR1FLJ30803，KIAA1280，FLJ13089，LOC120224，ZNF75A，DNAJC5，SDOS，MRPS15，MGC2628，FLJ11236，FLJ20507FGFR1FLJ30803, KIAA1280, FLJ13089, LOC120224, ZNF75A, DNAJC5, SDOS, MRPS15, MGC2628, FLJ11236,

TRIM39，NESHBPFLJ10839SULF2.，FLJ10210，METL，FLJ12707，HUMAGCGB，FLJ13195，FLJ21016，BOK，FBXO25，TRIM39, NESHBPFLJ10839SULF2., FLJ10210, METL, FLJ12707, HUMAGCGB, FLJ13195, FLJ21016, BOK, FBXO25,

OSBPL5，DKFZP434N1511，KIAA1813，VANGL2，LOC124446，HDCMA18P，C20orf7，MGC1314，MS4A6AANLN，OSBPL5, DKFZP434N1511, KIAA1813, VANGL2, LOC124446, HDCMA18P, C20orf7, MGC1314, MS4A6AANLN,

MGC40499，KIAA1337，FLJ10116，NOTCH2，RRP40，PFKFB4FLJ14681，KIAA1026，C1orf6，MGC5384，LOC85565，PHAX，MGC40499, KIAA1337, FLJ10116, NOTCH2, RRP40, PFKFB4FLJ14681, KIAA1026, C1orf6, MGC5384, LOC85565, PHAX,

MGC11134，FEM1A，LACTB，T1M50L，ARNT，MS4A6A，PP1L1，C20orf3，MRPS15PGGT1B，CXADR，LBP-32，FLJ22004，MGC11134, FEM1A, LACTB, T1M50L, ARNT, MS4A6A, PP1L1, C20orf3, MRPS15PGGT1B, CXADR, LBP-32, FLJ22004,

FLJ32069，UACA，MGC2747，FLJ13187C1orf28，CBX6，C1orf13，NY-BR-1，FLJ20748，KIAA1821，FLJ31751，LSR68，FLJ32069, UACA, MGC2747, FLJ13187C1orf28, CBX6, C1orf13, NY-BR-1, FLJ20748, KIAA1821, FLJ31751, LSR68,

TRAD，USP28，FLJ10702，GBA2，B7-H3，DKFZp547D065，TH1L，TSGA2，RORC，ETL1，FLJ30634，MGC10702，TRAD, USP28, FLJ10702, GBA2, B7-H3, DKFZp547D065, TH1L, TSGA2, RORC, ETL1, FLJ30634, MGC10702,

TEX27MGC33602，MGC2555，LOC55893，LOC128439，EDIL3，KIAA0146，RFXANNK，HS6ST1，NEK6，FLJ20186，TEX27MGC33602, MGC2555, LOC55893, LOC128439, EDIL3, KIAA0146, RFXANNK, HS6ST1, NEK6, FLJ20186,

MGC15416HSPC159，SCAMP2，LOC133619，NGEF，C14orf58LOC91012，MGC12972，MGC1034，CYT19KIAA0819，MGC15416HSPC159, SCAMP2, LOC133619, NGEF, C14orf58LOC91012, MGC12972, MGC1034, CYT19KIAA0819,

LOC55893PHCCA，KCNK6，CRIPT，CDW92MGC3195，GTARPAPOLG，MGC24180，KIAA1126MTA3，MGC24103，moblak，LOC55893PHCCA, KCNK6, CRIPT, CDW92MGC3195, GTARPAPOLG, MGC24180, KIAA1126MTA3, MGC24103, moblak,

MS4A6A，DAG1，KIAA1394，MGC13114，KIAA1337，FLJ40021，DPP9，KIAA0789ZNF144，TMPIT，MGC13114SYAP1，MS4A6A, DAG1, KIAA1394, MGC13114, KIAA1337, FLJ40021, DPP9, KIAA0789ZNF144, TMPIT, MGC13114SYAP1,

FBXO32，BOCCD44，LSM10，KIAA1673，CTL2C21orf63MGC2560，ZFP385，TM4SF9，DNAH5，PGGT1B，FBXO32, BOCCD44, LSM10, KIAA1673, CTL2C21orf63MGC2560, ZFP385, TM4SF9, DNAH5, PGGT1B,

DKFZp586M1819，1D4，CLIC6，C20orf64，YAP1，FLJ21615，GRP58，LOC149267，C20orf7FLJ37933，FLJ90586，FLJ22626，DKFZp586M1819, 1D4, CLIC6, C20orf64, YAP1, FLJ21615, GRP58, LOC149267, C20orf7FLJ37933, FLJ90586, FLJ22626,

LOC51242，MGC4604，SDCCAG28，KIAA1321，TEAD2，RPS3A，LOC90701，FLJ32915，FLJ31434，PLJNC，TRPS1，LOC51242, MGC4604, SDCCAG28, KIAA1321, TEAD2, RPS3A, LOC90701, FLJ32915, FLJ31434, PLJNC, TRPS1,

MGC45441，LIN7B，DKFZP434H0820FLJ32468，DNALI1，COX412，HOXC9，FLJ20337CLMN，BCAA，OPN4，DGAT2，MGC45441, LIN7B, DKFZP434H0820FLJ32468, DNALI1, COX412, HOXC9, FLJ20337CLMN, BCAA, OPN4, DGAT2,

PRDM6，DKFZp761J1523，K1AA1244，ICMT，FGF11，C21orf97，C20orf169，VPS18，SIRT2，MGC15677，MGC4604FHOD2，PRDM6, DKFZp761J1523, K1AA1244, ICMT, FGF11, C21orf97, C20orf169, VPS18, SIRT2, MGC15677, MGC4604FHOD2,

DKFZp547M072，CGI-125，NLN，MAPILC3AFLJ31842，PGLYRP，FLJ32069，DKFZp547A023，MGC39325，RRP40，DKFZp547M072, CGI-125, NLN, MAPILC3AFLJ31842, PGLYRP, FLJ32069, DKFZp547A023, MGC39325, RRP40,

KIAA1880，LOC116254LOC51061SYTL2，KIAA0076，KIAA1580，GPT2MGC4840KIAA1345FLJ12577，Tenr，CCT5，KIAA1880, LOC116254LOC51061SYTL2, KIAA0076, KIAA1580, GPT2MGC4840KIAA1345FLJ12577, Tenr, CCT5,

FANCF，USP21，KIAA1273，DKFZP434F091，MGC13007MGC16131，SEC5FLJ22215，FBXO22，MGC16491，MGC16028，FANCF, USP21, KIAA1273, DKFZP434F091, MGC13007MGC16131, SEC5FLJ22215, FBXO22, MGC16491, MGC16028,

MGC2601MGC15906，C20orf45C17orf28，IL17BR，STK111P，SEC61A1，STAU2，FAPP2，FLJ25429，CAC-1，ROCK1，MGC2601MGC15906, C20orf45C17orf28, IL17BR, STK111P, SEC61A1, STAU2, FAPP2, FLJ25429, CAC-1, ROCK1,

MS4A7，DKFZp434D0215，FLJ20442，HFELOC148523，LOC90353，HIPK2，ERBB21P，CDKN2B，CGI-09，DPP7，DUSP16，MS4A7, DKFZp434D0215, FLJ20442, HFELOC148523, LOC90353, HIPK2, ERBB21P, CDKN2B, CGI-09, DPP7, DUSP16,

CGN，CLONE24922MSCP，DKFZp547E052，MGC45714，MGC5370，MAP4KISLC4A11，MGC26568，PPIL2，MGC27034，CGN, CLONE24922MSCP, DKFZp547E052, MGC45714, MGC5370, MAP4KISLC4A11, MGC26568, PPIL2, MGC27034,

FBXO30，DKFZp547C195，MIC2L1，DHRSXHTPAP，VIK，FLJ23841，DKFZP434D146，HPS3，IPP，SEMA6ADNAJC5，FBXO30, DKFZp547C195, MIC2L1, DHRSXHTPAP, VIK, FLJ23841, DKFZP434D146, HPS3, IPP, SEMA6ADNAJC5,

ULBP2，LOC120224，FLJI1036LOC90580，LOC92906，WDR5，RAB35FLJ10697，MAPT，FLJ14825，KIAA1295，MGC2217，ULBP2, LOC120224, FLJI1036LOC90580, LOC92906, WDR5, RAB35FLJ10697, MAPT, FLJ14825, KIAA1295, MGC2217,

ACTR8，SENP2，LMLN，LTB4DH，MGC11257，MGC15476，SART1，TNN13，LOC128153，SCDPRO1912，KIAA1896，ACTR8, SENP2, LMLN, LTB4DH, MGC11257, MGC15476, SART1, TNN13, LOC128153, SCDPRO1912, KIAA1896,

LOC80298，FLJ20533，SMCR7CGI-69LOC114977KIAA1691，C20orf102，VIP，FBXW5，TRIM35，SLC30A5，JAG1SLC13A3，LOC80298, FLJ20533, SMCR7CGI-69LOC114977KIAA1691, C20orf102, VIP, FBXW5, TRIM35, SLC30A5, JAG1SLC13A3,

COQ4，OVCOV1，GLJ4，RPC8，FLJ31153，C20orf162，NRP2ENAHARH2LOC55971，FLJ20038CerCAM，UBE4B，COQ4, OVCOV1, GLJ4, RPC8, FLJ31153, C20orf162, NRP2ENAHARH2LOC55971, FLJ20038CerCAM, UBE4B,

LOC57168ALS2CR9，SLC21A11，GPP108MRPL41，KIAA0831KIAA1970，DKFZp7621137INPP4B，ZFP67HSPC189，LOC57168ALS2CR9, SLC21A11, GPP108MRPL41, KIAA0831KIAA1970, DKFZp7621137INPP4B, ZFP67HSPC189,

PF1PCDHB6C2orf9KIAA1468，FL114399，DKFZp434G118，KIAA1500，FLJ14681KIAA0869FLJ22558APXL2，MGC16028，PF1PCDHB6C2orf9KIAA1468, FL114399, DKFZp434G118, KIAA1500, FLJ14681KIAA0869FLJ22558APXL2, MGC16028,

APMCF1，LOC90990，PCDH18，DKFZP564J0863，COG1UBE2H，KIAA1970，CTSB，MGC30052，FLJ90575，MMP28，APMCF1, LOC90990, PCDH18, DKFZP564J0863, COG1UBE2H, KIAA1970, CTSB, MGC30052, FLJ90575, MMP28,

MASS1，MGC13034，RIPK3，CCT4FLJ12519，GOLGA3RCPCP，MGC20983，FLJ35207EML4，TRUB1MRPL41ZNF213，MASS1, MGC13034, RIPK3, CCT4FLJ12519, GOLGA3RCPCP, MGC20983, FLJ35207EML4, TRUB1MRPL41ZNF213,

RP42，FLJ20813，SAMHD1，KRTAP4-8，C4orf1FBXO8，EPB41L4B，ZNF75A，STK36，PAWRFLII，DKFZp761A052，RP42, FLJ20813, SAMHD1, KRTAP4-8, C4orf1FBXO8, EPB41L4B, ZNF75A, STK36, PAWRFLII, DKFZp761A052,

C20orf23，AKIP，MGC4643，VT11A，LOC223082，PDK4，PSMB7，KIAA1710，MGC13272，MGC4342，GNG12，N33，C20orf23, AKIP, MGC4643, VT11A, LOC223082, PDK4, PSMB7, KIAA1710, MGC13272, MGC4342, GNG12, N33,

FLJ14800，FLJ21924，LOC220074，FLJ22474，DKFZP434P106，FLJ13236，PTENP1，FLJ21159KIAA1441，CGI-85，FAM3D，FLJ14800, FLJ21924, LOC220074, FLJ22474, DKFZP434P106, FLJ13236, PTENP1, FLJ21159KIAA1441, CGI-85, FAM3D,

DKFZP566J2046，LOC116441，TEAD1 LOC51249，PARVA，HSPC230，MGC5442FLJ23091LOC55893，PDCD6IP，OGN，DKFZP566J2046, LOC116441, TEAD1 LOC51249, PARVA, HSPC230, MGC5442FLJ23091LOC55893, PDCD6IP, OGN,

TRIM41，MGC42105，CPNE2，DKFZp547J144，KIAA1784，KIAA1337，SLC30A1RNAC，KIAA0429NRXN3，Spir-2，GGCX，TRIM41, MGC42105, CPNE2, DKFZp547J144, KIAA1784, KIAA1337, SLC30A1RNAC, KIAA0429NRXN3, Spir-2, GGCX,

KIAA1694，DNAJA4，CAPN13，NAP1L，RPS27LTMOD4KIAA1557，FLJ21415DKFZP564G092，CLN8PARVA，KIAA1694, DNAJA4, CAPN13, NAP1L, RPS27LTMOD4KIAA1557, FLJ21415DKFZP564G092, CLN8PARVA,

FLJ40021KIAA1708PC326，NOSTRIN，LOC129642，KIAA1301，CGI-85，MGC13102，LZIC，KIAA2025，FAPP2，FLJ22679，FLJ40021KIAA1708PC326, NOSTRIN, LOC129642, KIAA1301, CGI-85, MGC13102, LZIC, KIAA2025, FAPP2, FLJ22679,

SNX8，ZNT6，DUSP16，PANK2，FLJ14834，DKFZp434C0328，ROD1，FLJ34633，FLJ13391，ARHJ，FLJ11753，B29，OSAP，SNX8, ZNT6, DUSP16, PANK2, FLJ14834, DKFZp434C0328, ROD1, FLJ34633, FLJ13391, ARHJ, FLJ11753, B29, OSAP,

B2M，CYGB，DERMO1，MIR，WDR20，C20orf155，FLJ32919，MGC408，CLGSCYLlDKFZp761A132，DKFZp451G182，B2M, CYGB, DERMO1, MIR, WDR20, C20orf155, FLJ32919, MGC408, CLGSCYLlDKFZp761A132, DKFZp451G182,

FLJ90119，FLJ36991，SDCCAG43，PPP1R16A，MGC19764，FLJ13263，GNG2FLJ12517，MRPL20，MGC16212，SRA1，FLJ90119, FLJ36991, SDCCAG43, PPP1R16A, MGC19764, FLJ13263, GNG2FLJ12517, MRPL20, MGC16212, SRA1,

GEMIN7，FLJ37953，HBP1，KIAA1737，CTL2，KIAA1754，FOXA1，MGC13096，HDAC3BOC，FLJ30973，BRUNOL5SEL1L，GEMIN7, FLJ37953, HBP1, KIAA1737, CTL2, KIAA1754, FOXA1, MGC13096, HDAC3BOC, FLJ30973, BRUNOL5SEL1L,

SPTB，POU4F1，KIAA1337，MIZIP，NAGSCGI-72，PRO1853TRAF4，MGC32124，SNCAIPDKFZp434O0515，SMOC2，SPTB, POU4F1, KIAA1337, MIZIP, NAGSCGI-72, PRO1853TRAF4, MGC32124, SNCAIPDKFZp434O0515, SMOC2,

FLJ12770LOC113828，FLJ40432DKFZP434K0427，SFPQ，RNB6，BMF，GSH-2，REV1L，SLC27A4C1orf19，FLJ12770LOC113828, FLJ40432DKFZP434K0427, SFPQ, RNB6, BMF, GSH-2, REV1L, SLC27A4C1orf19,

SLC5AIKIAA0478，SPPH1，FZD8，MGC26877LOC150379STK36，LIMD1，KIAA1694，FLJ25357ELAVL2，BM-002，SLC5AIKIAA0478, SPPH1, FZD8, MGC26877LOC150379STK36, LIMD1, KIAA1694, FLJ25357ELAVL2, BM-002,

ProsteinFLJ20374，STK35，FLJ31434，CHRM1，DLC1，FLJ36155，FLJ21939，MGC21675LOC51320，FCRH3，FLJ10948，ProsteinFLJ20374, STK35, FLJ31434, CHRM1, DLC1, FLJ36155, FLJ21939, MGC21675LOC51320, FCRH3, FLJ10948,

MGC27034，MGC14801，MGC11102，SEC14L2KIAA1393，DKFZP434A0225，DKFZp434F054，SHANK2，OSGEP，MGC27034, MGC14801, MGC11102, SEC14L2KIAA1393, DKFZP434A0225, DKFZp434F054, SHANK2, OSGEP,

MGC45474，ARHGAP8，BTCILIF7GRLF1，DKFZP434B172，MRPL35，PAPOLG，MGC33662，XPO5CTEN，DSCR9，MGC45474, ARHGAP8, BTCILIF7GRLF1, DKFZP434B172, MRPL35, PAPOLG, MGC33662, XPO5CTEN, DSCR9,

ITGB6FLJ14768，STEAP2KIAA1522，FLJ32069，PCDHB3C20orf136，XRN2MARK1，DKFZp547O146，FLJ12517，ITGB6FLJ14768, STEAP2KIAA1522, FLJ32069, PCDHB3C20orf136, XRN2MARK1, DKFZp547O146, FLJ12517,

FLJ10597GK001，CITED4，IGL@，GALNT13MGC26963，RASAL2FLJ20605，LOC112609，NLGN3，C7orf2，HSPC182，FLJ10597GK001, CITED4, IGL@, GALNT13MGC26963, RASAL2FLJ20605, LOC112609, NLGN3, C7orf2, HSPC182,

DTNASNX9，ALS2CR9KIAA1219KIAA1190C14orf31HSPC065，KIAA1221，FLJ10252，C4orf7，KIAA1363，NCAG1，DTNASNX9, ALS2CR9KIAA1219KIAA1190C14orf31HSPC065, KIAA1221, FLJ10252, C4orf7, KIAA1363, NCAG1,

NAV1，C14orf28，KLP1，ZDHHC9，MGC2615，SMUG1，PHLDA1，AD-003，BRPF3，ASCL2MGC15523，RELA，ROPN1，NAV1, C14orf28, KLP1, ZDHHC9, MGC2615, SMUG1, PHLDA1, AD-003, BRPF3, ASCL2, MGC15523, RELA, ROPN1,

FZD4，ZDHHC4，KRTAP3-1，PCDHB16KIAA1036，SLC2A12MSTP043，FLJ32731AMID，FLJ30277，CKLFSF2，TLR7，FZD4, ZDHHC4, KRTAP3-1, PCDHB16KIAA1036, SLC2A12MSTP043, FLJ32731AMID, FLJ30277, CKLFSF2, TLR7,

SEMA6DNOPE，DKFZP434P0111，SDS3，KSP37，PDCD6SNX14，AIBG，SLC31A1，MK-STYX，SNTG1LOC80298，SEMA6DNOPE, DKFZP434P0111, SDS3, KSP37, PDCD6SNX14, AIBG, SLC31A1, MK-STYX, SNTG1LOC80298,

FLJ25534，MGC10485，FLJ10035，NEUGRIN，BK65A6.2，NKD2，TJP2TRPS1FLJ20753，PPPIR1A，LOC123169，FLJ25534, MGC10485, FLJ10035, NEUGRIN, BK65A6.2, NKD2, TJP2TRPS1FLJ20753, PPPIR1A, LOC123169,

LOC112817，ZNF341，TM4SF9，FLJ90586Spir-1REN，FLJ10210，CEGF3，NOXA1，FLJ14981，RIMS1，PCDH20FLJ20360，LOC112817, ZNF341, TM4SF9, FLJ90586Spir-1REN, FLJ10210, CEGF3, NOXA1, FLJ14981, RIMS1, PCDH20FLJ20360,

DKFZp761H0421，MSX1，DKFZp434F2322FLJ10188，SPP2，MUM2SYT12，pknbeta，MGC11349，RNF40MGC4734，DKFZp761H0421, MSX1, DKFZp434F2322FLJ10188, SPP2, MUM2SYT12, pknbeta, MGC11349, RNF40MGC4734,

MAP1LC3A，FLJ13687，CNTN3，MGC19604，TLR8，FBXW7，HM13，TLE1AK1P，SMURF2，FLJ21963，MRPL44，PRKAG3，MAP1LC3A, FLJ13687, CNTN3, MGC19604, TLR8, FBXW7, HM13, TLE1AK1P, SMURF2, FLJ21963, MRPL44, PRKAG3,

DREV1HSA243666，FENS-1LOC51693FLJ10486，HAVCR2，HDAC3，AHRR，CXCL14，CGI-DREV1HSA243666, FENS-1LOC51693FLJ10486, HAVCR2, HDAC3, AHRR, CXCL14, CGI-

09MGC13251DKFZp434E2321，C14orf102KIAA1434，PHCAKIAA1145，FLJ00028，AMOTL1，TMPRSS6，ODF3，09MGC13251DKFZp434E2321, C14orf102KIAA1434, PHCAKIAA1145, FLJ00028, AMOTL1, TMPRSS6, ODF3,

MGC4604，DJ667H12.2，VGL2FLJ10052FLJ13881，UK114，DSG2SLC12A4TBCD，MAP1B，OSBPL10GALNT10，MGC4604, DJ667H12.2, VGL2FLJ10052FLJ13881, UK114, DSG2SLC12A4TBCD, MAP1B, OSBPL10GALNT10,

DKFZp5471094MGC35352OSBPL6，TRIM7，FLJ30473，MGC2562，DLG1，DKFZp434P0531，KIAA1554ESDNKIAA1910，DKFZp5471094MGC35352OSBPL6, TRIM7, FLJ30473, MGC2562, DLG1, DKFZp434P0531, KIAA1554ESDNKIAA1910,

SEC15BKIAA1172DSCR1L2，PSMB5OSBP2，GPR34，MGC15854，HDAC5LOC90990，DKFZP564B1023，SEC15BKIAA1172DSCR1L2, PSMB5OSBP2, GPR34, MGC15854, HDAC5LOC90990, DKFZP564B1023,

CASP2NUP133Spir-2，LOC151534，C22orf23，FLJ90811，DKFZp43411930，NET-2，LOC113026，HOOK3MGC8721，BLVRA，CASP2NUP133Spir-2, LOC151534, C22orf23, FLJ90811, DKFZp43411930, NET-2, LOC113026, HOOK3MGC8721, BLVRA,

PLA2G12，DAPP1，FBG3MGC10974，LOC114990，DKFZp547M2010，FLJ20542，LOC144455CGI-94BRUNOL5HKE2，PLA2G12, DAPP1, FBG3MGC10974, LOC114990, DKFZp547M2010, FLJ20542, LOC144455CGI-94BRUNOL5HKE2,

PRND，WFDC3FLJ30990，FLJ23654，KIAA0876，NDUFS1WASL，KRT61RS，KIAA1684，RU2，DKFZP434K0427，PRND, WFDC3FLJ30990, FLJ23654, KIAA0876, NDUFS1WASL, KRT61RS, KIAA1684, RU2, DKFZP434K0427,

DKFZp434B217，KIAA1549DKFZp434F2322，MGC4126ENTPD2，GPRC5C，RGNEFFLJ31052CEGF3SYN2，DKFZp434B217, KIAA1549DKFZp434F2322, MGC4126ENTPD2, GPRC5C, RGNEFFLJ31052CEGF3SYN2,

C11ORF30MGC3038，ITGA11KIAA1053LOC57822，LOC130589，RASGRP4，DKFZp434H2111，NFIA DKFZP434C0328，C11ORF30MGC3038, ITGA11KIAA1053LOC57822, LOC130589, RASGRP4, DKFZp434H2111, NFIA DKFZP434C0328,

FLJ20209，NDUFS2SENP8SLC2A4RG，p25，C20orf167KIAA1909，MGC4238，MGC16372，CD5，IGKC，KCNQ4，FLJ20209, NDUFS2SENP8SLC2A4RG, p25, C20orf167KIAA1909, MGC4238, MGC16372, CD5, IGKC, KCNQ4,

ZD52F10CCL28，FLJ20539KIAA1357，EPB41L4B，MGC14128，SLC1A5RHEB2，HSPC182，FLJ22527，MGC21621，ZD52F10CCL28, FLJ20539KIAA1357, EPB41L4B, MGC14128, SLC1A5RHEB2, HSPC182, FLJ22527, MGC21621,

MGC5370KIAA1130，KIAA1554C9orf11 FLJ319371MP-2C20orf51，KRTAP17-1，DKFZP434E2318，MGC5370KIAA1130, KIAA1554C9orf11 FLJ319371MP-2C20orf51, KRTAP17-1, DKFZP434E2318,

DKFZP564B1162RPL29，PRO1489HSPA9BKIAA1688，KIAA1324NCOA5，AXIN2，LOC92689，KIAA1272FLJ14642，DKFZP564B1162RPL29, PRO1489HSPA9BKIAA1688, KIAA1324NCOA5, AXIN2, LOC92689, KIAA1272FLJ14642,

FLJ37440，FLJ12604，RGS8，MS4A6AZNF216，LOC84570，KIAA1126，SMOC1，TSCOTMGC18257，RDH13，FLJ37440, FLJ12604, RGS8, MS4A6AZNF216, LOC84570, KIAA1126, SMOC1, TSCOTMGC18257, RDH13,

CIQGKIAA1576，ZFP28GNA14，FLJ39155FLJ32069LOC155066，MGC19764FLJ10159，MGC16309LOC55862，CIQGKIAA1576, ZFP28GNA14, FLJ39155FLJ32069LOC155066, MGC19764FLJ10159, MGC16309LOC55862,

PCDHB1437867.00，LOC56851，SNRK，MGC13017，ADAMTS16AGMATPCDHB10，LOC113179，NOL6，C20orf55，PCDHB1437867.00, LOC56851, SNRK, MGC13017, ADAMTS16AGMATPCDHB10, LOC113179, NOL6, C20orf55,

PALMD，GFER，BNIP-S，KIAA1337AXIN2，MGC39807，LIP8KIAA1053，MGC45378FLJ11273，PALMD, GFER, BNIP-S, KIAA1337AXIN2, MGC39807, LIP8KIAA1053, MGC45378FLJ11273,

FLJ23129DKFZp58611420KIAA1210COX7B2，TCF7L2，USP21，DKFZp564O1278，FLJ23129DKFZp58611420KIAA1210COX7B2, TCF7L2, USP21, DKFZp564O1278,

FAAHDPCRINUMBMGC35285JUBEVX1，LMO4AMOTL1，C2orf7TMPRSS3，ARHGEF7CSRP2BP SBBI31，SSBP4，FAAHDPCRINUMBMGC35285JUBEVX1, LMO4AMOTL1, C2orf7TMPRSS3, ARHGEF7CSRP2BP SBBI31, SSBP4,

FLJ23654，CPMDKFZp762K222，DPP9CA5BKIAA1817C14orf92，MYO3A，VIK，CACNG4，NYD-SP21LUC7L，SFRS12，FLJ23654, CPMDKFZp762K222, DPP9CA5BKIAA1817C14orf92, MYO3A, VIK, CACNG4, NYD-SP21LUC7L, SFRS12,

LIPHDIS3，GCC1，FLJ10504，CASP14，KIAA1387，DAB21P，KIAA2028C20orf40GPR92FLJ32658FLJ25027，UQCRC1，LIPHDIS3, GCC1, FLJ10504, CASP14, KIAA1387, DAB21P, KIAA2028C20orf40GPR92FLJ32658FLJ25027, UQCRC1,

EVC，COG1FLJ25555MOV10ALDRL6，HTGN29MGC12466，IBA2，MGC15548ADD3，GSN，EVC, COG1FLJ25555MOV10ALDRL6, HTGN29MGC12466, IBA2, MGC15548ADD3, GSN,

C14orf50MGC22805MGC39650，KIAA1203FLJ14311，HRMT1L1，MASS1，CGN，IGHG3，ESPN，ZDHHC12，C14orf50MGC22805MGC39650, KIAA1203FLJ14311, HRMT1L1, MASS1, CGN, IGHG3, ESPN, ZDHHC12,

PCDHB4THRSP，FGFR2，LOC91461FLJ25604DRAPC1，ARL8BACH1，KIAA1921，GPR81，KIAA1145ARHGEF7，retSDR3，PCDHB4THRSP, FGFR2, LOC91461FLJ25604DRAPC1, ARL8BACH1, KIAA1921, GPR81, KIAA1145ARHGEF7, retSDR3,

C20orf6ARFGAPINSE1TPSG1MRPL4，KIAA1870，X102，KIAA0599，CACNG6，FLJ22301，ZIC2，KIAA0599，MGC4796C20orf6ARFGAPINSE1TPSG1MRPL4, KIAA1870, X102, KIAA0599, CACNG6, FLJ22301, ZIC2, KIAA0599, MGC4796

HT036，DQX1，SYTL4ICAP-1A，KIAA0350，KIAA0872，GMPPB，FLJ37953，LMLN，NOL6，POLR2J2Hes4，LOC57038，HT036, DQX1, SYTL4ICAP-1A, KIAA0350, KIAA0872, GMPPB, FLJ37953, LMLN, NOL6, POLR2J2Hes4, LOC57038,

TRPM6，ABCC13，BCAR1FLJ30803FLJ32069KIAA1909，TIMM8BEML4MGC15606MGC35048，NRP2PCA3，IL17BR，TRPM6, ABCC13, BCAR1FLJ30803FLJ32069KIAA1909, TIMM8BEML4MGC15606MGC35048, NRP2PCA3, IL17BR,

DKFZp727A071，MGC14128，GABRB3，MRP63，PGBD2GATA5，FLJ14735，ENTPD6，SYNE，2PRIC285，MGC2555，DKFZp727A071, MGC14128, GABRB3, MRP63, PGBD2GATA5, FLJ14735, ENTPD6, SYNE, 2PRIC285, MGC2555,

LOC90378GLCATS，GCN5L1，DKFZp434F2322，MSCPFLJ30681，ZNFN1A4PRO0971TTTY6C14orf47CTXLFTCD，LOC90378GLCATS, GCN5L1, DKFZp434F2322, MSCPFLJ30681, ZNFN1A4PRO0971TTTY6C14orf47CTXLFTCD,

MGC2835MGC12435，STYXFLJ12076C20orf106TEX11MGC19825，TPM2HOXD10，KIAA1554，FLJ20014，FLJ20748，MGC2835MGC12435, STYXFLJ12076C20orf106TEX11MGC19825, TPM2HOXD10, KIAA1554, FLJ20014, FLJ20748,

PPP1R14C，ARHV，ALDOAEGFR-RSC20orf92FLJ14594MSCP，PRO0038SLC25A15，RSP3，PPPIR9A，PPP1R14C, ARHV, ALDOAEGFR-RSC20orf92FLJ14594MSCP, PRO0038SLC25A15, RSP3, PPPIR9A,

EPHA7MGC35521GFAP，ICEBERGFOXP3，FLJ33516GPR55，ZNF398，PRO1635FLJ33903FLJ32203，ORMDL3，EPHA7MGC35521GFAP, ICEBERGFOXP3, FLJ33516GPR55, ZNF398, PRO1635FLJ33903FLJ32203, ORMDL3,

LOC51315，FLJ32752ELP2LIMDIKIAA1357DOCK1，FLJ14721，STCIALAS2，HMT-1PADI1，PTPN23FLJ10210，FLJ10826，LOC51315, FLJ32752ELP2LIMDIKIAA1357DOCK1, FLJ14721, STCIALAS2, HMT-1PADI1, PTPN23FLJ10210, FLJ10826,

ELAVL3，LOC90668 FLJ32069，NOL6，LGALS1LOC55971，FLJ20273，SSB1FAD104，GPR107TRA@，SORCS2，ELAVL3, LOC90668 FLJ32069, NOL6, LGALS1LOC55971, FLJ20273, SSB1FAD104, GPR107TRA@, SORCS2,

LOC91010FGFRL1，UQCR，SEC14L2，DENRST6GalNAcI，KISEGLN1，ZNF219SNAP29，TNKS2QP-CSLJC4A11，PURB，LOC91010FGFRL1, UQCR, SEC14L2, DENRST6GalNAcI, KISEGLN1, ZNF219SNAP29, TNKS2QP-CSLJC4A11, PURB,

KIAA1163，FOXP1，Cl2orf22，TCF7L2，CDH23，FLJ13955KIAA1828，FLJ33008LOC115704，SLC13A3ASB1，KIAA1163, FOXP1, Cl2orf22, TCF7L2, CDH23, FLJ13955KIAA1828, FLJ33008LOC115704, SLC13A3ASB1,

DKFZp7621194，CPNE4，GRIN3A，MSTP043，BHLHB5ADMPRBM6，MGC13275，KIAA1889，KRTAP3-3LOXL2，DKFZp7621194, CPNE4, GRIN3A, MSTP043, BHLHB5ADMPRBM6, MGC13275, KIAA1889, KRTAP3-3LOXL2,

LOC51290，C11orf23FLJ20309，MGC26778NAV1，ARHUFLJ23749，FLJ33071NUMBL，PTPNS1L2MGC3040SMAP-5，LOC51290, C11orf23FLJ20309, MGC26778NAV1, ARHUFLJ23749, FLJ33071NUMBL, PTPNS1L2MGC3040SMAP-5,

MGC2835CDGAPCHFR，FLJ90440，DKFZp434G0522FLJ10300，TRIP11，HSFY，HOOK3，GTF3A，FLJ12634，MGC2835CDGAPCHFR, FLJ90440, DKFZp434G0522FLJ10300, TRIP11, HSFY, HOOK3, GTF3A, FLJ12634,

NEO1TEAD2PTPN2，BCL2L1，KIAA1557 KPNB2，ACPP，CISH，DKFZP434P106，ASPH，DOT1L，FLJ22944SRGAP1，NEO1TEAD2PTPN2, BCL2L1, KIAA1557 KPNB2, ACPP, CISH, DKFZP434P106, ASPH, DOT1L, FLJ22944SRGAP1,

OLFM2，SIN3A，ASB12，CECR7MGC40397NFKB1A，POLRMT，CGI-149C21orf84，MTMR9，GATA4，XYLT1，OLFM2, SIN3A, ASB12, CECR7MGC40397NFKB1A, POLRMT, CGI-149C21orf84, MTMR9, GATA4, XYLT1,

PCDHB7SEC15L，C20orf160 MGC33302Clorf19，COL12A1，EGLN3，FLJ21032MGC3040，ODZ2，ING5，PCDHB7SEC15L, C20orf160 MGC33302Clorf19, COL12A1, EGLN3, FLJ21032MGC3040, ODZ2, ING5,

C12orf2HS6ST2AQP1，MGC10981MGC33607FLJ14399PRACDCAL1，MGC40222，TMOD3，TEFSDS-RS1，C12orf2HS6ST2AQP1, MGC10981MGC33607FLJ14399PRACDCAL1, MGC40222, TMOD3, TEFSDS-RS1,

LOC115098KIAA1573MLL3，FLJ14103AK3 ARPM1，CARD14MGC12916，ALS2CR12，FLN29，FLJ12697TOB2，LOC115098KIAA1573MLL3, FLJ14103AK3 ARPM1, CARD14MGC12916, ALS2CR12, FLN29, FLJ12697TOB2,

N33GTF21，BHLHB3GPC6，CAMK2D，KRTAP4-13，BDP1，DKFZp761H079，DKFZP564J047CED-6，EB-1，MGC4659N33GTF21, BHLHB3GPC6, CAMK2D, KRTAP4-13, BDP1, DKFZp761H079, DKFZP564J047CED-6, EB-1, MGC4659

GPR110，DOCKl，FLJ20211，SCN11A，LOC118471，LOC151568 ZFHX2SLA/LP，PCANAP7，HDAC3，POU5F1，GGTL3，GPR110, DOCKl, FLJ20211, SCN11A, LOC118471, LOC151568 ZFHX2SLA/LP, PCANAP7, HDAC3, POU5F1, GGTL3,

C7，FLJ25410，SCAND2，C20orf136，FLJ21616，EB-1，FLJ25067，KIF9KIAA1276，LOC55864，FLJ32771，DKFZp667B1218，C7, FLJ25410, SCAND2, C20orf136, FLJ21616, EB-1, FLJ25067, KIF9KIAA1276, LOC55864, FLJ32771, DKFZp667B1218,

DNAJC9LOC51319，FLJ10902，FLJ36525，MESDC2DDX12MGC33993KIAA1399，LLT1，DKFZP434F091，DNAJC9LOC51319, FLJ10902, FLJ36525, MESDC2DDX12MGC33993KIAA1399, LLT1, DKFZP434F091,

FLJ12697GPR24，SE70-2，NANSFLJ12571，IL-17RC，TRIM7，NXPH1，ROR2，C20orf60，KLHL5，ZNF265，BECNISCARA3，FLJ12697GPR24, SE70-2, NANSFLJ12571, IL-17RC, TRIM7, NXPH1, ROR2, C20orf60, KLHL5, ZNF265, BECNISCARA3,

PRO1580，MGC35392DKFZP434N178，PEX5R，FLJ31528，LOC135763CLECSF9，MGC41906，FBXO11ZNFNIA4，PRO1580, MGC35392DKFZP434N178, PEX5R, FLJ31528, LOC135763CLECSF9, MGC41906, FBXO11ZNFNIA4,

SPINOFBXO22，IHPK3 C20orf167MAP2FLJ25270，STRBP，MUC13KIAA1878，SNX9MGC26143KIAA1887，SPINOFBXO22, IHPK3 C20orf167MAP2FLJ25270, STRBP, MUC13KIAA1878, SNX9MGC26143KIAA1887,

KIAA1712ASB4，BRUNOL4PDE11A，ARG99，FLJ30162，ATP6V1G3，MGC10702，KIAA1712ASB4, BRUNOL4PDE11A, ARG99, FLJ30162, ATP6V1G3, MGC10702,

ARSDKCNJ2CAMK2DMGC12335KIAA1617HNTEB-1，GRP58，C21orf59，KIAA1720，LOC221468CCL27CGI-ARSDKCNJ2CAMK2DMGC12335KIAA1617HNTEB-1, GRP58, C21orf59, KIAA1720, LOC221468CCL27CGI-

62MGC10204，TNKS1BP1RRP40，FRABINDLX6APOAIFLJ30532，FLJ23403C7orf2 DNER，PDE11A，MAFMGC14276，62MGC10204, TNKS1BP1RRP40, FRABINDLX6APOAIFLJ30532, FLJ23403C7orf2 DNER, PDE11A, MAFMGC14276,

DLL1，LOC146542，SH3GLB2KIAA1952LOC93109ENDOGLYXIMGC10724，IL411，CGI-105，Cl4orf44，DLL1, LOC146542, SH3GLB2KIAA1952LOC93109ENDOGLYXIMGC10724, IL411, CGI-105, Cl4orf44,

PAX6ASAH2MGC12435，PGA5，and AGPAT3.PAX6ASAH2MGC12435, PGA5, and AGPAT3.

                                        表6Table 6

                             UPTG和UPNTG中相比下调的Down-regulated in UPTG and UPNTG

CD24，HSPD1，E1F3S6，TIMM17A，DENR，PAI-RBP1，KIAA0101，H2AFZ，SLC38A1，HNRPH1，RPS11，DEK，ZNF131，CD24, HSPD1, E1F3S6, TIMM17A, DENR, PAI-RBP1, KIAA0101, H2AFZ, SLC38A1, HNRPH1, RPS11, DEK, ZNF131,

HSA9761，MGC3077，CD24，CCT6A，RNPC2，ANKT，CSE1L，RABGGTB，HSA9761，SIP，HMGB2，SEMA3F，HINT1，HSA9761, MGC3077, CD24, CCT6A, RNPC2, ANKT, CSE1L, RABGGTB, HSA9761, SIP, HMGB2, SEMA3F, HINT1,

HMGB1，SERPI，RPL27A，FH，DUSP4，SET，KIAA0179，HMGN3，TOP2B，OAT，NUDT4，PCNA，BM11，SIP，SDCCAG1，HMGB1, SERPI, RPL27A, FH, DUSP4, SET, KIAA0179, HMGN3, TOP2B, OAT, NUDT4, PCNA, BM11, SIP, SDCCAG1,

PBP，MAC30，SFRS5，ATP1B3，EIF4E，CRABP2，LRPPRC DKCI，MIRP63，STK6，CARD10，MRPS18B，TCF3，TCF3，PBP, MAC30, SFRS5, ATP1B3, EIF4E, CRABP2, LRPPRC DKCI, MIRP63, STK6, CARD10, MRPS18B, TCF3, TCF3,

MGC2747，FLJ20422，IF2，NCL，EIF5，TFAP2B，TIMM9，PPPICC，ZWINT，HSD17B1，ATP5O，CBX3，CRFG，PXMP4，MGC2747, FLJ20422, IF2, NCL, EIF5, TFAP2B, TIMM9, PPPICC, ZWINT, HSD17B1, ATP5O, CBX3, CRFG, PXMP4,

UBA2，RNASE3L，USP7，LANPL，PTTG1，RANBP7，YES1，CDC2，RBM15，GMPS，PSMD1，TCF3，HSP105B，EMS1，UBA2, RNASE3L, USP7, LANPL, PTTG1, RANBP7, YES1, CDC2, RBM15, GMPS, PSMD1, TCF3, HSP105B, EMS1,

NONO，TOMM20-PENDING，LDHB，DKFZP586L0724，DDX27，JMJ，CENPF，LRPPRC，ID4，EIF1A，PSMC6，ID2，NONO, TOMM20-PENDING, LDHB, DKFZP586L0724, DDX27, JMJ, CENPF, LRPPRC, ID4, EIF1A, PSMC6, ID2,

SEC13L，TYMS，LUC7A，SNRPA1，RRM1，RARG-1，SMAP，FEN1，TCN1，ZNF146，ABCE1，DC8，MTCH2，FLJ20152，SEC13L, TYMS, LUC7A, SNRPA1, RRM1, RARG-1, SMAP, FEN1, TCN1, ZNF146, ABCE1, DC8, MTCH2, FLJ20152,

CCNB1，CKS2，FLJ23445，TDG，DNMT1，MAC30，RPA40，GMNN，APOBEC3B，STMN1，EIF1A，MTHFD1，MGC5560，CCNB1, CKS2, FLJ23445, TDG, DNMT1, MAC30, RPA40, GMNN, APOBEC3B, STMN1, EIF1A, MTHFD1, MGC5560,

USP1，ZRF1，E1F5A，WDR3，FLJ20530，RPS21，BAZ1A，MCM6，MICB，OPA1，LAMA5，ECT2，RAD21，RNASEH1，USP1, ZRF1, E1F5A, WDR3, FLJ20530, RPS21, BAZ1A, MCM6, MICB, OPA1, LAMA5, ECT2, RAD21, RNASEH1,

FLJ13081，STXBP3，PAI-RBP1，OSR2，FLJ20006，KIAA0186，C19orf2，NUP107，TAF2，GCSH，FLNB，ZNF363，SEMA4C，FLJ13081, STXBP3, PAI-RBP1, OSR2, FLJ20006, KIAA0186, C19orf2, NUP107, TAF2, GCSH, FLNB, ZNF363, SEMA4C,

RAE1，GSS，NEK2，GTSE1，PAI-RBP1，ABCE1，FLJ20986，MAD2L1，VEGF，LZLP，KIAA1025，KIAA0092，ANP32B，RAE1, GSS, NEK2, GTSE1, PAI-RBP1, ABCE1, FLJ20986, MAD2L1, VEGF, LZLP, KIAA1025, KIAA0092, ANP32B,

SRRM1，NXT2，TOPBP1，FLJ20485，SFRS7，SMC4L1，CPSF6，LIN7C，FARSL，NDUFB6，FLJ12888，LANPL，ENDOFIN，SRRM1, NXT2, TOPBP1, FLJ20485, SFRS7, SMC4L1, CPSF6, LIN7C, FARSL, NDUFB6, FLJ12888, LANPL, ENDOFIN,

KR18，FLJ11029，DLG7，WDR12，DC12，CDC5L，SLC35A3，PlGF，PRKRIR，MTO1，CASP6，FLJ11149，FLJ22637，LDHB，KR18, FLJ11029, DLG7, WDR12, DC12, CDC5L, SLC35A3, PlGF, PRKRIR, MTO1, CASP6, FLJ11149, FLJ22637, LDHB,

PPID，GTPBG3，HMMR，SLC31A1，POLE2，KIAA0984，DJ434O14.5，RAB6KIFL，ASE-1，HNRPA1，FLJLJ23468，CALR，PPID, GTPBG3, HMMR, SLC31A1, POLE2, KIAA0984, DJ434O14.5, RAB6KIFL, ASE-1, HNRPA1, FLJLJ23468, CALR,

MELK，SLC25A13，TFDP1，RES4-25，DC13，CGI-111，ARH，FLJ14547，TSN，CYP2B6，PDX1，LCE，FANCG，DHFR，MELK, SLC25A13, TFDP1, RES4-25, DC13, CGI-111, ARH, FLJ14547, TSN, CYP2B6, PDX1, LCE, FANCG, DHFR,

KIAA0020，QDPR，MTJF2，HLXB9，SART3，JAG2，CKAP2，PRC1，SNRPD1，LOC51184，RAN，DLD，PREI3，SRRM2，KIAA0020, QDPR, MTJF2, HLXB9, SART3, JAG2, CKAP2, PRC1, SNRPD1, LOC51184, RAN, DLD, PREI3, SRRM2,

RAD1，CCNB2，FLJ13657，KIAA1116，RACGAP1，FLJ13576，DKFZp564B0769，RFC3，KIAA1630，CCT6A，TIP120A，RAD1, CCNB2, FLJ13657, KIAA1116, RACGAP1, FLJ13576, DKFZp564B0769, RFC3, KIAA1630, CCT6A, TIP120A,

RUVBL2，FLJ23277，DDX18，PMSCL1，LEPROTL1，SCGB1D2，TIMM13，C4orf1，KRTHB6，DD5，CID，PNN，ORC6L，RUVBL2, FLJ23277, DDX18, PMSCL1, LEPROTL1, SCGB1D2, TIMM13, C4orf1, KRTHB6, DD5, CID, PNN, ORC6L,

KIAA0170，ASK，DLEU1，SFRS3，SLC19A1，HIP2，PPP2R1B，BIRC5，EPS15，MGC13138，HNRPD，STK6，HSPA8，KIAA0170, ASK, DLEU1, SFRS3, SLC19A1, HIP2, PPP2R1B, BIRC5, EPS15, MGC13138, HNRPD, STK6, HSPA8,

METAP1，KIAA0776，HSPC128，KIAA0419，MAGOH，CHORDC1，APPBP1，UBL3，RAD51，LOC55871，GLRA2，CUL4A，METAP1, KIAA0776, HSPC128, KIAA0419, MAGOH, CHORDC1, APPBP1, UBL3, RAD51, LOC55871, GLRA2, CUL4A,

ARHGAP8，KIAA0648，COX17，SUDD，RAP1GDS1，FLJ14639，BCL9，EZH2，TRIP13，FLJ11210，TOMM70A，PTP4A1，ARHGAP8, KIAA0648, COX17, SUDD, RAP1GDS1, FLJ14639, BCL9, EZH2, TRIP13, FLJ11210, TOMM70A, PTP4A1,

AMD1，DUT，KPNA2，CYP3A4，RFC4，OPA1，RNF6，IBTK，LBRR，MGC13138，KIAA0097，KIAA0532，OIP2，VRP，HDAC9，AMD1, DUT, KPNA2, CYP3A4, RFC4, OPA1, RNF6, IBTK, LBRR, MGC13138, KIAA0097, KIAA0532, OIP2, VRP, HDAC9,

KLC2，FLJ20700，AD24，ALMS1，FLJ21901，DKFZp547P234，FLJ10656，TOP2A，MYC，TAF4，POLR2E，KIAA0528，KLC2, FLJ20700, AD24, ALMS1, FLJ21901, DKFZp547P234, FLJ10656, TOP2A, MYC, TAF4, POLR2E, KIAA0528,

CRY1，MST4，ETFA，HOXC6，MTX2，HMGCR，RPC5，TOPK，DKFZP5641052，CENTA1，FLJ20758，KCNMA1，KNSL6，CRY1, MST4, ETFA, HOXC6, MTX2, HMGCR, RPC5, TOPK, DKFZP5641052, CENTA1, FLJ20758, KCNMA1, KNSL6,

CGI-30，MRS2L，PAICS，ZNF85，DJ434O14.5，RABGGTB，HEY1，KIAA0485，KTN1，KIAA1012，CDC20，CGI-30, MRS2L, PAICS, ZNF85, DJ434O14.5, RABGGTB, HEY1, KIAA0485, KTN1, KIAA1012, CDC20,

DKFZP434L0718，CEPT1，MYNN，FLJ10637，ANXA9，RNPS1，RBBP4，SSH-3，LOC90355，CAMLG，KPNB2，FLJ23259，DKFZP434L0718, CEPT1, MYNN, FLJ10637, ANXA9, RNPS1, RBBP4, SSH-3, LOC90355, CAMLG, KPNB2, FLJ23259,

VRK1，FBXO5，HSP70-4，DNAJC9，MYCBP，S164，NTRK3，TAF9，SPG4，DKFZp667G2110，CDKN3，INHBC，PEX11A，VRK1, FBXO5, HSP70-4, DNAJC9, MYCBP, S164, NTRK3, TAF9, SPG4, DKFZp667G2110, CDKN3, INHBC, PEX11A,

CDC27，HMGB3，THOC1，FLJ12151，DKFZp564B0769，HSU79266，DMN，C10orf3，THOC2，NDUFA6，GCSH，PPAT，CDC27, HMGB3, THOC1, FLJ12151, DKFZp564B0769, HSU79266, DMN, C10orf3, THOC2, NDUFA6, GCSH, PPAT,

RHAG，SMC2L1，SE70-2，KPNB2，LSM6，FLJ10377，IL1RN，KIAA0547，FLJ14007，SCLY，KIAA0379，UBE3A，RHAG, SMC2L1, SE70-2, KPNB2, LSM6, FLJ10377, IL1RN, KIAA0547, FLJ14007, SCLY, KIAA0379, UBE3A,

HTATSF1，LOC51685，AGL，BET1，FLJ13782，UMPK，SMARCE1，LSM5，CENPF，EEF1E1，TPT，FLJ10719，IF2，CGI-12，HTATSF1, LOC51685, AGL, BET1, FLJ13782, UMPK, SMARCE1, LSM5, CENPF, EEF1E1, TPT, FLJ10719, IF2, CGI-12,

UCHL5，FLJ20628，ERN2，BLM，FLJ21940，PDCD2，STRIN，UMPS，MRPS30，APBA2BP，TCEB1，CREB1，MGC9084，UCHL5, FLJ20628, ERN2, BLM, FLJ21940, PDCD2, STRIN, UMPS, MRPS30, APBA2BP, TCEB1, CREB1, MGC9084,

NOLA1，BUB1B，MGC10471，RFC5，RRP4，FLJ13187，CCT5，HSA6591，CHAF1A，FACL3，IMPA1，FLJ23558，CDC25A，NOLA1, BUB1B, MGC10471, RFC5, RRP4, FLJ13187, CCT5, HSA6591, CHAF1A, FACL3, IMPA1, FLJ23558, CDC25A,

CDC5L，BTN2A1，FLJ20422，ELF2，DKFZp586F1019，FLJ22624，LOC51659，CRFG，WHSC2，HN1L，OAZ3，CD1A，CLPX，CDC5L, BTN2A1, FLJ20422, ELF2, DKFZp586F1019, FLJ22624, LOC51659, CRFG, WHSC2, HN1L, OAZ3, CD1A, CLPX,

CABC1，CLASP2，HSPA9B，KIAA0007，SLC1A3，NPM3，SUSP1，SLC16A5，M6A，UBE2J1，TBC1D4，C20orf1，TBXA2R，CABC1, CLASP2, HSPA9B, KIAA0007, SLC1A3, NPM3, SUSP1, SLC16A5, M6A, UBE2J1, TBC1D4, C20orf1, TBXA2R,

UVRAG，MLH3，FLJ20331，PEG10，PRPF4B，KIAA0332，MPZL1，KPNB1，FLJ10204，TFAM，FLJ20281，FLJ10604，LAT1-UVRAG, MLH3, FLJ20331, PEG10, PRPF4B, KIAA0332, MPZL1, KPNB1, FLJ10204, TFAM, FLJ20281, FLJ10604, LAT1-

3TM，KIF2，RBM12，MK167，HRB2，KIAA0056，ZAP3，COX11，SNRPD1，AMD1，TRN-SR，FLJ20641，RBICC1，KIF4A，3TM, KIF2, RBM12, MK167, HRB2, KIAA0056, ZAP3, COX11, SNRPD1, AMD1, TRN-SR, FLJ20641, RBICC1, KIF4A,

FLJ20093，TPR，RAD50，PPP1R12A，HNRPD，PIR51，PSPH，TTC4，HIC2，SLC39A4，RLF，KNSL7，NOL3，ZNF-U69274，FLJ20093, TPR, RAD50, PPP1R12A, HNRPD, PIR51, PSPH, TTC4, HIC2, SLC39A4, RLF, KNSL7, NOL3, ZNF-U69274,

EIF4ENIF1，PDCD4，CTSC，CYP2C9，KIAA0677，BCL11A，LOC56906，T1A1，SYN2，RNAC，RDX，FOXM1，HRASLS3，EIF4ENIF1, PDCD4, CTSC, CYP2C9, KIAA0677, BCL11A, LOC56906, T1A1, SYN2, RNAC, RDX, FOXM1, HRASLS3,

STAG2，HMMR，KIAA0376，CAPN10，CHEK1，NICE-4，MRPL19，TSN，DKFZP434M154，PPKID，NEK4，SMC5，MGC1223，STAG2, HMMR, KIAA0376, CAPN10, CHEK1, NICE-4, MRPL19, TSN, DKFZP434M154, PPKID, NEK4, SMC5, MGC1223,

SUV39H1，ESPL1，RANBP2，FLJ23018，SNAPC4，LGN，HYA22，JAG2，KIAA0644，NPR3，FOP，PKMYT1，APPBP2，SUV39H1, ESPL1, RANBP2, FLJ23018, SNAPC4, LGN, HYA22, JAG2, KIAA0644, NPR3, FOP, PKMYT1, APPBP2,

HSPC135，C20orf20，EIF4E，ZNF239，FLJ20909，CNTNAP2，ZNF292，LIPT1，FZD7，KIAA0971，SSH-3，MRE11A，HSPC135, C20orf20, EIF4E, ZNF239, FLJ20909, CNTNAP2, ZNF292, LIPT1, FZD7, KIAA0971, SSH-3, MRE11A,

KIAA0090，PAWR，SMC2L1，CGI-112，SOX13，HBB，KIAA1193，CAP350，RRS1，MTCP1，HBA1，GRPR，LCT，RAD51C，KIAA0090, PAWR, SMC2L1, CGI-112, SOX13, HBB, KIAA1193, CAP350, RRS1, MTCP1, HBA1, GRPR, LCT, RAD51C,

PRKDC，SPAG5，POLQ，BRCA1，GNA13，FLJ14346，ZNF24，CENPA，E2F3，DDX18，SFRS2，PSP1，FLJ14827，BFAR，PRKDC, SPAG5, POLQ, BRCA1, GNA13, FLJ14346, ZNF24, CENPA, E2F3, DDX18, SFRS2, PSP1, FLJ14827, BFAR,

FANCC，DMXL1，CUL3，C6orf15，BCLG，SIL，LOC133619，MGC2306，KIAA1096，GMEB2，ASCL1，EBP，FZD3，PRDM2，FANCC, DMXL1, CUL3, C6orf15, BCLG, SIL, LOC133619, MGC2306, KIAA1096, GMEB2, ASCL1, EBP, FZD3, PRDM2,

KNSL1，FJX1，PPPIR3D，SRP72，DKFZP564D0462，CCNF，PAI-RBP1，PRO1496，RBBP6，TEB4，SP192，DCTN4，KNSL1, FJX1, PPPIR3D, SRP72, DKFZP564D0462, CCNF, PAI-RBP1, PRO1496, RBBP6, TEB4, SP192, DCTN4,

B4GALT2，SRF，ZNF200，DNCL11，SCYE1，PPI5PIV，FLJ22087，SLC29A1，FLJ12439，VDR，TIMELESS，TAF15，CGA，B4GALT2, SRF, ZNF200, DNCL11, SCYE1, PPI5PIV, FLJ22087, SLC29A1, FLJ12439, VDR, TIMELESS, TAF15, CGA,

FLJ21816，SHMT2，SRISNF2L，DKFZP547E2110，OIP5，MGc2603，FLJ11896，C18B11，IGLJ3，PPARBP，DCX，TAF5，FLJ21816, SHMT2, SRISNF2L, DKFZP547E2110, OIP5, MGc2603, FLJ11896, C18B11, IGLJ3, PPARBP, DCX, TAF5,

MGC5306，LIM，PTER，PPIL2，FLJ10998，NSEP1，KIAA0332，MCM4，DLAT，KIAA0453，RPL23AP7，TTF1，WRN，TTK，MGC5306, LIM, PTER, PPIL2, FLJ10998, NSEP1, KIAA0332, MCM4, DLAT, KIAA0453, RPL23AP7, TTF1, WRN, TTK,

MARK3，SF3B3，FLJ20552，TIMM8A，PANK3，LIN7C，FLJ20225，FLJ10287，MFN2，FLJ21908，REV3L，MGC5566，ZNF42，MARK3, SF3B3, FLJ20552, TIMM8A, PANK3, LIN7C, FLJ20225, FLJ10287, MFN2, FLJ21908, REV3L, MGC5566, ZNF42,

MSH5，HCAP-G，FLJ20591，SPHK1，E2F1，FLJ14054，CCNE2，MGC4701，C1orf33，BITE，MCM5，KCNK15，AGTPBP1，MSH5, HCAP-G, FLJ20591, SPHK1, E2F1, FLJ14054, CCNE2, MGC4701, C1orf33, BITE, MCM5, KCNK15, AGTPBP1,

FLJ20274，CLPTM1，LANCL1，FLJ20125，FLJ11785，BARD1，MYOC，RB1CC1，FLJ23151，RFC1，SLC25A12，FLJ10330，FLJ20274, CLPTM1, LANCL1, FLJ20125, FLJ11785, BARD1, MYOC, RB1CC1, FLJ23151, RFC1, SLC25A12, FLJ10330,

TMPO，KIAA0157，STC2，UBCE71P5，MGC5306，COL13A1，TMSNB，PTTG3，FLJ40452，MADH6，IF2，SRP72，FLJ20003，TMPO, KIAA0157, STC2, UBCE71P5, MGC5306, COL13A1, TMSNB, PTTG3, FLJ40452, MADH6, IF2, SRP72, FLJ20003,

USP2，YY1，FLJ23053，KIAA0276，TIA1，PRDM10，OXTR，HRASLS，BAZIB，M96，SLC7A5，CYP26A1，PB1，TCBAP0758，USP2, YY1, FLJ23053, KIAA0276, TIA1, PRDM10, OXTR, HRASLS, BAZIB, M96, SLC7A5, CYP26A1, PB1, TCBAP0758,

TLE3，POLD3，LIV-1，HNRPL，FLJ10407，CHAT，UPF3B，RAMP3，TIMM17A，G3BP，PCDH7，FLJ90754，MCLC，EPHB3，TLE3, POLD3, LIV-1, HNRPL, FLJ10407, CHAT, UPF3B, RAMP3, TIMM17A, G3BP, PCDH7, FLJ90754, MCLC, EPHB3,

STXBP6，CSTF2T，GYG2，PRKCBP1，RRN3，FBXL2，MDM1，PNN，SMPD2，TTF2，TFR2，GDAP2，FLJ10989，MATR3，STXBP6, CSTF2T, GYG2, PRKCBP1, RRN3, FBXL2, MDM1, PNN, SMPD2, TTF2, TFR2, GDAP2, FLJ10989, MATR3,

PRO1598，PAF53，OGT，HNRPH3，H326，VDR，KIAA0843，UTX，KIAA1172，RYBP，FLJ20005，SCML2，SF3B1，KLHL3，PRO1598, PAF53, OGT, HNRPH3, H326, VDR, KIAA0843, UTX, KIAA1172, RYBP, FLJ20005, SCML2, SF3B1, KLHL3,

NOLC1，ING1L，KIAA1467，ROBO1，TGIF2，C8orf4，NUDE1，PDCD4，FLJ11004，AKR1C1，DKC1，COCH，FLJ20666，NOLC1, ING1L, KIAA1467, ROBO1, TGIF2, C8orf4, NUDE1, PDCD4, FLJ11004, AKR1C1, DKC1, COCH, FLJ20666,

HSPC121，FLJ10261，PMFBP1，RAD1，SLC4A4，FGFR2，SMARCC1，BAZ1A，CGI-130，NESGl，FLJ13909，GRM6，HSPC121, FLJ10261, PMFBP1, RAD1, SLC4A4, FGFR2, SMARCC1, BAZ1A, CGI-130, NESGl, FLJ13909, GRM6,

FLJ13942，SOX12，FDX1，LGN，GRIN1，BTN2A1，NCBP2，NMU，CDC6，OAZ，CDC7L1，CNNM4，NOL3，FLJ10038，FLJ13942, SOX12, FDX1, LGN, GRIN1, BTN2A1, NCBP2, NMU, CDC6, OAZ, CDC7L1, CNNM4, NOL3, FLJ10038,

KIR2DS1，KPNB3，SLC4A4，FLJ22390，SLC6A13，NY-REN-24，KIAA0923，LOC113251，SIP，ERCC6，DKFZP586A0522，KIR2DS1, KPNB3, SLC4A4, FLJ22390, SLC6A13, NY-REN-24, KIAA0923, LOC113251, SIP, ERCC6, DKFZP586A0522,

RAB11B，ZNF197，WHIP，KIAA0040，KIF5C，GTF2H3，PAPA-1，HNRPH3，NDST1，C9orf12，KIAA1069，MAC30，RAB11B, ZNF197, WHIP, KIAA0040, KIF5C, GTF2H3, PAPA-1, HNRPH3, NDST1, C9orf12, KIAA1069, MAC30,

PPP2R1B，ZNF363，KIAA0931，NFRKB，MGC12760，HSU79274，SELP，RAB33B，MYH11，TIAL1，MCM10，PPP2R1B, ZNF363, KIAA0931, NFRKB, MGC12760, HSU79274, SELP, RAB33B, MYH11, TIAL1, MCM10,

DKFZP434F1735，KIAA0553，SAFB，FLJ12455，DRIM，CFLAR，KIAA0542，HTR1B，SMC4L1，TIMP3，MLLT2，DKFZP434F1735, KIAA0553, SAFB, FLJ12455, DRIM, CFLAR, KIAA0542, HTR1B, SMC4L1, TIMP3, MLLT2,

ARHGAP1，KIAA0255，WASF1，POP1，KIAA0286，PASK，DACH，SF3B3，CDC2，RCL，IL2RA，IRX5，DUT，FLJ12684，ARHGAP1, KIAA0255, WASF1, POP1, KIAA0286, PASK, DACH, SF3B3, CDC2, RCL, IL2RA, IRX5, DUT, FLJ12684,

FLJ20640，NSPC1，ABCG1，T，ZNF174，PPP4R2，SPAG4，FLJ21596，ZNF11B，FLJ13449，HBA1，E2F3，CDC2，BICD1，FLJ20640, NSPC1, ABCG1, T, ZNF174, PPP4R2, SPAG4, FLJ21596, ZNF11B, FLJ13449, HBA1, E2F3, CDC2, BICD1,

RAP2A，CSTF2，LSM8，DYRK1A，FLJ21940，H2AFP，DATF1，ANGPT1，C20orf46，FLJ20147，ZAP，CASP2，K1F14，RAP2A, CSTF2, LSM8, DYRK1A, FLJ21940, H2AFP, DATF1, ANGPT1, C20orf46, FLJ20147, ZAP, CASP2, K1F14,

DDX17，TRIAD3，TAX1BP1，PEX7，KIAA0182，TIMM44，CIAO1，FLJ13490，MED6，FBLN1，SMN1，OR10H3，DDX17, TRIAD3, TAX1BP1, PEX7, KIAA0182, TIMM44, CIAO1, FLJ13490, MED6, FBLN1, SMN1, OR10H3,

ARP3BETA，DLAT，TXNRD2，RC3，HUMGT198A，MTHFS，CAT56，CRSP6，DCLRE1A，ACRV1，TAF1，PPAT，SEMA4G，ARP3BETA, DLAT, TXNRD2, RC3, HUMGT198A, MTHFS, CAT56, CRSP6, DCLRE1A, ACRV1, TAF1, PPAT, SEMA4G,

CXCL9，CUL2，AGRN，ZFP100，KIR2DS3，RECQL4，PTPN13，LOC93081，IRF4，IGL@，CYP2B7，CLASP1，MCF2L，KLK5，CXCL9, CUL2, AGRN, ZFP100, KIR2DS3, RECQL4, PTPN13, LOC93081, IRF4, IGL@, CYP2B7, CLASP1, MCF2L, KLK5,

COPS7B，B3GALT3，DKC1，YES1，CHPPR，MGC21654，TROAP，FLJ23311，MKL1，KIAA0650，MRPS34，SMARCC1，COPS7B, B3GALT3, DKC1, YES1, CHPPR, MGC21654, TROAP, FLJ23311, MKL1, KIAA0650, MRPS34, SMARCC1,

PEX11A，ZNF212，GABR2，NUP98，S1GLEC7，ZFD25，RRM1，TFIP11，M96，AD024，AP1S2，TIMM17A，GM2A，TAS2R1，PEX11A, ZNF212, GABR2, NUP98, S1GLEC7, ZFD25, RRM1, TFIP11, M96, AD024, AP1S2, TIMM17A, GM2A, TAS2R1,

RARG，GD12，FARS1，ROBO4，RINZF，FOXF2，CASP10，CITEDI，RPGRIP1，PHTF1，37870.00，PP35，MGC4659，RARG, GD12, FARS1, ROBO4, RINZF, FOXF2, CASP10, CITEDI, RPGRIP1, PHTF1, 37870.00, PP35, MGC4659,

KIAA0092，EPHB1，KCNJ10，HOXD4，NUP160，PTPRD，PRODH，PTBP2，PFKFB2，SGK2，ACADSB，BRIX，EML4，KIAA0092, EPHB1, KCNJ10, HOXD4, NUP160, PTPRD, PRODH, PTBP2, PFKFB2, SGK2, ACADSB, BRIX, EML4,

EDNRA，CHRNB3，NUP155，KIAA0648，SBMACAP3，LOC57406，AND-1，CRSP2，STAG1，SH3BP2，NR6A1，MGC2827，EDNRA, CHRNB3, NUP155, KIAA0648, SBMACAP3, LOC57406, AND-1, CRSP2, STAG1, SH3BP2, NR6A1, MGC2827,

HNRPH3，S1P1，FLJ21986，CTH，PDEF，HABP2，RPGR，COQ7，TTTY2，FLJ11767，LOC81691，HSPC111，MGC39851，HNRPH3, S1P1, FLJ21986, CTH, PDEF, HABP2, RPGR, COQ7, TTTY2, FLJ11767, LOC81691, HSPC111, MGC39851,

TAP2，NUF1P1，GABRA4，CDH2，SMTN，ZNF305，C8orf1，ULBP1，VAMP1，FLJ20477，LHX6，CD6，NSBP1，KLF3，TAP2, NUF1P1, GABRA4, CDH2, SMTN, ZNF305, C8orf1, ULBP1, VAMP1, FLJ20477, LHX6, CD6, NSBP1, KLF3,

SLC13A3，LOC55862，LCK，CDC25C，CGI-32，DKFZP434D193，MBD4，GNB3，BAIAP3，FARS1，CHRNB1，GCAT，SLC13A3, LOC55862, LCK, CDC25C, CGI-32, DKFZP434D193, MBD4, GNB3, BAIAP3, FARS1, CHRNB1, GCAT,

KIAA0342，STK18，MPHOSPH10，CRMP1，UNC84A，CACNB1，KIAA1053，KIAA0953，SERPINA5，FLJ20433，SIGLEC6，KIAA0342, STK18, MPHOSPH10, CRMP1, UNC84A, CACNB1, KIAA1053, KIAA0953, SERPINA5, FLJ20433, SIGLEC6,

DKFZp762E1312，LAT，SORD，GGA2，FLJ21945，FGFR4，DBR1，LMNB2，ADCYAP1，NR4A1，LIM，AGC1，FDX1，DKFZp762E1312, LAT, SORD, GGA2, FLJ21945, FGFR4, DBR1, LMNB2, ADCYAP1, NR4A1, LIM, AGC1, FDX1,

FLJ20244，ZNF24，DCLRE1B，IL23A，EIF2S1，INCENP，FLJ21820，ZNF264，KIAA0964，CASP8，ORC2L，CHAC，FLJ20244, ZNF24, DCLRE1B, IL23A, EIF2S1, INCENP, FLJ21820, ZNF264, KIAA0964, CASP8, ORC2L, CHAC,

TNFRSF13B，MOST2，ABCB9，D1O3，RABL2A，FA1M，DCT，CLCA1，TRIM29，GK，GNA14，TDPGD，FLJ20186，RAD54L，TNFRSF13B, MOST2, ABCB9, D1O3, RABL2A, FA1M, DCT, CLCA1, TRIM29, GK, GNA14, TDPGD, FLJ20186, RAD54L,

SSX3，FLJ10193，HT010，HEC，KIR2DL5，CASQ2，TRA@，ZNF335，ING3，HSPC055，ITlH2，BUB1，MADCAM1，AXOT，SSX3, FLJ10193, HT010, HEC, KIR2DL5, CASQ2, TRA@, ZNF335, ING3, HSPC055, ITlH2, BUB1, MADCAM1, AXOT,

KIAA0295，RPL17，NRXN1，P2RX5，GASC1，NUP210，ZNF236，RAD21，ANKTM1，EDNRA，HSPD1，CORO2B，NY-REN-KIAA0295, RPL17, NRXN1, P2RX5, GASC1, NUP210, ZNF236, RAD21, ANKTM1, EDNRA, HSPD1, CORO2B, NY-REN-

58，FKBP1B，AQP8，KIAA0922，SNRPA1，AR1H2，ASGR2，C6orf35，IL1RN-SLC38A3，NFYC，CACNG4，SEZ6L，GLP1R，58, FKBP1B, AQP8, KIAA0922, SNRPA1, AR1H2, ASGR2, C6orf35, IL1RN-SLC38A3, NFYC, CACNG4, SEZ6L, GLP1R,

NUF1P1，G2AN，FLJ13949，FABP7，S100A1，TRIM36，LOC93408，AP15，PAD13，TADA3L，EPN2，TNFSF4，MIP，RIPK2，NUF1P1, G2AN, FLJ13949, FABP7, S100A1, TRIM36, LOC93408, AP15, PAD13, TADA3L, EPN2, TNFSF4, MIP, RIPK2,

F5，KCNJ3-HADHA，MS4A1，NEK3，KIAA0275，DTR，MNAT1，ZNF223，FNTA-NRCAM，POLG2，ADH6，CAP2，KCNJ5，F5, KCNJ3-HADHA, MS4A1, NEK3, KIAA0275, DTR, MNAT1, ZNF223, FNTA-NRCAM, POLG2, ADH6, CAP2, KCNJ5,

SFRP1，APOBEC3C，IL7R，P125，UGCGL2，AS1C4，AMFR，HSN44A4A，RAB5A，OXCT，RAB3GAP，D6S1101，OTOR，SFRP1, APOBEC3C, IL7R, P125, UGCGL2, AS1C4, AMFR, HSN44A4A, RAB5A, OXCT, RAB3GAP, D6S1101, OTOR,

LTBP1，R1N1，LDB1，PRKAB2，KIAA1006，PLK，PRO2000，MOCS1，RGNEF，PDZ-GEF1，INA，MASP2，RSC1A1，RoXaN，LTBP1, R1N1, LDB1, PRKAB2, KIAA1006, PLK, PRO2000, MOCS1, RGNEF, PDZ-GEF1, INA, MASP2, RSC1A1, RoXaN,

CLDN6，HSAJ2425，KIAA0469，ING4，REM，KIAA0092，SKP2，OGT，CBL，KIAA1240，QK1，ETFDH，PPP2R1B，MDS031，CLDN6, HSAJ2425, KIAA0469, ING4, REM, KIAA0092, SKP2, OGT, CBL, KIAA1240, QK1, ETFDH, PPP2R1B, MDS031,

CED-6，SLC11A2，GPX5，CRKL，PC4-FLJ10858，APOC4，CUGBP1，REG1B，DKFZP564B147，C14orf104，PAX4，TRA@，CED-6, SLC11A2, GPX5, CRKL, PC4-FLJ10858, APOC4, CUGBP1, REG1B, DKFZP564B147, C14orf104, PAX4, TRA@,

RECQL5，ENG，CDC2L1，FLJ22087，HYA22，DEFA4，GIOT-3，ASPM，ANK3，TNFAIP2，SLIT2，WBSCR20B，EIF5A，RECQL5, ENG, CDC2L1, FLJ22087, HYA22, DEFA4, GIOT-3, ASPM, ANK3, TNFAIP2, SLIT2, WBSCR20B, EIF5A,

PTHLH，ATPW，CASP8AP2，HSPB3，RPS4Y，UNC84A，FLJ20624，CHST5，STARD5，SSX2，IL22，TAF1B，FEM1B，PTHLH, ATPW, CASP8AP2, HSPB3, RPS4Y, UNC84A, FLJ20624, CHST5, STARD5, SSX2, IL22, TAF1B, FEM1B,

KCNA1，GPR15，C1orf34，CGI-07，WDR8，SLA，HGC6.2，GRIN1，CXorf6，KIAA1034，EDG4，CUL4B，CSPG3，TFEB，KCNA1, GPR15, C1orf34, CGI-07, WDR8, SLA, HGC6.2, GRIN1, CXorf6, KIAA1034, EDG4, CUL4B, CSPG3, TFEB,

P164RHOGEF，FLJ13105，CENPE，APP，MYL6，FLJ23441，PON1，ENDOG，SERPINC1，PGRMC1，TUBB5，CHRD，PAK6，P164RHOGEF, FLJ13105, CENPE, APP, MYL6, FLJ23441, PON1, ENDOG, SERPINC1, PGRMC1, TUBB5, CHRD, PAK6,

FLJ20045，PELP1，FLJ12735，DXS542，SH2D1A，PRO1728，HOXA6，NEUROD4，CGI-100，FLJ13386，AND-1，TBL3，FLJ20045, PELP1, FLJ12735, DXS542, SH2D1A, PRO1728, HOXA6, NEUROD4, CGI-100, FLJ13386, AND-1, TBL3,

GZMM，FLJ90005，FGFR1，L0C51231，FNBP1，P11，PPP1R15A，VDR，CPSF6，S164，C20orf14，KIAA0217，SGT，GZMM, FLJ90005, FGFR1, L0C51231, FNBP1, P11, PPP1R15A, VDR, CPSF6, S164, C20orf14, KIAA0217, SGT,

KIAA0332，DKFZP586E1923，FLJ10884，MCF2，MAP4，AAK1，HS3ST3A1，LOC90806，ALDH3A2，MUF1，NCKAP1，KIAA0332, DKFZP586E1923, FLJ10884, MCF2, MAP4, AAK1, HS3ST3A1, LOC90806, ALDH3A2, MUF1, NCKAP1,

FLJ10618，LILRB3，GAGE5，TMEM1，CD6，ADAM22，BM039，NEF3，ITCH，PPP2R2B，PLG，SNAPC1，DXS9879E，MPDZ，FLJ10618, LILRB3, GAGE5, TMEM1, CD6, ADAM22, BM039, NEF3, ITCH, PPP2R2B, PLG, SNAPC1, DXS9879E, MPDZ,

CDK3，CD209L，SLC21A9，SHB，Rab11-FIP2，MAP4K5，DGKE，MTMR3，KCNK5，CLCNKA，SGCE，FLJ10565，MCM7，CDK3, CD209L, SLC21A9, SHB, Rab11-FIP2, MAP4K5, DGKE, MTMR3, KCNK5, CLCNKA, SGCE, FLJ10565, MCM7,

AK5，NCR3，SERPINB4，TPST1，alpha4GnT，NPEPL1，PRLR，MPHOSPH9，IL18RAP，PMSCL1，HS322B1A，TCF2，TPD52，AK5, NCR3, SERPINB4, TPST1, alpha4GnT, NPEPL1, PRLR, MPHOSPH9, IL18RAP, PMSCL1, HS322B1A, TCF2, TPD52,

HIVEP2，KRTHB5，KRTAP1-1，DMD，C10ORF6，AGC1，FLJ23436，PTK7，COL9A1，CGI-01，EPHB6，AVIL，LOC54550，HIVEP2, KRTHB5, KRTAP1-1, DMD, C10ORF6, AGC1, FLJ23436, PTK7, COL9A1, CGI-01, EPHB6, AVIL, LOC54550,

NASP，OAZIN，SERPINA6，GPR44，VCY，DIAPH2，384D8-2，MAPK11，GALNT4，PTGES2，WNT2B，STX6，STK17A，NASP, OAZIN, SERPINA6, GPR44, VCY, DIAPH2, 384D8-2, MAPK11, GALNT4, PTGES2, WNT2B, STX6, STK17A,

PPFIA1，CALCA，CCNA2，DOC2B，NID，BAZ2A，WNT10B，FBXW1B，SPRR3，MINK，B3GNT4，CDK6，BHMT，SRPK2，PPFIA1, CALCA, CCNA2, DOC2B, NID, BAZ2A, WNT10B, FBXW1B, SPRR3, MINK, B3GNT4, CDK6, BHMT, SRPK2,

PGCP，CNK，SSB，CDC6，GART，DLX2，PLEK，PTPN7，UBQLN3，IF144，TCOF1，FGF16，COPEB，SOCS4，FLJ11222，PGCP, CNK, SSB, CDC6, GART, DLX2, PLEK, PTPN7, UBQLN3, IF144, TCOF1, FGF16, COPEB, SOCS4, FLJ11222,

MRPL12，WDR9，DKFZP434G2226，CLECSF9，NCR3，GPR49，EP400，DKFZP586M0622，PCDHA9，CIQTNF3，STAB1，MRPL12, WDR9, DKFZP434G2226, CLECSF9, NCR3, GPR49, EP400, DKFZP586M0622, PCDHA9, CIQTNF3, STAB1,

PRKDC，BEX1，FZD9，CAPN7，BCR，FLJ11577，IGL@，ARR3，PTHLH，AP4S1，ABCG5，SNTG1，CRTAC1，ZNF335，PRKDC, BEX1, FZD9, CAPN7, BCR, FLJ11577, IGL@, ARR3, PTHLH, AP4S1, ABCG5, SNTG1, CRTAC1, ZNF335,

FLJ10979，HSU84971，POLI，KIAA0643，DKFZp43411916，PPIG，TRG@，MAPK12，INGIL，HIF3A，CDX4，CYHR1，FLJ10979, HSU84971, POLI, KIAA0643, DKFZp43411916, PPIG, TRG@, MAPK12, INGIL, HIF3A, CDX4, CYHR1,

TRAP100，UCHL5，CLOCK，SLC17A7，HFL-EDDG1，ATF7，FLJ20105，HRH4，FALZ，SLC23A1，NRF1，BTN2A2，TRAP100, UCHL5, CLOCK, SLC17A7, HFL-EDDG1, ATF7, FLJ20105, HRH4, FALZ, SLC23A1, NRF1, BTN2A2,

FLJ20581，DKFZP761H1710，FLJ10376，GLRA3，C20orf30，C4orf6，ELK4，PLCG1，CNR1，KNSL5，KIDINS220，ING4，FLJ20581, DKFZP761H1710, FLJ10376, GLRA3, C20orf30, C4orf6, ELK4, PLCG1, CNR1, KNSL5, KIDINS220, ING4,

PPFIBP1，SGSH，PRKAR1B，UBE4B，INSL3，DKFZP434F1735，MTMR8，KRTHA2，MPHOSPH9，SQLE，OGG1，OSMR，PPFIBP1, SGSH, PRKAR1B, UBE4B, INSL3, DKFZP434F1735, MTMR8, KRTHA2, MPHOSPH9, SQLE, OGG1, OSMR,

AFM，HSPBP1，VGF，HCGIX，U1SNRNPBP，FLJ23447，FLJ10057，SPRR2B，GRIK3，MARK4，WIZ，CORT，MGEA6，AFM, HSPBP1, VGF, HCGIX, U1SNRNPBP, FLJ23447, FLJ10057, SPRR2B, GRIK3, MARK4, WIZ, CORT, MGEA6,

BMP7，FLJ10648，BRAP，DKFZP547E1010，C21orf59，STK6，KLK2，GRIN1，HOXB7，SMURF1，PCDH16，BCL11A，BMP7, FLJ10648, BRAP, DKFZP547E1010, C21orf59, STK6, KLK2, GRIN1, HOXB7, SMURF1, PCDH16, BCL11A,

SPPHI，FLJ12838，SSR3，KIAA0940，P2RY2，HSU84971，ZNF134，CNTNAP2，ADAM23，MAGEA6，SPAG6，SPPHI, FLJ12838, SSR3, KIAA0940, P2RY2, HSU84971, ZNF134, CNTNAP2, ADAM23, MAGEA6, SPAG6,

DKFZp761P1010，DTNB，CHAF1B，MLL，DGCR8，MGC3101，SENP3，FLJ12331，LATS1，IPP，FXYD2，FLJ23360，DKFZp761P1010, DTNB, CHAF1B, MLL, DGCR8, MGC3101, SENP3, FLJ12331, LATS1, IPP, FXYD2, FLJ23360,

FLJ20898，LUC7A，NDRG4，LIN-28，CXorf15，FLJ13910，ELK1，MGC4294，TBL1Y，FLJ12985，B7H2，FLJ13693，FLJ10945，FLJ20898, LUC7A, NDRG4, LIN-28, CXorf15, FLJ13910, ELK1, MGC4294, TBL1Y, FLJ12985, B7H2, FLJ13693, FLJ10945,

FLJ20313，DKFZP566C0424，IGHM，TPS1，GFAP，PEX1，NEU3，FLJ10719，NF1C，GTSE1，SIAT7D，PDYN，SELPLG，FLJ20313, DKFZP566C0424, IGHM, TPS1, GFAP, PEX1, NEU3, FLJ10719, NF1C, GTSE1, SIAT7D, PDYN, SELPLG,

B7H2，PIGO，SCNN1D，NMBR，NCAM2，YWHAE，SIP1，FLJ14084，PROZ，ATF2，PPM1F，INSM1，CABP5，ZNF124，B7H2, PIGO, SCNN1D, NMBR, NCAM2, YWHAE, SIP1, FLJ14084, PROZ, ATF2, PPM1F, INSM1, CABP5, ZNF124,

SP110，SPTA1，MGC2776，BMP8，GAL，SCA7，FLJ11850，FCGR2B，PROSC，PDE4D，MGC11335，AKAP3，CARF，DKKL1-SP110, SPTA1, MGC2776, BMP8, GAL, SCA7, FLJ11850, FCGR2B, PROSC, PDE4D, MGC11335, AKAP3, CARF, DKKL1-

pending，UGT1A1，SHANK2，LSS，GUCY2F，RANBP3，SLC16A7，PIP5K1A，SCAMP-4，LOC92579，SLC7A8，CR2，pending, UGT1A1, SHANK2, LSS, GUCY2F, RANBP3, SLC16A7, PIP5K1A, SCAMP-4, LOC92579, SLC7A8, CR2,

FLJ20707，FLJ21106，MADH5，CPS1，COL14A1，PROL3，CUL2，CHAF1A，OAS2，SOX10，MFAP4，TCFL4，FLJ12618，FLJ20707, FLJ21106, MADH5, CPS1, COL14A1, PROL3, CUL2, CHAF1A, OAS2, SOX10, MFAP4, TCFL4, FLJ12618,

SUSP1，MAGEA9，KIAA0322，SLC19A3，AKAP11，USP7，DC11，KIAA0616，BC008967，OR7C2，CACNG3，PEL12，SUSP1, MAGEA9, KIAA0322, SLC19A3, AKAP11, USP7, DC11, KIAA0616, BC008967, OR7C2, CACNG3, PEL12,

FLJ14050，DMPK，FLJ23071，CCL14，IGHM，BM039，GASC1，BIRC4，MGC5601，KCNK10，SLC22A8，MGC14817，FLJ14050, DMPK, FLJ23071, CCL14, IGHM, BM039, GASC1, BIRC4, MGC5601, KCNK10, SLC22A8, MGC14817,

GRCC8，LARGE，ZDHHC11，ANXA13，FLJ14107，FLJ10246，C11orf5，POLA2，SULV，PARD3，LW-1，CCL13，CLCA2，GRCC8, LARGE, ZDHHC11, ANXA13, FLJ14107, FLJ10246, C11orf5, POLA2, SULV, PARD3, LW-1, CCL13, CLCA2,

ME1，RAD51C，SSTR3，STK12，ADAMTS2，MRPS12，SMCY，TUBA4，KIAA0794，CCL11，WFDC1，TRY6，MAP2K2，ME1, RAD51C, SSTR3, STK12, ADAMTS2, MRPS12, SMCY, TUBA4, KIAA0794, CCL11, WFDC1, TRY6, MAP2K2,

ACOX1，KIAA0874，C1of16，NRG1，RCN2，CLDN18，MYL3，FLJ13150，LNPEP，SLC25A21，PDE10A，STAG3，TNN13，ACOX1, KIAA0874, C1of16, NRG1, RCN2, CLDN18, MYL3, FLJ13150, LNPEP, SLC25A21, PDE10A, STAG3, TNN13,

CHC1，MAP3K7，OSRF，HMX1，HRG，FLJ11292，PAL，KIAA1659，VARS2，HSRTSBETA，IL5RA，CYP3A4，FLJ23556，CHC1, MAP3K7, OSRF, HMX1, HRG, FLJ11292, PAL, KIAA1659, VARS2, HSRTSBETA, IL5RA, CYP3A4, FLJ23556,

MAPK4，C16orf3，GPD2，HOXA3，MMP7，FLJ10786，C6.1A，KIAA0892，PCDH11Y，TRB@，METL，PRKAA2，ZNF76，MAPK4, C16orf3, GPD2, HOXA3, MMP7, FLJ10786, C6.1A, KIAA0892, PCDH11Y, TRB@, METL, PRKAA2, ZNF76,

FTSJ1，FLJ90130，FLT3，GNAO1，SCNN1G，TAF9L，PRV1，SNX13，CENP1，CNNM1，FTCD，NEK1，FLJ11336，FLJ14803，FTSJ1, FLJ90130, FLT3, GNAO1, SCNN1G, TAF9L, PRV1, SNX13, CENP1, CNNM1, FTCD, NEK1, FLJ11336, FLJ14803,

C9orf16，H1P1，PPIF，GS3955，NFATC3，DOK1，ROPN1，MAGEC1，HGF，PRLR，CTSL2，NKTR.SAA2，HOXD11，PROX1，C9orf16, H1P1, PPIF, GS3955, NFATC3, DOK1, ROPN1, MAGEC1, HGF, PRLR, CTSL2, NKTR.SAA2, HOXD11, PROX1,

MAP3K12，MORF，FLJ10619，SULT2A1，ERF，DKFZP586A0522，KCNQ2，KIAA1387，DFFB，MGC4172，MOCS3，ITGB3，MAP3K12, MORF, FLJ10619, SULT2A1, ERF, DKFZP586A0522, KCNQ2, KIAA1387, DFFB, MGC4172, MOCS3, ITGB3,

PIB5PA，ZNF117，KCNA4，KIAA0999，HFE，CYP2A6，A2BP1，RASGRP2，AMELY，GABRG3，ITGA8，DUSP3，PTGS1，PIB5PA, ZNF117, KCNA4, KIAA0999, HFE, CYP2A6, A2BP1, RASGRP2, AMELY, GABRG3, ITGA8, DUSP3, PTGS1,

KIAA0748，CACNA1G，CENPC1，POT1，COL6A1，ST7，FLJ13052，MS4A12，DLG5，TECTA，ETV5，HEYl，NECL1，KIAA0748, CACNA1G, CENPC1, POT1, COL6A1, ST7, FLJ13052, MS4A12, DLG5, TECTA, ETV5, HEYl, NECL1,

DICER1，ALOX12P2，KIAA1025，FURIN，WISP2，CSDA，ALDH1A2，USP19，TRG@，SFRS7，CDX2，MRPS31，NSAP1，DICER1, ALOX12P2, KIAA1025, FURIN, WISP2, CSDA, ALDH1A2, USP19, TRG@, SFRS7, CDX2, MRPS31, NSAP1,

CUL4B，ABCC2，IQGAP1，WHSC1L1，ALCAM，SERPINB10，MDS028，KOC1，ELF2，DKFZP434A1022，GPM6B，C2GNT3，CUL4B, ABCC2, IQGAP1, WHSC1L1, ALCAM, SERPINB10, MDS028, KOC1, ELF2, DKFZP434A1022, GPM6B, C2GNT3,

CYLC1，FLJ11506，CEBPA，LIMK1，CPR2，CLTB，TNR，PLA2G3，GPR30，APOL3，TSKS，HCGIV-6，KCNJ2，MGC5347，CYLC1, FLJ11506, CEBPA, LIMK1, CPR2, CLTB, TNR, PLA2G3, GPR30, APOL3, TSKS, HCGIV-6, KCNJ2, MGC5347,

MAP1A，PPARD，TMPO、LOC63923，CYP2E1，RYK，PRKAR1B，FLJ11336，FLJ10748，PRO2958，CHN2，CELSR1，LCN1，MAP1A, PPARD, TMPO, LOC63923, CYP2E1, RYK, PRKAR1B, FLJ11336, FLJ10748, PRO2958, CHN2, CELSR1, LCN1,

SLC15A2，USP5，ZFR，CYB5-M，SLC27A5，MJD，KIAA1096，HTR2C，NACA，APC，ELK4，JM1，KCNAB1，GDF2，ST7L，SLC15A2, USP5, ZFR, CYB5-M, SLC27A5, MJD, KIAA1096, HTR2C, NACA, APC, ELK4, JM1, KCNAB1, GDF2, ST7L,

TGT，AMY1A，ESR1，TLX1，TBX1，KIAA0967，KIAA0146，C1QR1，ARHGDIG，KCNIP2，HDAC6，MTHFR，NTRK3，TGT, AMY1A, ESR1, TLX1, TBX1, KIAA0967, KIAA0146, C1QR1, ARHGDIG, KCNIP2, HDAC6, MTHFR, NTRK3,

HAVCR1，FLJ22269，PLXNB1，CRACC，EGR4，PMS2L6，POGZ，FLJ21148，FLJ20359，B4GALT1，KIAA1354，CSF3，HAVCR1, FLJ22269, PLXNB1, CRACC, EGR4, PMS2L6, POGZ, FLJ21148, FLJ20359, B4GALT1, KIAA1354, CSF3,

SLC17A6，PAK2，ZF，CLECSF6，FLJ21120，ZAP3，FLJ20127，VAMP1，DCLRElC，DRIL2，FLJ11608，SFTPC，GABPB2，SLC17A6, PAK2, ZF, CLECSF6, FLJ21120, ZAP3, FLJ20127, VAMP1, DCLRElC, DRIL2, FLJ11608, SFTPC, GABPB2,

ICAM1，PRO2405，TC10，XEDAR，CART，L3MBTL，PMS2L3，R32184_3，TCL1A，MIP-T3，FLJ14639，PLGL，HPGD，ICAM1, PRO2405, TC10, XEDAR, CART, L3MBTL, PMS2L3, R32184_3, TCL1A, MIP-T3, FLJ14639, PLGL, HPGD,

MERTK，EIF3S6，PPYR1，RPE，GLS，VAV2，TFAM，SLC6A1，RORA，PLVAP，PCDHB6，HDAC7A，MGC10731，ARTN，MERTK, EIF3S6, PPYR1, RPE, GLS, VAV2, TFAM, SLC6A1, RORA, PLVAP, PCDHB6, HDAC7A, MGC10731, ARTN,

HAO1，POU4F3，KCNJ4，ATP9B，F10，LSS，MPP6，TGIF2，ITGA6，KIAA0682，NUDT13，MGC4293，DKFZP564O0523，HAO1, POU4F3, KCNJ4, ATP9B, F10, LSS, MPP6, TGIF2, ITGA6, KIAA0682, NUDT13, MGC4293, DKFZP564O0523,

PACRG，ACLY，FLJ14627，OCM，SLC4A5，HNRPF，KRTHAI，FLJ21940，KIAA0632，SSX3，TNFRSF9，C22orf19，PACRG, ACLY, FLJ14627, OCM, SLC4A5, HNRPF, KRTHAI, FLJ21940, KIAA0632, SSX3, TNFRSF9, C22orf19,

SLC19A1，LSR7，ZFP36L1，SLIT3，DIP13B，C20orf27，ARHGEF2，EST-YD1，PROL5，RAB3B，LAMB4，PPP2R5B，CRYGD，SLC19A1, LSR7, ZFP36L1, SLIT3, DIP13B, C20orf27, ARHGEF2, EST-YD1, PROL5, RAB3B, LAMB4, PPP2R5B, CRYGD,

TGM5，ADAM22，AGMAT，PKNOX1，DSC1，TOP1，TU3A，CACNA1G，IDUA，LTBP4，MYRIP，ABLIMI，CALD1，ZNF46，TGM5, ADAM22, AGMAT, PKNOX1, DSC1, TOP1, TU3A, CACNA1G, IDUA, LTBP4, MYRIP, ABLIMI, CALD1, ZNF46,

CDKN2C，FLJ20958，RPS8，MAGEB1，KIAA0683，RHAG，BLu，TFF2，XPNPEP2，TYR，FAP48，NCYM，HIF3A，MBNL，CDKN2C, FLJ20958, RPS8, MAGEB1, KIAA0683, RHAG, BLu, TFF2, XPNPEP2, TYR, FAP48, NCYM, HIF3A, MBNL,

LRP16，PLXNC1，LOC51145，C21orf2，ARHGAP8，FLJ32069，FGFR2，NICE-4，PRKWNK1，LOC65243，DIO1，MDM2，LRP16, PLXNC1, LOC51145, C21orf2, ARHGAP8, FLJ32069, FGFR2, NICE-4, PRKWNK1, LOC65243, DIO1, MDM2,

PRDM13，CA-11，PSK，TNFSF15，OPRM1，HSPC048，SPN，NBS1，BIRC4，CDC27，HRH2，TRIO，CACNA11，TFR2，HAN11，PRDM13, CA-11, PSK, TNFSF15, OPRM1, HSPC048, SPN, NBS1, BIRC4, CDC27, HRH2, TRIO, CACNA11, TFR2, HAN11,

NEUROD6，CADPS，MGC12386，ORC5L，TNXB，F2R，PRO2831，CDH18，FLJ11106，DBP，PAX8，DLG1，CDC25A，NEUROD6, CADPS, MGC12386, ORC5L, TNXB, F2R, PRO2831, CDH18, FLJ11106, DBP, PAX8, DLG1, CDC25A,

CEGF3，FLJ10921，HRH4，FLJ20456，IL12B，CACNAlF，E2F5，PRP17，LGALS8，MGC3771，SLC6A3，RAC2，KIAA0286，CEGF3, FLJ10921, HRH4, FLJ20456, IL12B, CACNAlF, E2F5, PRP17, LGALS8, MGC3771, SLC6A3, RAC2, KIAA0286,

MGC12488，NR0B1-AD7C-NTP，IGL@，TULP1，PSMD11，COL13A1，UBE3B，FLJ20401，AKAP1，CRTL1，SPF45，MGC12488, NR0B1-AD7C-NTP, IGL@, TULP1, PSMD11, COL13A1, UBE3B, FLJ20401, AKAP1, CRTL1, SPF45,

FLJ10895，CCL13，COL16A1，CHIA，RAMP2，SSTR1，FYB，TXNDC4，SCAM-1，DYRK1A，KIR3DL2，CNK2，Di-Ras2，FLJ10895, CCL13, COL16A1, CHIA, RAMP2, SSTR1, FYB, TXNDC4, SCAM-1, DYRK1A, KIR3DL2, CNK2, Di-Ras2,

MCCC2，KRTAP2-4，KIAA0523，IGHM，ODF2，RXRA，GABRA2，CLST11240，POLR2A，SRY，TAS2R7，BLR1，MCCC2, KRTAP2-4, KIAA0523, IGHM, ODF2, RXRA, GABRA2, CLST11240, POLR2A, SRY, TAS2R7, BLR1,

DKFZP586H2123，FLJ21007，SPON1，EN1GMA，KIAA0140，RPL5，DESC1，DNAJC9，PTK9，MGC10715，SNCA，DKFZP586H2123, FLJ21007, SPON1, EN1GMA, KIAA0140, RPL5, DESC1, DNAJC9, PTK9, MGC10715, SNCA,

CEZANNE，TBCE，HOOK1，COVA1，C21orf62，AGXT2L1，SLC24A1，SYCP2，C17orf1A，OR5V1，HCN2，KLF12，AIM1L，CEZANNE, TBCE, HOOK1, COVA1, C21orf62, AGXT2L1, SLC24A1, SYCP2, C17orf1A, OR5V1, HCN2, KLF12, AIM1L,

LOC51336，PRC17，ITGB3，PRO1992，POMC，PRO0149，B3GAT3，L3MBTL，APG-1，C12orf2，MOX2，ARHGAP11A，LOC51336, PRC17, ITGB3, PRO1992, POMC, PRO0149, B3GAT3, L3MBTL, APG-1, C12orf2, MOX2, ARHGAP11A,

ATP5G2，HLA-DOA，GPC4，LOC57406，COL2A1，GABPA，SCN4A，RBP4，PHF7，GRID2，OSBPL7，MRPL9，MYH2，TFP1，ATP5G2, HLA-DOA, GPC4, LOC57406, COL2A1, GABPA, SCN4A, RBP4, PHF7, GRID2, OSBPL7, MRPL9, MYH2, TFP1,

FLJ10159，IPF1，IL20RA，THRA，LOX，CMAH，KIAA0616，CYP1A1，MADH5，FLJ40021，FLJ20069，FBXO22，GABRB3，FLJ10159, IPF1, IL20RA, THRA, LOX, CMAH, KIAA0616, CYP1A1, MADH5, FLJ40021, FLJ20069, FBXO22, GABRB3,

CYP2D6，TNRC4，FLJ22582，NR2C1，PK428，CBFA2T2，KCNK13，DCT，KCNG1，FLJ10648，CENTB1，ADAR3，HTN1，CYP2D6, TNRC4, FLJ22582, NR2C1, PK428, CBFA2T2, KCNK13, DCT, KCNG1, FLJ10648, CENTB1, ADAR3, HTN1,

PDCD1，TRP，EFNB1，TFDP2，ATP2B2，TNFRSF7，MRPL4，PTP4A3，SIGLEC8，PPP3CC，ENTPD5，BAG5，FLJ20047，PDCD1, TRP, EFNB1, TFDP2, ATP2B2, TNFRSF7, MRPL4, PTP4A3, SIGLEC8, PPP3CC, ENTPD5, BAG5, FLJ20047,

GL12，CCL21，EPNl，TONDU，RAP2B，CGI-72，ZNF384，C20orf42，MEF2C，RAB28，TAF1C，USP18，GPR42，HTR2A，GL12, CCL21, EPN1, TONDU, RAP2B, CGI-72, ZNF384, C20orf42, MEF2C, RAB28, TAF1C, USP18, GPR42, HTR2A,

PDE4D1P，DKFZP564C196，TXK，H2AFJ，FLJ20623，GPM6A，FOXJ1，MGC29761，IGHM，RAI15，CSTF1，KIAA0800，PDE4D1P, DKFZP564C196, TXK, H2AFJ, FLJ20623, GPM6A, FOXJ1, MGC29761, IGHM, RAI15, CSTF1, KIAA0800,

CSH1，KRT20，RAD51，TAF7L，FLJ10849，PTK9，RGS11，CDH20，FLJ20034，RFRP，FOXD2，HSA9761，PQBP1，DGCR6L，CSH1, KRT20, RAD51, TAF7L, FLJ10849, PTK9, RGS11, CDH20, FLJ20034, RFRP, FOXD2, HSA9761, PQBP1, DGCR6L,

FLJ11132，OR2W1，CRYBA1，LMOD1，PDPK1，GPR56，KIAA0296，SERPINB13，KLHL5，ZNF79，BCDO1，PSORT，FLJ11132, OR2W1, CRYBA1, LMOD1, PDPK1, GPR56, KIAA0296, SERPINB13, KLHL5, ZNF79, BCDO1, PSORT,

EPHA7，DKFZP434J046，PRO0800，SV2B，C12orf3，SGCA，BMX，MHC2TA，RAD51L1，CYB5-M，VIL2，FNBP2，LEC3，EPHA7, DKFZP434J046, PRO0800, SV2B, C12orf3, SGCA, BMX, MHC2TA, RAD51L1, CYB5-M, VIL2, FNBP2, LEC3,

RBM9，BRALI，NGFR，DDX34,MAPK8IP2，ANKTM1，DDEF1，ARL7，STK18，AQP4，MDM2，SYNE-1，FOXO3A，RBM9, BRALI, NGFR, DDX34, MAPK8IP2, ANKTM1, DDEF1, ARL7, STK18, AQP4, MDM2, SYNE-1, FOXO3A,

TNNT2，TITF1，ZIC3，PPBP，FLJ12542，SLC18A1，IGKC，HFE，PRO0038，NPPA，IL-17RC，CXCR3，DOM3Z，GADD45A，TNNT2, TITF1, ZIC3, PPBP, FLJ12542, SLC18A1, IGKC, HFE, PRO0038, NPPA, IL-17RC, CXCR3, DOM3Z, GADD45A,

GL012，CNOT2，TOB2，TFDP1，FLJ21617，MTRF1，APBA2，TTS-2.2，CNOT4，F9，PRO2133，CRABP1，CACNG1，IGFBP5，GL012, CNOT2, TOB2, TFDP1, FLJ21617, MTRF1, APBA2, TTS-2.2, CNOT4, F9, PRO2133, CRABP1, CACNG1, IGFBP5,

CTNND2，DKFZP564D166，MYT2，EV15，HYA22，CHK，HSPC073，RRBP1，FOSL2，FLJ21302，MGC2889，PRKCL1，TSPY，CTNND2, DKFZP564D166, MYT2, EV15, HYA22, CHK, HSPC073, RRBP1, FOSL2, FLJ21302, MGC2889, PRKCL1, TSPY,

JAG1，NDUFA5，IL1RN，CRH，CXCL11，MYH8，PURG，SLC7A1，KIAA0953，ELAVL2，SP100，KIAA0675，MLLT4，JAG1, NDUFA5, IL1RN, CRH, CXCL11, MYH8, PURG, SLC7A1, KIAA0953, ELAVL2, SP100, KIAA0675, MLLT4,

ZNF198，CD38，BHLHB2，LLT1，FLJ10210，PMS2L9，SOCS2，LIN7A，HOXA7，FLJ10661，ELAC2，CYP3A4，P2RX2，ZNF198, CD38, BHLHB2, LLT1, FLJ10210, PMS2L9, SOCS2, LIN7A, HOXA7, FLJ10661, ELAC2, CYP3A4, P2RX2,

MAPK81P3，ADAM28，NPR3，DEF6，UTRN，PHC3，FBN1，DKFZP566K0524，ZNF132，OR2J2，GJA8，PSIP2，ED1，PP2447，MAPK81P3, ADAM28, NPR3, DEF6, UTRN, PHC3, FBN1, DKFZP566K0524, ZNF132, OR2J2, GJA8, PSIP2, ED1, PP2447,

WSX1，LCP1，MAP2K3，KLF12，TFP1，BTN3A1，GCM2，FMR2，DDX3，PRO1768，KIAA1641，HEMK，SLC8A1，LALBA，WSX1, LCP1, MAP2K3, KLF12, TFP1, BTN3A1, GCM2, FMR2, DDX3, PRO1768, KIAA1641, HEMK, SLC8A1, LALBA,

RBAF600，FLJ10572，MSR1，KPNA4，CIAS1，MEP1B，NR4A2，PKNOX1，GLP1R，FOXP3，dJ222E13.1，KIAA0471，KERA，RBAF600, FLJ10572, MSR1, KPNA4, CIAS1, MEP1B, NR4A2, PKNOX1, GLP1R, FOXP3, dJ222E13.1, KIAA0471, KERA,

COL4A3，NPTXR，KIAA0447，ARHGDIA，ACACB，KIAA0847，CASP2，BRIP1，LRP8，IGL@，PCTK2，TFR2，PLA2G5，COL4A3, NPTXR, KIAA0447, ARHGDIA, ACACB, KIAA0847, CASP2, BRIP1, LRP8, IGL@, PCTK2, TFR2, PLA2G5,

HSPC056，IL16，FLJ12178，TBX1，KCNJ13，WT1，PRKACG，DKFZp547G183，MYO3A，DSC2，ANAPC2，ALDH1B1，HSPC056, IL16, FLJ12178, TBX1, KCNJ13, WT1, PRKACG, DKFZp547G183, MYO3A, DSC2, ANAPC2, ALDH1B1,

CD1B，MGC14433，GPHN，IGHM，GUCYIA2，HPSE2，GHRH，BAGE，CYP2E1，GTSE1，MSCP，ADAM8，PAPOLG，CGI-CD1B, MGC14433, GPHN, IGHM, GUCYIA2, HPSE2, GHRH, BAGE, CYP2E1, GTSE1, MSCP, ADAM8, PAPOLG, CGI-

14，SIRPB1，RGN，PGGT1B，ELL，RRP4，APOL2，POU3P1，JAM1，SYP，SERPINI1，FLJ12595，NRG2，PDE3B，HIRA，14, SIRPB1, RGN, PGGT1B, ELL, RRP4, APOL2, POU3P1, JAM1, SYP, SERPINI1, FLJ12595, NRG2, PDE3B, HIRA,

DDX9，LTBP4，FLJ11783，GABARAPL3，DRD3，XP5，FLJ20190，TRPC6，ADRA1A，DSPG3，KIAA0564，KPNB2，DDX9, LTBP4, FLJ11783, GABARAPL3, DRD3, XP5, FLJ20190, TRPC6, ADRA1A, DSPG3, KIAA0564, KPNB2,

DKFZP564O0523，UGT2B15，AP4E1，RGS7，ZNF10，PIWIL2，HLF，CYP4F2，INVS，ITSN1，FCGR3B，ARF4L，REL，DKFZP564O0523, UGT2B15, AP4E1, RGS7, ZNF10, PIWIL2, HLF, CYP4F2, INVS, ITSN1, FCGR3B, ARF4L, REL,

RGS20，EPOR，FLJ21168，MSTP9，ULK1，NRF1，T1GD6，GPR88，DUOX2，GP5，SSB3，FSHPRH1，RHOBTB3，C1QBP，RGS20, EPOR, FLJ21168, MSTP9, ULK1, NRF1, T1GD6, GPR88, DUOX2, GP5, SSB3, FSHPRH1, RHOBTB3, C1QBP,

CDSN，FSBP，CFDP1，ELK3，TUBD1，KIRREL，BAAT，CEP2，GGA2，KIAA0874，CRB1，FLJ11726，P2Y10，PCDH11Y，CDSN, FSBP, CFDP1, ELK3, TUBD1, KIRREL, BAAT, CEP2, GGA2, KIAA0874, CRB1, FLJ11726, P2Y10, PCDH11Y,

GPM6B，FLJ10715，TRIM9，FCAR，FGF22，FLJ13993，DIM1，GIPC2，KIAA0626，SNIP1，Gene Symbol，LARS，C15orf15，GPM6B, FLJ10715, TRIM9, FCAR, FGF22, FLJ13993, DIM1, GIPC2, KIAA0626, SNIP1, Gene Symbol, LARS, C15orf15,

KIAA0783，MGC2714，FLJ10036，HSPC154，FLJ10486，FLJ30596，FKBP5，SERF1A，REC14，OCLN，FLJ21924，LOC51249，KIAA0783, MGC2714, FLJ10036, HSPC154, FLJ10486, FLJ30596, FKBP5, SERF1A, REC14, OCLN, FLJ21924, LOC51249,

FRSB，AD034，CCNB1，FAM3B，MLL3，IBA2，SEPP1，C14orf31，HMGB1，C14orf35，MGC4308，FLJ10407，GRCC8，FRSB, AD034, CCNB1, FAM3B, MLL3, IBA2, SEPP1, C14orf31, HMGB1, C14orf35, MGC4308, FLJ10407, GRCC8,

C20orf129，FLJ20060，Spir-1，LANPL，RBBP7，KPNA4，FLJ10486，MKKS，SNX5，SART3，FLJ14494，FLJ21087，HOXB9，C20orf129, FLJ20060, Spir-1, LANPL, RBBP7, KPNA4, FLJ10486, MKKS, SNX5, SART3, FLJ14494, FLJ21087, HOXB9,

NUCKS，PPP4R2，C14orf47，EHF，MGC14439，LOC55871，AP1S2，TRNT1，FLJ25059，MGC10198，KIAA2024，KIAA1309，NUCKS, PPP4R2, C14orf47, EHF, MGC14439, LOC55871, AP1S2, TRNT1, FLJ25059, MGC10198, KIAA2024, KIAA1309,

HSPC014，LAPTM4A，GPR54，ARL61P2，DNMT3A，DKFZP564B1023，KIAA0114，ATF71P，HSPCB，HDAC3，FLJ39370，HSPC014, LAPTM4A, GPR54, ARL61P2, DNMT3A, DKFZP564B1023, KIAA0114, ATF71P, HSPCB, HDAC3, FLJ39370,

FLJ20093，PP2447，LOC139231，MGC41917，MGC20262，CSRP2BP，LOC51193，GRP58，HEY2，ANLN，UBL5，CDCA7，FLJ20093, PP2447, LOC139231, MGC41917, MGC20262, CSRP2BP, LOC51193, GRP58, HEY2, ANLN, UBL5, CDCA7,

KIAA1321，KIAA11323，UHRF1，HDAC3，KIAA1911，FLJ00166，KIAA1453，DKFZP434A0131，NY-BR-1，37865.00，Rpol-2，KIAA1321, KIAA11323, UHRF1, HDAC3, KIAA1911, FLJ00166, KIAA1453, DKFZP434A0131, NY-BR-1, 37865.00, Rpol-2,

MGC5306，BOC，FLJ25804，FLJ14728，BDP1，PSCD3，AF15Q14，HDCMA18P，PRO2000，LOC152518，GART，TRIPIN，MGC5306, BOC, FLJ25804, FLJ14728, BDP1, PSCD3, AF15Q14, HDCMA18P, PRO2000, LOC152518, GART, TRIPIN,

DKFZp313A2432，PSA，PGGT1B，MGC4832，LOC85028，FIGNL1，PECR，CBFA2T2，HOXC9，CPSF2，SLC25A19，DKFZp313A2432, PSA, PGGT1B, MGC4832, LOC85028, FIGNL1, PECR, CBFA2T2, HOXC9, CPSF2, SLC25A19,

C20orf45，FLJ32915，ZNF367，PANK1，LOC131118，FLJ14909，MGEA5，TRIM46，Rpo1-2，DKFZP434C245，AKAP10，C20orf45, FLJ32915, ZNF367, PANK1, LOC131118, FLJ14909, MGEA5, TRIM46, Rpo1-2, DKFZP434C245, AKAP10,

CDCA1，H326，DKFZp761A078，FLJ20333，NEDD1，AUTL1，TRAP25，KIAA1143，GPHN，LARS，DKFZP434D193，CDCA1, H326, DKFZp761A078, FLJ20333, NEDD1, AUTL1, TRAP25, KIAA1143, GPHN, LARS, DKFZP434D193,

FANCD2，PRO2000，DKFZp313A2432，FLJ12439，MK1671P，LOC115004，FLJ11220，MCM10，MRPL1，NDUFS8，PHF5A，FANCD2, PRO2000, DKFZp313A2432, FLJ12439, MK1671P, LOC115004, FLJ11220, MCM10, MRPL1, NDUFS8, PHF5A,

OAZIN，LOC92345，KIAA1708，KIAA1982，MGC2628，PXMP4，KIAA1804，ELYS，HNRPD，ZNF6，MRPL42，KIAA1287，OAZIN, LOC92345, KIAA1708, KIAA1982, MGC2628, PXMP4, KIAA1804, ELYS, HNRPD, ZNF6, MRPL42, KIAA1287,

TRUB1，TOMM22，FLJ25070，SPPH1，ZIC2，C6.1A，CG1-77，MGC33864，MK167IP，TUBE，VIK，MGC14798，FLJ20354，TRUB1, TOMM22, FLJ25070, SPPH1, ZIC2, C6.1A, CG1-77, MGC33864, MK167IP, TUBE, VIK, MGC14798, FLJ20354,

KIAA0140，GTF2H3，FLJ12787，DLD，ARIH2，KIAA2023，KIAA0864，CDC23，MGC13096，TRF4-2，OSBPL6，MNAB，KIAA0140, GTF2H3, FLJ12787, DLD, ARIH2, KIAA2023, KIAA0864, CDC23, MGC13096, TRF4-2, OSBPL6, MNAB,

RODI，USHlC，MGC16372，FLJ20333，FZD8，MCM10，FLJ23445，WDR4，OFD1，AK2，REV1L，COQ3，ASCL2，EG1，RODI, USHlC, MGC16372, FLJ20333, FZD8, MCM10, FLJ23445, WDR4, OFD1, AK2, REV1L, COQ3, ASCL2, EG1,

TReP-132，CAB56184，FLJ13081，HELLS，FLJ10378，C20orf61，EPHA8，DTNA，HSU53209，NAGS，LOC84524，TReP-132, CAB56184, FLJ13081, HELLS, FLJ10378, C20orf61, EPHA8, DTNA, HSU53209, NAGS, LOC84524,

LOC91120，LZK1，DKFZP4341092，FLJ14431，FLJ20354，HS6ST2，FLJ20333，KIAA0140，FLJ23476，C14orf31，LOC55871，LOC91120, LZK1, DKFZP4341092, FLJ14431, FLJ20354, HS6ST2, FLJ20333, KIAA0140, FLJ23476, C14orf31, LOC55871,

C14orf75，C20orf42，TBX1，CRMP5，Jade-1，CASPR4，FLJ11132，DKFZp547O146，MRPL50，LOC51193，FUT10，FLJ30655，C14orf75, C20orf42, TBX1, CRMP5, Jade-1, CASPR4, FLJ11132, DKFZp547O146, MRPL50, LOC51193, FUT10, FLJ30655,

SELB，KIAA1524，FLJ14813，FLJ38608，TRIM7，SYT12，FANCD2，FLJ25078，FLJ11294，KIAA1357，STRIN，pKnbeta，SELB, KIAA1524, FLJ14813, FLJ38608, TRIM7, SYT12, FANCD2, FLJ25078, FLJ11294, KIAA1357, STRIN, pKnbeta,

NSD1，DKFZP434B1727，BCRP2，FKSG14，EIF3S9，MGC2744，KIAA1595，C14orf106，LOC144455，KLK12，KIAA1374，NSD1, DKFZP434B1727, BCRP2, FKSG14, EIF3S9, MGC2744, KIAA1595, C14orf106, LOC144455, KLK12, KIAA1374,

BCoR，GABRB3，TIMM22，FLJ25416，BRUNOL5，MGC24665，ARX，DKFZP434K0427，KIAA1915，C7orrf11，MtFMT，BCoR, GABRB3, TIMM22, FLJ25416, BRUNOL5, MGC24665, ARX, DKFZP434K0427, KIAA1915, C7orrf11, MtFMT,

FLJ21439，MAP2K7，DKFZp434H2111，ARFGEF2，PRO1489，PTPN1，MGC13204，FLJ23322，MGC16386，MGC45B66，FLJ21439, MAP2K7, DKFZp434H2111, ARFGEF2, PRO1489, PTPN1, MGC13204, FLJ23322, MGC16386, MGC45B66,

FLJ30626，CML66，ZNF295，ARL8，LOC115106，MGC12466，SNX5，FLJ22344，MGC10850，AKT2，NCOA5，KIAA1713，FLJ30626, CML66, ZNF295, ARL8, LOC115106, MGC12466, SNX5, FLJ22344, MGC10850, AKT2, NCOA5, KIAA1713,

MGA，FLJ20032，RNPC2，DKFZP434E2318，MLL3，SYNPR，FLJ10989，C2orf7，LOC115827，LOC91862，MGC13016，USF1，MGA, FLJ20032, RNPC2, DKFZP434E2318, MLL3, SYNPR, FLJ10989, C2orf7, LOC115827, LOC91862, MGC13016, USF1,

DGKZ，LAMA3，DKFZp564B0769，A2BP1，KIAA1560，LOC221002，BG1，ENT4，RNF3，CHAC，ICAM2，FLJ10493，DGKZ, LAMA3, DKFZp564B0769, A2BP1, KIAA1560, LOC221002, BG1, ENT4, RNF3, CHAC, ICAM2, FLJ10493,

EIF3S6，TRA@，FLJ25604，TUBGCP6，GATA5，PGS1，HT014，C20orf6，NAV2，KIAA1357，GABRB3，FLJ10378，HSPC150，EIF3S6, TRA@, FLJ25604, TUBGCP6, GATA5, PGS1, HT014, C20orf6, NAV2, KIAA1357, GABRB3, FLJ10378, HSPC150,

ADCY3，BIGM103，MGC3067，APC10，BOC，LOC120379，KPNA4，FKBP7，C14orf50，FLJ22557，NUDT10，DDX17，ADCY3, BIGM103, MGC3067, APC10, BOC, LOC120379, KPNA4, FKBP7, C14orf50, FLJ22557, NUDT10, DDX17,

FLJ22729，TA-NFKBH，FLJ10785，FLJ32745，WH1P，CTLA4，MRPL30，MRPS25，FLJ10498，CDO1，FTCD，SPTB，FLJ22729, TA-NFKBH, FLJ10785, FLJ32745, WH1P, CTLA4, MRPL30, MRPS25, FLJ10498, CDO1, FTCD, SPTB,

KIAA1323，DKFZp761F0118，MGC2452，AKAP13，LMLN，LOC112840，FLJT10，TP73，PDCD7，KIAA1274，Tenr，CRR9，KIAA1323, DKFZp761F0118, MGC2452, AKAP13, LMLN, LOC112840, FLJT10, TP73, PDCD7, KIAA1274, Tenr, CRR9,

KIS，SPG7，HSFY，LOC92691，POLH，SMC6，MSCP，FLJ10378，DKFZp434F1819，CSTF3，CPNE4，HINT3，HSPCA，KIS, SPG7, HSFY, LOC92691, POLH, SMC6, MSCP, FLJ10378, DKFZp434F1819, CSTF3, CPNE4, HINT3, HSPCA,

KIAA0982，P53AIP1，ING5，DKFZp434D0513，ST12，SEC14L2，BCL11A，EPI64，FLJ25530，GPR49，IRA1，ARHGEF7，KIAA0982, P53AIP1, ING5, DKFZp434D0513, ST12, SEC14L2, BCL11A, EPI64, FLJ25530, GPR49, IRA1, ARHGEF7,

USH1C，RBM6，DSCR8，FLJ35863，NXPH1，MGC46719，MGC10981，ZNF398，CYBB，MGC4170，KRTAP9-4，NCOA61P，USH1C, RBM6, DSCR8, FLJ35863, NXPH1, MGC46719, MGC10981, ZNF398, CYBB, MGC4170, KRTAP9-4, NCOA61P,

HCAP-G，DMRT2，CORO1A，C12orf22，MLL，KIAA1753，DMRT3，KIAA1557，RAD18，FTCD，EIF2C2，KIF13A，HCAP-G, DMRT2, CORO1A, C12orf22, MLL, KIAA1753, DMRT3, KIAA1557, RAD18, FTCD, EIF2C2, KIF13A,

DLL3，KRT19，TRA@，SCAND2，FLJ25286，ZDHHC4，SEC13L，GPR92，ZNF207，FLJ14600，USP2，HDAC9，DLL3, KRT19, TRA@, SCAND2, FLJ25286, ZDHHC4, SEC13L, GPR92, ZNF207, FLJ14600, USP2, HDAC9,

PRKWNK3，D1SPB，CENPH，MGC29667，LOC149420，PRPF18，CHD2，KIAA0599，MGC16824，IRTA1，ZFP28，PRKWNK3, D1SPB, CENPH, MGC29667, LOC149420, PRPF18, CHD2, KIAA0599, MGC16824, IRTA1, ZFP28,

LOC112840，KIAA1411，LOC51194，SLC4A5，LOC115098，KIAA1720，MGC40397，FLJ36874，NESH，TMF1，LGR6，PF1，LOC112840, KIAA1411, LOC51194, SLC4A5, LOC115098, KIAA1720, MGC40397, FLJ36874, NESH, TMF1, LGR6, PF1,

MGC16943，TUFM，HERC2，DKFZP434N1511，FLJ12697，NLN，FLJ32827，CSRP2BP，RUFY2，RBM11，UBE21，YAP，MGC16943, TUFM, HERC2, DKFZP434N1511, FLJ12697, NLN, FLJ32827, CSRP2BP, RUFY2, RBM11, UBE21, YAP,

LRP15，CFLAR，OSBPL5，NPD007，Z1C4，OR51E2，MGC17301，PAX6，FLJ12697，MGC35366，U2AF1，TU12B1-TY，LRP15, CFLAR, OSBPL5, NPD007, Z1C4, OR51E2, MGC17301, PAX6, FLJ12697, MGC35366, U2AF1, TU12B1-TY,

BAG2，SLA/LP，BICD2，KIAA1465，DKFZp434G0522，ZNF354B，FLJ10420，DARS，KIAA1337，DKFZP434C0826，BAG2, SLA/LP, BICD2, KIAA1465, DKFZp434G0522, ZNF354B, FLJ10420, DARS, KIAA1337, DKFZP434C0826,

KIAA1712，CDGAP，FLJ10324，ARHGEF7，DKFZp434G0625，HES6，MY050，CSNK2A1，MPHOSPH9，HDAC10，KIAA1712, CDGAP, FLJ10324, ARHGEF7, DKFZp434G0625, HES6, MY050, CSNK2A1, MPHOSPH9, HDAC10,

KCNJ16，LOC135763，EKN1，ORAOV1，FLJ31528，POU4F1，MGC42174，SYNGAP1，RRP40，MGC10744，FLJ12363，KCNJ16, LOC135763, EKN1, ORAOV1, FLJ31528, POU4F1, MGC42174, SYNGAP1, RRP40, MGC10744, FLJ12363,

TTC7L1，DKFZP761N09121，ZDHHC11，MGC8721，IRTA2，ODAG，TRPM7，KIAA1878，TM4-B，DKFZp761H039，TTC7L1, DKFZP761N09121, ZDHHC11, MGC8721, IRTA2, ODAG, TRPM7, KIAA1878, TM4-B, DKFZp761H039,

ADAMTS9，CGI-203，KIAA1881，FLJ20003，SPPL2B，FLJ13386，RPC5，CTLA4，FL137034，DKFZP586N2124，ADAMTS9, CGI-203, KIAA1881, FLJ20003, SPPL2B, FLJ13386, RPC5, CTLA4, FL137034, DKFZP586N2124,

DKFZP434D0127，KIAA1966，KIAA1946，MGC20255，SPINO，FLJ90013，ALS2CR7，SH3GLB2，FLJ33962，FLJ23027，DKFZP434D0127, KIAA1966, KIAA1946, MGC20255, SPINO, FLJ90013, ALS2CR7, SH3GLB2, FLJ33962, FLJ23027,

PROK1，GABPB1，MIPOL1，MCM6，BAP29，VIT1，SYNGAP1，PEL11，FLJ25477，WBP1，ROCK1，ABTB1，LG14，PROK1, GABPB1, MIPOL1, MCM6, BAP29, VIT1, SYNGAP1, PEL11, FLJ25477, WBP1, ROCK1, ABTB1, LG14,

WNT5B，CLDN6，FBXO2，C18orf2，GAJ，TRIM7，FLJ13993，PEX5R，CECR6，PR，LOC151648，POSH，HRIHFB2072，WNT5B, CLDN6, FBXO2, C18orf2, GAJ, TRIM7, FLJ13993, PEX5R, CECR6, PR, LOC151648, POSH, HRIHFB2072,

SOX7，L0C139231，DKFZP434K0410，SOX6，CHPT1，NUP133，PSG5，FLJ22688，YME1L1，DKFZp313A2432，SOX7, L0C139231, DKFZP434K0410, SOX6, CHPT1, NUP133, PSG5, FLJ22688, YME1L1, DKFZp313A2432,

M11S1，FBXO5，KIAA1444，BCR，EPB41L5，RNPC2，HTAT1P2，KIAA0436，NSI-BP，LENG3，GLS，MIXL1，WDR9，M11S1, FBXO5, KIAA1444, BCR, EPB41L5, RNPC2, HTAT1P2, KIAA0436, NSI-BP, LENG3, GLS, MIXL1, WDR9,

DKFZP586M0122，KNSL5，G3BP，KCNJ2，PTBP1，DKFZp434N1415，SEMA6D，LOC63929，PTER，NAV1，FLJ39441，DKFZP586M0122, KNSL5, G3BP, KCNJ2, PTBP1, DKFZp434N1415, SEMA6D, LOC63929, PTER, NAV1, FLJ39441,

M1DORU，MGC14793，BAT4，FLJ12987，SEPP1，NYD-SP17，ZnTL2，FLJ35725，C6orf12，GSBS，MGC40157，KIAA1458，M1DORU, MGC14793, BAT4, FLJ12987, SEPP1, NYD-SP17, ZnTL2, FLJ35725, C6orf12, GSBS, MGC40157, KIAA1458,

AUTS2，FBXL12，KIAA1453，C20orf44，MGC20533，PGS1，FLJ11053，MRPS10，EML4，MGC14793，POLR3K，RINZF，AUTS2, FBXL12, KIAA1453, C20orf44, MGC20533, PGS1, FLJ11053, MRPS10, EML4, MGC14793, POLR3K, RINZF,

MOBP，FLJ12298，PIST，DELGEF，MGC2629，NPHP1，DKFZp434D1428，ARNTL2，NDUFB1，DKFZP667C165，MOBP, FLJ12298, PIST, DELGEF, MGC2629, NPHP1, DKFZp434D1428, ARNTL2, NDUFB1, DKFZP667C165,

FKSG42，HAL，WBSCR22，MRPS25，DHCR24，LY6G6D，LCHN，DKFZp761A052，DKFZP434G156，TBX3，FLJ21839，FKSG42, HAL, WBSCR22, MRPS25, DHCR24, LY6G6D, LCHN, DKFZp761A052, DKFZP434G156, TBX3, FLJ21839,

BRUNOL4，NYD-TSPG，KIAA1706，STYX，MMD，LOC113521，TRIM35，ZNFNIA4，DKFZP586B0319，KIAA1798，BRUNOL4, NYD-TSPG, KIAA1706, STYX, MMD, LOC113521, TRIM35, ZNFNIA4, DKFZP586B0319, KIAA1798,

FLJ30829，FLJ14281，DKFZP586G1517，MGC2629，DDHDI，CRSP6，FLJ11252，TRB@，GNAS，FLJ12975，KIAA1458，FLJ30829, FLJ14281, DKFZP586G1517, MGC2629, DDHDI, CRSP6, FLJ11252, TRB@, GNAS, FLJ12975, KIAA1458,

COL12A1，SPINO，KIAA0478，FLJ20085，SOX7，DRF1，TBDN100，BHMT2，ZFP91，SRMS，MGC15523，KIAA1919，COL12A1, SPINO, KIAA0478, FLJ20085, SOX7, DRF1, TBDN100, BHMT2, ZFP91, SRMS, MGC15523, KIAA1919,

FLJ23816，FLJ11125，C20orf151，STK31，RTBDN，FKSG83，GL14，FLJ22548，KIAA1912，C20orf42，TRIPIN，NDUFS7，FLJ23816, FLJ11125, C20orf151, STK31, RTBDN, FKSG83, GL14, FLJ22548, KIAA1912, C20orf42, TRIPIN, NDUFS7,

HSPC135，MGC20460，YR-29，SCDGF-B，KCNJ15，CLLD8，ZDHHC5，MGC10724，MGC33215，DKFZp547E052，HSPC135, MGC20460, YR-29, SCDGF-B, KCNJ15, CLLD8, ZDHHC5, MGC10724, MGC33215, DKFZp547E052,

DEFB118，MGC24039，KIAA1046，FLJ10936，ACMSD，B2M，TGM7，MGC3165，TRPM8，WHIP，LZK1，L0C90990，DEFB118, MGC24039, KIAA1046, FLJ10936, ACMSD, B2M, TGM7, MGC3165, TRPM8, WHIP, LZK1, L0C90990,

IRTA2，KIAA1560，NXF2，KIAA1317，DXYS155E，FLJ31958，HSPC154，H19，BAP29，PRKRA，PLAC3，LOC58486，IRTA2, KIAA1560, NXF2, KIAA1317, DXYS155E, FLJ31958, HSPC154, H19, BAP29, PRKRA, PLAC3, LOC58486,

FABP4，LOC130617，JAM3，LOC57019，TF，USP24，FLJ20222，FLJ20354，KIAA1836，MGC3040，SAC2，BARHL1，FABP4, LOC130617, JAM3, LOC57019, TF, USP24, FLJ20222, FLJ20354, KIAA1836, MGC3040, SAC2, BARHL1,

DSCAML1，STK35，KIAA1337，KIAA1276，LOC115557，FLJ14600，ROCK1，FLJ38359，MGC33215，ATP9B，UBE3B，DSCAML1, STK35, KIAA1337, KIAA1276, LOC115557, FLJ14600, ROCK1, FLJ38359, MGC33215, ATP9B, UBE3B,

C7orf3，PRKWNK4，DKFZp434J0617，MAPK1，PRKCE，KIAA2028，GBTS1，KIAA0716，DMRTC2，FLJ10998，C7orf3, PRKWNK4, DKFZp434J0617, MAPK1, PRKCE, KIAA2028, GBTS1, KIAA0716, DMRTC2, FLJ10998,

FLJ32069，LOC115330，FANCA，DGCR14，KIAA1337，FLJ23577，FLJ22761，FLJ35155，FLJ22329，FLJ14427，FLJ32069, LOC115330, FANCA, DGCR14, KIAA1337, FLJ23577, FLJ22761, FLJ35155, FLJ22329, FLJ14427,

FLJ20557，FLJ20321，ROCK1，PPP2R2C，BCoR， FLJ00058，LAMA1，FLJ20898，FLJ31606，PCDHB4，DKFZp547M109，FLJ20557, FLJ20321, ROCK1, PPP2R2C, BCoR, FLJ00058, LAMA1, FLJ20898, FLJ31606, PCDHB4, DKFZp547M109,

CLASP2，KCNQ5，LOC51240，FKSG79，OAZIN，FLJ13576，MGC4473，LACRT，NAG73，HSA251708，HSJ001348，CLASP2, KCNQ5, LOC51240, FKSG79, OAZIN, FLJ13576, MGC4473, LACRT, NAG73, HSA251708, HSJ001348,

TRA@，DKFZP434A236，MNAB，HAP1，MGC24995，DKFZP566C134，KIAA1501，MGC13090，C8orf13，GGTL3，TRA@, DKFZP434A236, MNAB, HAP1, MGC24995, DKFZP566C134, KIAA1501, MGC13090, C8orf13, GGTL3,

FLJ35757，CRYPTIC，C14orf35，KIAA2015，FLJ12303，LOC92033，FLJ20171，FLJ31340，TMPRSS2，RIP60，ZNF272，FLJ35757, CRYPTIC, C14orf35, KIAA2015, FLJ12303, LOC92033, FLJ20171, FLJ31340, TMPRSS2, RIP60, ZNF272,

FLJ20641，RP4-622L5，CENTA2，C20orf64，HHLA2，DPM1，PRKCL2，GNG2，and RTN4IP1.FLJ20641, RP4-622L5, CENTA2, C20orf64, HHLA2, DPM1, PRKCL2, GNG2, and RTN4IP1.

                                                      表7ATable 7A

                                     未传代致瘤性细胞和HSC中相比上调的基因Up-regulated genes in unpassaged tumorigenic cells compared with HSC

KRT19，C3，GOLPH2，CRIP1，PTGIS，BF，RA13，CA12，S100A8，PPL，TUBB，CXADR，NNMT，ITGB5，COL3A1，FN1，CIS，KRT19, C3, GOLPH2, CRIP1, PTGIS, BF, RA13, CA12, S100A8, PPL, TUBB, CXADR, NNMT, ITGB5, COL3A1, FN1, CIS,

CD14，EFEMP1，COL1A2，GJA1，FLJ20151，LGALS3，TACSTD2，LGALS1，FN1，MUC16，COL1A2，KRT7，RARRES1，CD14, EFEMP1, COL1A2, GJA1, FLJ20151, LGALS3, TACSTD2, LGALS1, FN1, MUC16, COL1A2, KRT7, RARRES1,

DSP，ID4，HRASLS3，S100A11，CYR61，SLPI，C4A，LGMN，S100A9，SERPINB2，MAFB，COBL，WT1，TGFB1，SPUVE，DSP, ID4, HRASLS3, S100A11, CYR61, SLPI, C4A, LGMN, S100A9, SERPINB2, MAFB, COBL, WT1, TGFB1, SPUVE,

CD24，DKFZp564A176，ANXA2P2，S100A10，ROR1，EGFL6，FN1，MUC1，ALDH1A3，PARVA，CDH3，FN1，TIMP1，MGP，CD24, DKFZp564A176, ANXA2P2, S100A10, ROR1, EGFL6, FN1, MUC1, ALDH1A3, PARVA, CDH3, FN1, TIMP1, MGP,

AGR2，KRT18，DC12，CH13L1，CD24，FLJ20273，ID3，H11，HLA-DQA1，ANXA2，SERP1NA3，RAB31，ANXA2，RAB31，AGR2, KRT18, DC12, CH13L1, CD24, FLJ20273, ID3, H11, HLA-DQA1, ANXA2, SERP1NA3, RAB31, ANXA2, RAB31,

EMS1，FERIL3，KIAA1199，CX3CR1，FLJ11619，KLK11，CD24，TIMP2，CCND1，LOC51760，FLRT2，HP，GPRC5B，EMS1, FERIL3, KIAA1199, CX3CR1, FLJ11619, KLK11, CD24, TIMP2, CCND1, LOC51760, FLRT2, HP, GPRC5B,

IL13RA2，APOE，GAS1，PPIC，MAPK13，KIAA0882，APM2，PLAT，MYL9，MYO6，COL3A1，ANXA2，RAB31，IGHG3，IL13RA2, APOE, GAS1, PPIC, MAPK13, KIAA0882, APM2, PLAT, MYL9, MYO6, COL3A1, ANXA2, RAB31, IGHG3,

PMP22，FAT，S100A8，MARCO，PTPRK，PTPRF，CD163，DF，C4B，COL1A1，IGKC，TFF1，TGM2，CTSL，ITGB5，PMP22, FAT, S100A8, MARCO, PTPRK, PTPRF, CD163, DF, C4B, COL1A1, IGKC, TFF1, TGM2, CTSL, ITGB5,

GALNAC4S-6ST，1F，RARRES2，ADAM9，VCAM1，CD9，ID4，APOC1，PDEF，VIL2，GRIA2，RIG，MET，GNG12，CD163，GALNAC4S-6ST, 1F, RARRES2, ADAM9, VCAM1, CD9, ID4, APOC1, PDEF, VIL2, GRIA2, RIG, MET, GNG12, CD163,

FLJ22662，CAV1，PRG4，CDH11，IF127，TM4SFI，NNMT，DUSP4，THBS2，COL6A1，FGFR2，TNXB，A2M，UPK1B，BCHE，FLJ22662, CAV1, PRG4, CDH11, IF127, TM4SFI, NNMT, DUSP4, THBS2, COL6A1, FGFR2, TNXB, A2M, UPK1B, BCHE,

IF130，MAF，KIAA0752，TPD52L1，KRT8，FXYD3，CKAP4，ALDH1A2，ANXA8，BCMP1，ALDH8A1，ASS，EFEMP1，LTF，IF130, MAF, KIAA0752, TPD52L1, KRT8, FXYD3, CKAP4, ALDH1A2, ANXA8, BCMP1, ALDH8A1, ASS, EFEMP1, LTF,

FLJ20151，TIA-2，SELENBP1，CTSH，GPR64，TJP1，RARRES1，SYN47，PDGFRA，PRSS11，AQP1，COL5A2，EPHA2，FLJ20151, TIA-2, SELENBP1, CTSH, GPR64, TJP1, RARRES1, SYN47, PDGFRA, PRSS11, AQP1, COL5A2, EPHA2,

ITSN1，SULF1，PTPN3，LGALS2，OGN，CTSB，IER3，FMO1，SNCAIP，PPAP2A，MGC2376，GATA6，ILIR1，CD1C，MEIS2，ITSN1, SULF1, PTPN3, LGALS2, OGN, CTSB, IER3, FMO1, SNCAIP, PPAP2A, MGC2376, GATA6, ILIR1, CD1C, MEIS2,

TACC2，C1R，AQP3，LR8，SLC7A8，S100A6，ATIP1，MIG2，TNXB，MAOB，DCAMKL1，DPP7，ANXA3，RBP4，ziziminl，TACC2, C1R, AQP3, LR8, SLC7A8, S100A6, ATIP1, MIG2, TNXB, MAOB, DCAMKL1, DPP7, ANXA3, RBP4, ziziminl,

CH13L1，FARP1，CLMN，BNC，HCA112，CSPG2，CD24，EMS1，CEBPD，IL13RA1，RIL，COL4A5，KDELR3，CAP2，MAF，CH13L1, FARP1, CLMN, BNC, HCA112, CSPG2, CD24, EMS1, CEBPD, IL13RA1, RIL, COL4A5, KDELR3, CAP2, MAF,

TFP12，DOC1，CSPG2，LG12，Z391G，CYP1B1，CAV1，ALP，ERBB2，LAMA4，CSPG2，LOC113146，LAMP3，ARGBP2，TFP12, DOC1, CSPG2, LG12, Z391G, CYP1B1, CAV1, ALP, ERBB2, LAMA4, CSPG2, LOC113146, LAMP3, ARGBP2,

MNDA，DKFZp56411922，CAV2，MARCKS，TPM2，LOC92689，GFPT1，N33，SECTM1，WFDC2，CLU，ROR1，TST，EFS2，MNDA, DKFZp56411922, CAV2, MARCKS, TPM2, LOC92689, GFPT1, N33, SECTM1, WFDC2, CLU, ROR1, TST, EFS2,

GUK1，C1QB，CPE，CRYAB，TSTA3，CALB2，EGFR-RS，PPAP2A，PTPRG，SAT，TFAP2C，C2，RCP，SULF1，SFN，GUK1, C1QB, CPE, CRYAB, TSTA3, CALB2, EGFR-RS, PPAP2A, PTPRG, SAT, TFAP2C, C2, RCP, SULF1, SFN,

LAMB1，IL13RA1，PHT2，BMPR1A，L1M，FLNC，N33，ST5，CSRP2，FLJ23091，PAPSS2，IGSF4，TNFRSF6，STEAP，LAMB1, IL13RA1, PHT2, BMPR1A, L1M, FLNC, N33, ST5, CSRP2, FLJ23091, PAPSS2, IGSF4, TNFRSF6, STEAP,

BACE2，SERPINB7，CALU，PDXK，PPIC，TACC2，CLDN4，GPNMB，RIN2，KIAA0599，LUM，KIAA0790，CARD10，MVP，BACE2, SERPINB7, CALU, PDXK, PPIC, TACC2, CLDN4, GPNMB, RIN2, KIAA0599, LUM, KIAA0790, CARD10, MVP,

PDGFRL，RRAS2，KIAA1078，AKAP12，ARHE，RNASE6，BLAME，TM4SF1，TIA-2，KIAA0869，MPZL1，NID2，DDR1，PDGFRL, RRAS2, KIAA1078, AKAP12, ARHE, RNASE6, BLAME, TM4SF1, TIA-2, KIAA0869, MPZL1, NID2, DDR1,

DUSP4，LAMA5，SGCE，UBD，LGALS3BP，ENPP2，SGSH，COPE，KRT5，SEMA3C，IGKC，COX5B，ELOVL1，S100A14，DUSP4, LAMA5, SGCE, UBD, LGALS3BP, ENPP2, SGSH, COPE, KRT5, SEMA3C, IGKC, COX5B, ELOVL1, S100A14,

APEG1，ALOX5，TM4SF6，LMNA，DSTN，RAB20，DNAJB2，TYROBP，UPK1B，KDR，P4HB，FLJ11856，Clorf34，ADM，APEG1, ALOX5, TM4SF6, LMNA, DSTN, RAB20, DNAJB2, TYROBP, UPK1B, KDR, P4HB, FLJ11856, Clorf34, ADM,

NR2F2，PLXNB2，ITPR3，S100B，SOX9，DCN，EPS8，EFA6R，ZFPM2，PPFIBP2，SERPINF1，NQO1，NMA，AADAC，NR2F2, PLXNB2, ITPR3, S100B, SOX9, DCN, EPS8, EFA6R, ZFPM2, PPFIBP2, SERPINF1, NQO1, NMA, AADAC,

COL6A2，SERPINE1，MT1X，MGC3047，NCKAP1，DDR1，TLE1，EPN3，TBX3，CDS1，HSPB1，DPP4，CTSB，NEO1，COL6A2, SERPINE1, MT1X, MGC3047, NCKAP1, DDR1, TLE1, EPN3, TBX3, CDS1, HSPB1, DPP4, CTSB, NEO1,

TMEM8，NF1B，FKBP2，TNFRSF11B，FGR，FMOD，P4HA2，TNFRSF12A，ERBB3，NQO1，LAMC1，PRO1489，IGFBP3，TMEM8, NF1B, FKBP2, TNFRSF11B, FGR, FMOD, P4HA2, TNFRSF12A, ERBB3, NQO1, LAMC1, PRO1489, IGFBP3,

MYOIC，KIAA1026，SLC6A8，PDE4A，HML2，FLJ21562，C8FW，MS4A6A，KCNK1，C3AR1，AK1，MT2A，KLK10，MYOIC, KIAA1026, SLC6A8, PDE4A, HML2, FLJ21562, C8FW, MS4A6A, KCNK1, C3AR1, AK1, MT2A, KLK10,

KIAA0429，IGSF3，ARNT2，DCN，C12orf5，CD24，C4.4A，SFN，CRABP2，VIL2，CLECSF6，HCK，SIX2，TSSC3，CCR7，KIAA0429, IGSF3, ARNT2, DCN, C12orf5, CD24, C4.4A, SFN, CRABP2, VIL2, CLECSF6, HCK, SIX2, TSSC3, CCR7,

GFPT2，TUBB-5，ENAH，SLC16A4，C11orf9，FLJ20761，SAR1，GPC1，MYO1D，RGS16，DCN，MT1L，PCDHA12，SGSH，GFPT2, TUBB-5, ENAH, SLC16A4, C11orf9, FLJ20761, SAR1, GPC1, MYO1D, RGS16, DCN, MT1L, PCDHA12, SGSH,

RHBDL2，GLUL，CKMT1，NPAS2，EMP2，DAB2，DSCR1L1，MATN2，BLVRB，PLAB，MT1G，WIT-1，OASIS，PPP1R3C，RHBDL2, GLUL, CKMT1, NPAS2, EMP2, DAB2, DSCR1L1, MATN2, BLVRB, PLAB, MT1G, WIT-1, OASIS, PPP1R3C,

NQO1，AMOTL2，TNNT1，AZGP1，PARG1，SLC7A7，COL5A2，NEDD4L，DCN，SERPINA1，DFNA5，SAMHD1，IQGAP1，NQO1, AMOTL2, TNNT1, AZGP1, PARG1, SLC7A7, COL5A2, NEDD4L, DCN, SERPINA1, DFNA5, SAMHD1, IQGAP1,

THBD，DPYS，ADAMTS5，MGC10848，NEBL，RA12，TUFT1，KCNJ15，LIF，CD151，DAF，IL1R2，NRXN3，HK3，FCN1，THBD, DPYS, ADAMTS5, MGC10848, NEBL, RA12, TUFT1, KCNJ15, LIF, CD151, DAF, IL1R2, NRXN3, HK3, FCN1,

CXCL1，CALD1，PCDH7，C1orf13，TRD@，NF1B，VEGFC，CCL22，CD63，CTSZ，KYNU，ADFP，HRH1，CTGF，GRIK2，CXCL1, CALD1, PCDH7, C1orf13, TRD@, NF1B, VEGFC, CCL22, CD63, CTSZ, KYNU, ADFP, HRH1, CTGF, GRIK2,

ANG，KIAA0790，SNK，CST3，SDR1，KIAA0703，MGC35048，ANXA9，YAP1，ADH1B，CLDN1，TIP-1，COL18A1，DOK5，ANG, KIAA0790, SNK, CST3, SDR1, KIAA0703, MGC35048, ANXA9, YAP1, ADH1B, CLDN1, TIP-1, COL18A1, DOK5,

GPRC5C，IGSF4，ABCA8，KDELR3，PPAP2C，KIAA0440，IGF2R，VLDLR，OSBPL10，SLC12A8，NPD009，RPL37A，GPRC5C, IGSF4, ABCA8, KDELR3, PPAP2C, KIAA0440, IGF2R, VLDLR, OSBPL10, SLC12A8, NPD009, RPL37A,

MAPT，FARP1，LAMP1，DAB2，KRT17，SSH-3，ABCA3，PHLDA1，FBXL2，LOC114990，LOX，ALDH3B1，RIG，SDC4，MAPT, FARP1, LAMP1, DAB2, KRT17, SSH-3, ABCA3, PHLDA1, FBXL2, LOC114990, LOX, ALDH3B1, RIG, SDC4,

CGI-38，ZFP36L1，FOLR2，DLG5，PFC，BGN，DSC3，WARS，FLJ21610，MGC2494，PCOLCE，FCER1G，FGF13，MD-2，CGI-38, ZFP36L1, FOLR2, DLG5, PFC, BGN, DSC3, WARS, FLJ21610, MGC2494, PCOLCE, FCER1G, FGF13, MD-2,

UGCG，BAG3，MAOA，CAPN2，CCR1，TRIM2，CLU，NR2F6，KIAA1598，GPR65，TRD@，PPARD，HSPA6，KIAA0436，UGCG, BAG3, MAOA, CAPN2, CCR1, TRIM2, CLU, NR2F6, KIAA1598, GPR65, TRD@, PPARD, HSPA6, KIAA0436,

DPI，GRN，ABCA1，CD59，ITGA3，NT5E，SLIT3，CDC42BPB，ZNF144，LTBP2，FER1L3，PCOLCE2，FST，CSTA，DPI, GRN, ABCA1, CD59, ITGA3, NT5E, SLIT3, CDC42BPB, ZNF144, LTBP2, FER1L3, PCOLCE2, FST, CSTA,

CLECSF6，HOMER-3，LDB2，SLC34A2，TEAD3，PMM1，EFEMP2，HN1，FLJ20539，TPM1，CXCL6，MPZL1，CLECSF6, HOMER-3, LDB2, SLC34A2, TEAD3, PMM1, EFEMP2, HN1, FLJ20539, TPM1, CXCL6, MPZL1,

DKFZP434B044，GS3955，CHST6，RPL5，IL1RL1，RIS1，SN，CDKNIA ，PIGPC1，SLC4A2，SMARCA1，GBP2，RNASE4，DKFZP434B044, GS3955, CHST6, RPL5, IL1RL1, RIS1, SN, CDKNIA, PIGPC1, SLC4A2, SMARCA1, GBP2, RNASE4,

EFNA1，MCP，DPP4，HSPA1A，LRP10，GRN，SLC39A1，PFN2，BC-2，WNT2，FLJ23186，TPM1，SIAT4A，RNASE1，PLS3，EFNA1, MCP, DPP4, HSPA1A, LRP10, GRN, SLC39A1, PFN2, BC-2, WNT2, FLJ23186, TPM1, SIAT4A, RNASE1, PLS3,

TIMM17A，DDR1，FLJ20366，EFNB2，PSPHL，MEOX2，KIAA0429，SDC2，MGC10796，SERPINB5，CAST，MYO6，CRIM1，TIMM17A, DDR1, FLJ20366, EFNB2, PSPHL, MEOX2, KIAA0429, SDC2, MGC10796, SERPINB5, CAST, MYO6, CRIM1,

TFP12，NCF2，FLJ22531，LISCH7，SLC7A11，MGC11242，PKNOX2，RARRES1，FBP1，CLIC4，CAST，C5R1，SPR，BCL6，TFP12, NCF2, FLJ22531, LISCH7, SLC7A11, MGC11242, PKNOX2, RARRES1, FBP1, CLIC4, CAST, C5R1, SPR, BCL6,

RIPX，GRN，KIAA0934，HSPB2，SPARCL1，CTSB，S100A11P，IGF1，BCAR3，ASTN，RRAS2，FLJ21562，KIAA0992，FHL2，RIPX, GRN, KIAA0934, HSPB2, SPARCL1, CTSB, S100A11P, IGF1, BCAR3, ASTN, RRAS2, FLJ21562, KIAA0992, FHL2,

HLA-DOB，LAMB1，MAP4K4，EFEMP2，KIAA1029，PP1057，SLC7A8，TLR7，MMP15，WDR1，GHR，TJP1，PCDHGC3，HLA-DOB, LAMB1, MAP4K4, EFEMP2, KIAA1029, PP1057, SLC7A8, TLR7, MMP15, WDR1, GHR, TJP1, PCDHGC3,

MMP19，ARHD，R1L，NOL3，WNT5A，RAB17，F-LAN-1，IGF1，BMPR1A，TLR2，FTS，EPB41L1，TPM1，CD1D，YKT6，MMP19, ARHD, R1L, NOL3, WNT5A, RAB17, F-LAN-1, IGF1, BMPR1A, TLR2, FTS, EPB41L1, TPM1, CD1D, YKT6,

GRIM19，WARS，AXL，MIF，CLIC3，MAPK13，SSB1，SEC61A1，PDGFRB，IL10RA，CLTB，PCNP，SNA12，SGCB，GRIM19, WARS, AXL, MIF, CLIC3, MAPK13, SSB1, SEC61A1, PDGFRB, IL10RA, CLTB, PCNP, SNA12, SGCB,

CYP39A1，FLJ90798，SBB131，FZD2，AMMECR1，SOCS5，KIF1C，S100A13，CLDN7，PBX1，TJP3，RGL，FKBP11，GRP58，CYP39A1, FLJ90798, SBB131, FZD2, AMMECR1, SOCS5, KIF1C, S100A13, CLDN7, PBX1, TJP3, RGL, FKBP11, GRP58,

EIF5，IGFBP1，FLJ13612，G0S2，TNFAIP1，TIP-1，PSEN2，PP1B，DAG1，ARF4，AHNAK，LOC115207，PCDHGA1，MST1R，EIF5, IGFBP1, FLJ13612, G0S2, TNFAIP1, TIP-1, PSEN2, PP1B, DAG1, ARF4, AHNAK, LOC115207, PCDHGA1, MST1R,

SH3GLB1，SC65，MGST3，BMP2，CTSB，TMSB10，TRIM38，ITSN1，MPZL1，ARHC，KIAA1078，PLTP，CRIM1，C11orf24，SH3GLB1, SC65, MGST3, BMP2, CTSB, TMSB10, TRIM38, ITSN1, MPZL1, ARHC, KIAA1078, PLTP, CRIM1, C11orf24,

KIAA0746，MGC2376，COLEC12，BBOX1，WNT2B，HUMPPA，PAM，MAP4，FLJ21918，SLC2A6，MYO1B，NFE2L1，KIAA0746, MGC2376, COLEC12, BBOX1, WNT2B, HUMPPA, PAM, MAP4, FLJ21918, SLC2A6, MYO1B, NFE2L1,

DXS9928E，SLC1A1，TUBGCP2，SULT1A1，QSCN6，LOC51159，PSK-1，CYB5R2，RA114，LICAM，KCNMA1，CD1E，DXS9928E, SLC1A1, TUBGCP2, SULT1A1, QSCN6, LOC51159, PSK-1, CYB5R2, RA114, LICAM, KCNMA1, CD1E,

HOXC6，THY1，PTOV1，EDG2，SUCLG2，AQP1，DDR1，TMEM4，EDG2，FLJ22833，KCNK15，KIAA0417，TCF21，HOXC6, THY1, PTOV1, EDG2, SUCLG2, AQP1, DDR1, TMEM4, EDG2, FLJ22833, KCNK15, KIAA0417, TCF21,

ASML3B，HSPC163，LAMA4，APOC1，DKFZp761F2014，SLC21A11，CXCL14，FCGR2A，FLJ20967，MRPS12，FLJ13110，ASML3B, HSPC163, LAMA4, APOC1, DKFZp761F2014, SLC21A11, CXCL14, FCGR2A, FLJ20967, MRPS12, FLJ13110,

KIAA0913，SHC1，DP1，TLE1，SLC2A10，PON2，SPAG4，ITSN1，ACTL7A，RBP1，ILIRAP，C22orf2，ATP1A1，DES，MST1，KIAA0913, SHC1, DP1, TLE1, SLC2A10, PON2, SPAG4, ITSN1, ACTL7A, RBP1, ILIRAP, C22orf2, ATP1A1, DES, MST1,

PHLDA1，KIAA0934，S100A2，ID4，ITGB4，CASK，SLC31A2，C21orf97，CD86，FBXO9，AP1M2，D2S448，ADCY9，PHLDA1, KIAA0934, S100A2, ID4, ITGB4, CASK, SLC31A2, C21orf97, CD86, FBXO9, AP1M2, D2S448, ADCY9,

PALMD，PTPN21，TRA@，PP1B，EPB41L4B，PNMA2，RSN，SYNGR2，SLI，FYCO1，CLTB，MGC16723，CKAP4，PLEC1，PALMD, PTPN21, TRA@, PP1B, EPB41L4B, PNMA2, RSN, SYNGR2, SLI, FYCO1, CLTB, MGC16723, CKAP4, PLEC1,

FLJ10521，B4GALT4，ID1，CDA08，OPTN，PTHLH，MYO1B，LIM，TLR5，FLJ23516，CAST，CTSL2，CSF2RA，C14orf58，FLJ10521, B4GALT4, ID1, CDA08, OPTN, PTHLH, MYO1B, LIM, TLR5, FLJ23516, CAST, CTSL2, CSF2RA, C14orf58,

SLC7A8，TREM2，CST6，ARHN，ST14，PTPN13，SLC5A7，DUSP5，B4GALT4，DKFZp667G2110，TWIST，SC65，PPP2R1B，SLC7A8, TREM2, CST6, ARHN, ST14, PTPN13, SLC5A7, DUSP5, B4GALT4, DKFZp667G2110, TWIST, SC65, PPP2R1B,

ITGB5，KIAA1096，EV15，RAB2，CTSD，SLIT3，KIAA0284，NPY1R，HERPUD1，PMM2，HSD3B1，HP1P，UNC119，ITGB5, KIAA1096, EV15, RAB2, CTSD, SLIT3, KIAA0284, NPY1R, HERPUD1, PMM2, HSD3B1, HP1P, UNC119,

KDELR2，FLJ10199，PLOD，GTF21RD1，SQSTM1，BDKRB2，WSB2，DPP3，LOXL1，SEMA5A，TMP21，CLTB，DNALI1，KDELR2, FLJ10199, PLOD, GTF21RD1, SQSTM1, BDKRB2, WSB2, DPP3, LOXL1, SEMA5A, TMP21, CLTB, DNALI1,

CXCL13，FZD1，CNN3，KDELR3，ADAMTS2，MD-1，TAT，FLJ20234，DKK1，FLJ10856，TM4SF6，KIAA0152，FBXO2，CXCL13, FZD1, CNN3, KDELR3, ADAMTS2, MD-1, TAT, FLJ20234, DKK1, FLJ10856, TM4SF6, KIAA0152, FBXO2,

CLECSF12，PRSS16，KIAA0103，UGDH，YIF1P，P8，SNTB2，GOSR2，KDELR2，D4S234E，HABP4，ANKRD3，CCL18，CLECSF12, PRSS16, KIAA0103, UGDH, YIF1P, P8, SNTB2, GOSR2, KDELR2, D4S234E, HABP4, ANKRD3, CCL18,

TEGT，EGFR，ATIP1，EPHB3，H_GS165L15.1，TCEB2，AGRN，NBL1，FLRT3，NPAS2，SCO2，MAOA，NFE2L1，APLP2，TEGT, EGFR, ATIP1, EPHB3, H_GS165L15.1, TCEB2, AGRN, NBL1, FLRT3, NPAS2, SCO2, MAOA, NFE2L1, APLP2,

MED8，LRP2，SMARCA1，TJP2，p47，FLJ10055，EPS8R1，TG1F，AGRN，SEMACAP3，DSC2，FBLN2，ORMDL2，MED8, LRP2, SMARCA1, TJP2, p47, FLJ10055, EPS8R1, TG1F, AGRN, SEMACAP3, DSC2, FBLN2, ORMDL2,

ADAMTS3，PTGDS，CENTG2，MMP14，SNARK，PTGER3，DPH2L1，PTPN21，DSCR1，PP1665，PTK9，AFFX-ADAMTS3, PTGDS, CENTG2, MMP14, SNARK, PTGER3, DPH2L1, PTPN21, DSCR1, PP1665, PTK9, AFFX-

HSAC07/X00351_M_at，HAMP，TOB1，FACL3，GMPPB，CSRP2，P4HB，NPC1L1，PIG7，VNN3，ARK5，PODXL，ACADVL，HSAC07/X00351_M_at, HAMP, TOB1, FACL3, GMPPB, CSRP2, P4HB, NPC1L1, PIG7, VNN3, ARK5, PODXL, ACADVL,

GNPI，FLJ10261，UPLC1，SFN，PEA15，MLCB，SLC31A1，ICAM1，UP，SLC4A4，C11of17，PTGER3，ZFP103，CYP-M，GNPI, FLJ10261, UPLC1, SFN, PEA15, MLCB, SLC31A1, ICAM1, UP, SLC4A4, C11of17, PTGER3, ZFP103, CYP-M,

HMOX1，SLC21A9，TCN1，SLC20A2，RBSK，WNT4，CYB3B，ANXA4，DNAJC3，MIRO-2，ARHGEF4，SULT1A3，GOLGA2，HMOX1, SLC21A9, TCN1, SLC20A2, RBSK, WNT4, CYB3B, ANXA4, DNAJC3, MIRO-2, ARHGEF4, SULT1A3, GOLGA2,

PTPRF，NDUFB7，TBC1D2，MSR1，CORO1B，FADD，ATP6V1D，ALDOA，EPLIN，MST1，TDO2，ETV2，CCR5，SERF2，PTPRF, NDUFB7, TBC1D2, MSR1, CORO1B, FADD, ATP6V1D, ALDOA, EPLIN, MST1, TDO2, ETV2, CCR5, SERF2,

GTPBP1，COL4A2，ASPH，ELMO3，DKFZP564A2416，BAIAP3，APLP2，PDE8A，IFNGR1，GREB1，ANXA2P3，CAPG，PTS，GTPBP1, COL4A2, ASPH, ELMO3, DKFZP564A2416, BAIAP3, APLP2, PDE8A, IFNGR1, GREB1, ANXA2P3, CAPG, PTS,

N33，MGC11256，PLA2G4C，HFE，FL190798，FLNA，LMNA，IRX5，SRPX，LOC160313，SLC33A1，CSTB，FLJ20152，N33, MGC11256, PLA2G4C, HFE, FL190798, FLNA, LMNA, IRX5, SRPX, LOC160313, SLC33A1, CSTB, FLJ20152,

ATP6V0E，HSPA1A，KRT6A，SAR1，POR，NDUFS8，CCL2，B4GALT1，TMSB4X，FLJ20701，ACTN1，IL4R，F5，CD5L，ATP6V0E, HSPA1A, KRT6A, SAR1, POR, NDUFS8, CCL2, B4GALT1, TMSB4X, FLJ20701, ACTN1, IL4R, F5, CD5L,

IGFBP3，ALOX5，AUH，CKAP1，CCR1，KIAA0843，UGTREL1，GAS2L1，AP1M2，RARRES3，PPGB，LY6E，GNB2，IGFBP3, ALOX5, AUH, CKAP1, CCR1, KIAA0843, UGTREL1, GAS2L1, AP1M2, RARRES3, PPGB, LY6E, GNB2,

CTNND1，FPR1，ALDOA，PC326，KIAA0980，PGM3，DHCR24，PTGDS，LAMB3，ALDH7A1，KIAA0716，TC10，CTNND1, FPR1, ALDOA, PC326, KIAA0980, PGM3, DHCR24, PTGDS, LAMB3, ALDH7A1, KIAA0716, TC10,

KIAA1096，ILIRN，C11orf24，FDXR，SERPINB3，COL6A1，FLJ20296，DTNA，IGF2R，TRIM36，FLJ22593，IFITM2，ARHD，KIAA1096, ILIRN, C11orf24, FDXR, SERPINB3, COL6A1, FLJ20296, DTNA, IGF2R, TRIM36, FLJ22593, IFITM2, ARHD,

KIAA0220，OCRL，SDC2，KIF3B，GALNT10，PRKAR1A，VTI1B，PSAP，PTPRO，FGF2，PCSK7，SUCLG2，ERP70，KIAA0220, OCRL, SDC2, KIF3B, GALNT10, PRKAR1A, VTI1B, PSAP, PTPRO, FGF2, PCSK7, SUCLG2, ERP70,

FLJ20254，MLP，CORO2A，IL13RA1，RGS16，MEIS3，FOLR1，LGALS8，LAD1，TGFBR3，NDUFA3，LANO，AFAP，SGPL1，FLJ20254, MLP, CORO2A, IL13RA1, RGS16, MEIS3, FOLR1, LGALS8, LAD1, TGFBR3, NDUFA3, LANO, AFAP, SGPL1,

UBXD2，GM2A，PCDHGA10，PACSIN3，CFL1，PAM，GOLGA2，GSTM3，CREB3，C14orf92，IGL@，FLJ21313，SYNE-2，UBXD2, GM2A, PCDHGA10, PACSIN3, CFL1, PAM, GOLGA2, GSTM3, CREB3, C14orf92, IGL@, FLJ21313, SYNE-2,

EPHX1，MRPL17，PCDHGC3，MAP3K6，DNCH1，TM7SF1，LARGE，VRP，IL6，KIAA1096，SARS，PSMD8，COX17，GPX4，EPHX1, MRPL17, PCDHGC3, MAP3K6, DNCH1, TM7SF1, LARGE, VRP, IL6, KIAA1096, SARS, PSMD8, COX17, GPX4,

SULF1，NEU1，ISGF3G，PLP2，CYR61，ATP6V1D，EIF5，FLJ20847，DKFZp761K1423，FLJ11526，EHD1，KMO，KIAA1735，SULF1, NEU1, ISGF3G, PLP2, CYR61, ATP6V1D, EIF5, FLJ20847, DKFZp761K1423, FLJ11526, EHD1, KMO, KIAA1735,

RGS3，SDFR1，ASM3A，FGFR2，FCGR3B，TPM4，CPE，FLOT1，CNGA1，SPHK2，FBXL7，SH3GLB1，LAMP2，EHD1，RGS3, SDFR1, ASM3A, FGFR2, FCGR3B, TPM4, CPE, FLOT1, CNGA1, SPHK2, FBXL7, SH3GLB1, LAMP2, EHD1,

PLXNB1，VCP，SNCB，ITGAV，FLJ21047，STAT3，PSMC4，CALD1，DES，ALDH3A2，VDR，PAPSS2，MGC13523，ARF1，PLXNB1, VCP, SNCB, ITGAV, FLJ21047, STAT3, PSMC4, CALD1, DES, ALDH3A2, VDR, PAPSS2, MGC13523, ARF1,

NDUFA2，PPAP2B，FUS1，ASNA1，TUBB4，MGC4504，RGS19IP1，ATP5H，TSTA3，Cab45，RDH11，ECGF1，TMEM2，NDUFA2, PPAP2B, FUS1, ASNA1, TUBB4, MGC4504, RGS19IP1, ATP5H, TSTA3, Cab45, RDH11, ECGF1, TMEM2,

GALE，WSB2，NSAP1，WFS1，HSPC003，GOLGA1，SH2D1A，FLJ20986，KRT17，UNC84A，MYL6，LAMC2，FGF18，GALE, WSB2, NSAP1, WFS1, HSPC003, GOLGA1, SH2D1A, FLJ20986, KRT17, UNC84A, MYL6, LAMC2, FGF18,

HS2ST1，RNPEP，TC10，FLJ14675，MGC3178，TM9SF1，GALNS，SORT1，HSPC019，SULT1A3，ENC1，RAB9A，CED-6，HS2ST1, RNPEP, TC10, FLJ14675, MGC3178, TM9SF1, GALNS, SORT1, HSPC019, SULT1A3, ENC1, RAB9A, CED-6,

C21orf97，HFE，FUCA1，KIAA0674，EHD1，PLAUR，CETN2，TPBG，CYP27A1，MAN1C1，PPPIR13B，ATP5J2，THBS3，C21orf97, HFE, FUCA1, KIAA0674, EHD1, PLAUR, CETN2, TPBG, CYP27A1, MAN1C1, PPPIR13B, ATP5J2, THBS3,

FKBP10，YKT6，PIGO，CYP4F12，LRPAP1，ITCH，MLF1，ACTN4，EIF2AK3，PDE4DIP，DZIP1，TUBB4，SEC24D，FKBP10, YKT6, PIGO, CYP4F12, LRPAP1, ITCH, MLF1, ACTN4, EIF2AK3, PDE4DIP, DZIP1, TUBB4, SEC24D,

KIAA0143，ITPK1，FLJ13110，AP2B1，IFITM2，SCN8A，STS，CDC42EP4，ARPC1A，CD2BP2，CACNG4，SULT1A2，TAF10，KIAA0143, ITPK1, FLJ13110, AP2B1, IFITM2, SCN8A, STS, CDC42EP4, ARPC1A, CD2BP2, CACNG4, SULT1A2, TAF10,

BRD2，TRAM，HSF2BP，UBC，ADAMTS9，AQP9，RALA，COL15A1，DYSF，LAMB2，RPL5，EHD1，CLCN3，ARF4L，BRD2, TRAM, HSF2BP, UBC, ADAMTS9, AQP9, RALA, COL15A1, DYSF, LAMB2, RPL5, EHD1, CLCN3, ARF4L,

HDLBP，NPR2，HRB，SQRDL，MIG2，NAV2，TBC1D1，TPD52L1，VTN，ARL1，CYB5，LGALS8，COPZ2，FLJ21916，HDLBP, NPR2, HRB, SQRDL, MIG2, NAV2, TBC1D1, TPD52L1, VTN, ARL1, CYB5, LGALS8, COPZ2, FLJ21916,

FLJ20421，P4HA1，TBL1X，ANGPTL2，KIAA0992，NRP1，SLC21A11，ICMT，STS，EIF5，PIP5K1C，RDS，PVRL3，PON2，FLJ20421, P4HA1, TBL1X, ANGPTL2, KIAA0992, NRP1, SLC21A11, ICMT, STS, EIF5, PIP5K1C, RDS, PVRL3, PON2,

HIG1，DLAT，LOC64182，RNF3，ACAA1，UQCR，FLOT1，TC10，DSTN，TEAD4，RER1，TREM1，IL17R，PLCE1，SLC6A8，HIG1, DLAT, LOC64182, RNF3, ACAA1, UQCR, FLOT1, TC10, DSTN, TEAD4, RER1, TREM1, IL17R, PLCE1, SLC6A8,

HIMAP4，PILR(ALPHA)，TRIM38，TXNDC4，CTSK，DSS1，LPHH1，SGCD，PEN-2，KIAA0527，RRAS，CD3D，LANCL2，HIMAP4, PILR(ALPHA), TRIM38, TXNDC4, CTSK, DSS1, LPHH1, SGCD, PEN-2, KIAA0527, RRAS, CD3D, LANCL2,

P2RY6，TUBB，RAC1，AAK1，LOC51762，ALOX5AP，GNB1，FKBP11，RNASEH1，EPB41L1，GPRK5，GP1，HMCS，P2RY6, TUBB, RAC1, AAK1, LOC51762, ALOX5AP, GNB1, FKBP11, RNASEH1, EPB41L1, GPRK5, GP1, HMCS,

PTGER3，SSR4，FKBP9，AK3，CBLC，SGPL1，PLCD1，MED8，ALDH3A2，IGSF6，KCNN2，HS3ST3A1，MLCB，TRIM38，PTGER3, SSR4, FKBP9, AK3, CBLC, SGPL1, PLCD1, MED8, ALDH3A2, IGSF6, KCNN2, HS3ST3A1, MLCB, TRIM38,

FCGR3A，IF135，ABCA1，DKFZp564A176，FSTL3，MAPKAP1，ENTPD3，FLJ23514，HS3ST1，IGHM，PM5，NDUFB2，FCGR3A, IF135, ABCA1, DKFZp564A176, FSTL3, MAPKAP1, ENTPD3, FLJ23514, HS3ST1, IGHM, PM5, NDUFB2,

TOMM22，ANGPTL2，KRT7，SSH-3，ELOVL1，NPEPL1，NEDD4L，PARVA，PTK2，SEMA3E，NCBP2，KMO，QP-C，ECM2，TOMM22, ANGPTL2, KRT7, SSH-3, ELOVL1, NPEPL1, NEDD4L, PARVA, PTK2, SEMA3E, NCBP2, KMO, QP-C, ECM2,

ATP9A，HMOX2，SMAP，SLC9A3R1，ATP1B1，PCDH7，EDF1，OPCML，NEDD5，FLJ10466，CBX6，CDH6，MAN2B1，ATP9A, HMOX2, SMAP, SLC9A3R1, ATP1B1, PCDH7, EDF1, OPCML, NEDD5, FLJ10466, CBX6, CDH6, MAN2B1,

CYB5，SLC38A6，FLJ12443，ASPH，MOB，HUMNPIIY20，DC50，PSMD5，LRRF1P1，FLJ22160，PAFAH1B1，CYB5, SLC38A6, FLJ12443, ASPH, MOB, HUMNPIIY20, DC50, PSMD5, LRRF1P1, FLJ22160, PAFAH1B1,

DKFZP586L151，BLAME，TAZ，ATP6V0B，APBA2BP，RISC，ADRA1A，PIG3，TNFRSF21，CBFA2T1，EML1，EPIM，DKFZP586L151, BLAME, TAZ, ATP6V0B, APBA2BP, RISC, ADRA1A, PIG3, TNFRSF21, CBFA2T1, EML1, EPIM,

APOE，WISP1，CA12，VIL2，RAI，FAAH，ATP6V0D1，CD97，JAG1，STX4A，Cab45，NFE2L2，PPP1R12B，ZMPSTE24，APOE, WISP1, CA12, VIL2, RAI, FAAH, ATP6V0D1, CD97, JAG1, STX4A, Cab45, NFE2L2, PPP1R12B, ZMPSTE24,

KIAA0500，IL17BR，RRAD，PGM1，CD59，ADAM19，NPEPPS，FJX1，GAA，SOX13，FLJ22638，BAIAP2，DUOX1，TGFA，KIAA0500, IL17BR, RRAD, PGM1, CD59, ADAM19, NPEPPS, FJX1, GAA, SOX13, FLJ22638, BAIAP2, DUOX1, TGFA,

FLJ20719，LMCD1，BBS4，MARCKS，GM2A，FLJ11200，MAPK3，WWP1，FLJ20152，SMARCA4，PSCA，MCJ，ARF4，FLJ20719, LMCD1, BBS4, MARCKS, GM2A, FLJ11200, MAPK3, WWP1, FLJ20152, SMARCA4, PSCA, MCJ, ARF4,

SLC35A2，SKD3，CDC42EP4，SLC22A1L，SSH-3，SMARCD3，PDLIM1，IL27w，CGI-135，COX5B，LOXL2，CRK，GOLGB1，SLC35A2, SKD3, CDC42EP4, SLC22A1L, SSH-3, SMARCD3, PDLIM1, IL27w, CGI-135, COX5B, LOXL2, CRK, GOLGB1,

PSMD4，MAGED1，CDC42EP1，HSPC171，SEC13L1，KIAA0265，PSEN2，XLKD1，STAB1，FLJ21079，FBLN1，INSM1，PSMD4, MAGED1, CDC42EP1, HSPC171, SEC13L1, KIAA0265, PSEN2, XLKD1, STAB1, FLJ21079, FBLN1, INSM1,

FLJ10252，MPDU1，MGC3067，FLJ11181，TPARL，TULIP1，DUSP8，UBXD2，CPD，HSPA4，FLJ11807，GPR1，CTNND1，FLJ10252, MPDU1, MGC3067, FLJ11181, TPARL, TULIP1, DUSP8, UBXD2, CPD, HSPA4, FLJ11807, GPR1, CTNND1,

TNFAIP2，MAGED1，MMP9，CKAP1，UGCGL1，SMP1，FLJ22678，BZRP，COX8，BDKRB1，HOXC4，，H19，NMES1，TNFAIP2, MAGED1, MMP9, CKAP1, UGCGL1, SMP1, FLJ22678, BZRP, COX8, BDKRB1, HOXC4, H19, NMES1,

SMOC2，PIGPC1，TEM8，PTGFRN，FLJ23091，IGKC，ALS2CR9，IMUP，MIG-6，MAL2，SPUVE，YAP1，CXCL16，MYO5B，SMOC2, PIGPC1, TEM8, PTGFRN, FLJ23091, IGKC, ALS2CR9, IMUP, MIG-6, MAL2, SPUVE, YAP1, CXCL16, MYO5B,

KIAA1244，PARVA，SYNE-1，FGG，AGR2，KIAA1500，RERG，NTN4，TMPRSS3，ARHU，RHPN2，GLIS2，UGCG，SULF2.，KIAA1244, PARVA, SYNE-1, FGG, AGR2, KIAA1500, RERG, NTN4, TMPRSS3, ARHU, RHPN2, GLIS2, UGCG, SULF2,

BOK，OGN，CLDN1，DKFZp434G171，FAD104，KIAA1165，ShrmL，PTGFRN，AD037，OSAP，LOC51760，MS4A6A，BOK, OGN, CLDN1, DKFZp434G171, FAD104, KIAA1165, ShrmL, PTGFRN, AD037, OSAP, LOC51760, MS4A6A,

FLJ20273，MS4A6A，FLJ23153，NAP1L，LRG，LOC55971，MGC14839，FLJ30532，UNC5H2，FLJ14299，TCEA3，CTL2，FLJ20273, MS4A6A, FLJ23153, NAP1L, LRG, LOC55971, MGC14839, FLJ30532, UNC5H2, FLJ14299, TCEA3, CTL2,

ORF1-FL49，LOC155465，ENAH，OSR-1，SBB131，DAG1，EDG3，PSK-1，MGC2615，ALS2CR9，DKFZP761L0424，TBX3，ORF1-FL49, LOC155465, ENAH, OSR-1, SBB131, DAG1, EDG3, PSK-1, MGC2615, ALS2CR9, DKFZP761L0424, TBX3,

FZD4，FLJ20171，DKFZp761P0423，NGEF，TOB1，CIQG，DNAL11，MGC35048，GUK1，DKFZp586C1021，KIAA1500，FZD4, FLJ20171, DKFZp761P0423, NGEF, TOB1, CIQG, DNAL11, MGC35048, GUK1, DKFZp586C1021, KIAA1500,

LOC83468，p25，CCL26，GNG12，SAMHD1，ID4，B4GALT1，DKFZp434D0215，GJB2，FLJ14957，PRO2605，MGC13040，LOC83468, p25, CCL26, GNG12, SAMHD1, ID4, B4GALT1, DKFZp434D0215, GJB2, FLJ14957, PRO2605, MGC13040,

CHDH，ALDOA，FST，TEAD2，KIAA2028，FLRT3，FLJ31842，CDKN2B，MGC16028，IRX3，TEAD1，MGC33662，MS4A6A，CHDH, ALDOA, FST, TEAD2, KIAA2028, FLRT3, FLJ31842, CDKN2B, MGC16028, IRX3, TEAD1, MGC33662, MS4A6A,

SEMA6D，DKFZp434E2321，PKIB，PKIB，KIAA1671，FLJ22174，LOC128153，COTL1，SAMHD1，MGC24103，UACA，SEMA6D, DKFZp434E2321, PKIB, PKIB, KIAA1671, FLJ22174, LOC128153, COTL1, SAMHD1, MGC24103, UACA,

SELM，CGI-85，NAP1L，CAMK2D，C4orf7，BOC，MGC11034，DKFZP564J0863，DKFZP434H0820，PARVA，SPP2，SELM, CGI-85, NAP1L, CAMK2D, C4orf7, BOC, MGC11034, DKFZP564J0863, DKFZP434H0820, PARVA, SPP2,

FLJ40432，STEAP2，PDGFA，BACE2，FLJ14834，LOC55971，ANGPTL1，MF12，KIAA1337，WNT7B，IPP，DKFZp547D065，FLJ40432, STEAP2, PDGFA, BACE2, FLJ14834, LOC55971, ANGPTL1, MF12, KIAA1337, WNT7B, IPP, DKFZp547D065,

MGC39325，CTL2，SAMHD1，LNX，MGC26963，KIAA1324，MGC16212，KIAA1921，ALS2CR9，CXCL14，SPPL2A，MGC39325, CTL2, SAMHD1, LNX, MGC26963, KIAA1324, MGC16212, KIAA1921, ALS2CR9, CXCL14, SPPL2A,

FLJ14525，ENPP5，MGC29643，TCF21，ECGF1，PCDHB14，CFL2，GRP58，TGFBR3，DKFZp434F2322，FLJ22474，RCP，FLJ14525, ENPP5, MGC29643, TCF21, ECGF1, PCDHB14, CFL2, GRP58, TGFBR3, DKFZp434F2322, FLJ22474, RCP,

KIAA1866，MGC10974，PHLDA1，MGC12335，SYTL2，LOC51242，PCDHA10，KIAA1145，KLF15，TMEPA1，GRIA2，KIAA1866, MGC10974, PHLDA1, MGC12335, SYTL2, LOC51242, PCDHA10, KIAA1145, KLF15, TMEPA1, GRIA2,

LOC92689，SIPL，H19，FAD104，C11orf15，MGC39329，MAFB，BCAR1，RDHL，C14orf50，DRAPC1，RORC，MYEOV，LOC92689, SIPL, H19, FAD104, C11orf15, MGC39329, MAFB, BCAR1, RDHL, C14orf50, DRAPC1, RORC, MYEOV,

GPR92，DUSP16，GFRA3，ZD52F10，FLJ14735，LOC113026，FLJ20048，CLDN11，CDH24，TLR8，FLJ31052，C(27)-3BETA-GPR92, DUSP16, GFRA3, ZD52F10, FLJ14735, LOC113026, FLJ20048, CLDN11, CDH24, TLR8, FLJ31052, C(27)-3BETA-

HSD，YAP1，EMS1，GATA5，FLJ23420，FLJ10035，IL28RA，MAF，HMT-1，DERMO1，DIRC2，HSPC163，ARHU，HSD, YAP1, EMS1, GATA5, FLJ23420, FLJ10035, IL28RA, MAF, HMT-1, DERMO1, DIRC2, HSPC163, ARHU,

LOC114990，MSTP043，CGN，DUSP16，ODZ2，INMT，GPR，CRBPIV，FLJ22558，KIAA1145，TCEB2，LOC55829，SEMA4B，LOC114990, MSTP043, CGN, DUSP16, ODZ2, INMT, GPR, CRBPIV, FLJ22558, KIAA1145, TCEB2, LOC55829, SEMA4B,

COL12A1，MGC11034，KIAA1576，MTA3，ATP1B1，C20orf155，SDCCAG28，MGC16028，CXADR，CTSB，KIAA0146，COL12A1, MGC11034, KIAA1576, MTA3, ATP1B1, C20orf155, SDCCAG28, MGC16028, CXADR, CTSB, KIAA0146,

MGC33602，CLDN12，RAB23，DKFZp434F2322，PRO2714，BTBD6，MRPS10，SNX9，IL411，DKFZP43411735，LOC91523，MGC33602, CLDN12, RAB23, DKFZp434F2322, PRO2714, BTBD6, MRPS10, SNX9, IL411, DKFZP43411735, LOC91523,

AFFX-HSAC07/X00351_M_at，RERG，FLJ14642，FLJ22833，MYO5B，SDCCAG28，RAB10，LBP-32，C14orf31，DLG5，AFFX-HSAC07/X00351_M_at, RERG, FLJ14642, FLJ22833, MYO5B, SDCCAG28, RAB10, LBP-32, C14orf31, DLG5,

FLJ22415，PCDHB16，MGC10204，C21orf63，DKFZP434K0427，NRP2，KIAA1870，TEAD2，SPTB，FLJ33516，SURF4，FLJ22415, PCDHB16, MGC10204, C21orf63, DKFZP434K0427, NRP2, KIAA1870, TEAD2, SPTB, FLJ33516, SURF4,

NPD007，PCDH20，MGC19825，MGC26818，MGC4604，KIAA1337，ESDN，FLJ23091，MacGAP，CGI-85，C8orf13，NPD007, PCDH20, MGC19825, MGC26818, MGC4604, KIAA1337, ESDN, FLJ23091, MacGAP, CGI-85, C8orf13,

FLJ40021，MS4A7，LTB4DH，PLEKHA1，SORCS2，CRIM1，FLJ11200，HS6ST2，FLJ10697，WW45，LOC132671，DCAL1，FLJ40021, MS4A7, LTB4DH, PLEKHA1, SORCS2, CRIM1, FLJ11200, HS6ST2, FLJ10697, WW45, LOC132671, DCAL1,

SNX9，DKFZp761K2222，IGSF9，LOC57168，LOC90701，GPCR1，AK2，FLJ31564，KIAA0599，ANGPTL1，FBXO25，SNX9, DKFZp761K2222, IGSF9, LOC57168, LOC90701, GPCR1, AK2, FLJ31564, KIAA0599, ANGPTL1, FBXO25,

KCNK6，MRPL41，FZD8，UGCGL1，COPZ1，RBMS1，C20orf23，Cab45，TRIM7，OAZ1N，FLJ10210，SYTL2，FLJ20442，KCNK6, MRPL41, FZD8, UGCGL1, COPZ1, RBMS1, C20orf23, Cab45, TRIM7, OAZ1N, FLJ10210, SYTL2, FLJ20442,

C20orf139，KIAA1394，C20orf110，MGC1314，C20orf52，CNN3，MacGAP，CAC-1，MAP1B，FLJ40021，PRIC285，RAP2B，C20orf139, KIAA1394, C20orf110, MGC1314, C20orf52, CNN3, MacGAP, CAC-1, MAP1B, FLJ40021, PRIC285, RAP2B,

TMPIT，KIF1B，GFRA1，DKFZp762A217，XPR1，EMILIN-2，FLJ32069，SMUG1，ARF1，NDUFB10，EHF，NT5E，CORTBP2，TMPIT, KIF1B, GFRA1, DKFZp762A217, XPR1, EMILIN-2, FLJ32069, SMUG1, ARF1, NDUFB10, EHF, NT5E, CORTBP2,

FLJ32194，FLJ90440，LOC147700，MGC21874，KRT19，PCDHA10，DTNA，RGC32，ULBP2，H2AFJ，CFL1，MGC2601，FLJ32194, FLJ90440, LOC147700, MGC21874, KRT19, PCDHA10, DTNA, RGC32, ULBP2, H2AFJ, CFL1, MGC2601,

DKFZP566F084，SLC26A9，KIAA1404，PX19，APOA1BP，WASL，TLR7，FLJ20739，FLJ25157，FLJ22833，MGC14353，DKFZP566F084, SLC26A9, KIAA1404, PX19, APOA1BP, WASL, TLR7, FLJ20739, FLJ25157, FLJ22833, MGC14353,

DKFZP566J2046，SNX8，BHLHB5，TAF10，FLJ14594，MRAS，FLJ14511，UBXD1，AMID，ANKRD9，ACTR3，TMEM9，DKFZP566J2046, SNX8, BHLHB5, TAF10, FLJ14594, MRAS, FLJ14511, UBXD1, AMID, ANKRD9, ACTR3, TMEM9,

DKFZp761N0624，FLJ20748，ROR2，LOC91461，TLE1，SEC14L2，BAT5，SSB1，E21G5，KIAA1357，MBC3205，FLJ11046，DKFZp761N0624, FLJ20748, ROR2, LOC91461, TLE1, SEC14L2, BAT5, SSB1, E21G5, KIAA1357, MBC3205, FLJ11046,

FLJ14681，HSPC242，DKFZp547A023，CED-6，KIAA1715，TNKS1BP1，ATP11A，EHD4，INADL，FLJ11011，KIF3B，FLJ14681, HSPC242, DKFZp547A023, CED-6, KIAA1715, TNKS1BP1, ATP11A, EHD4, INADL, FLJ11011, KIF3B,

DKFZP434K0427，FLJ32069，CSEN，DKFZp761D0614，MRPL41，PXMP4，LOC84518，LOC115265，LOC51255，ATP6V0B，DKFZP434K0427, FLJ32069, CSEN, DKFZp761D0614, MRPL41, PXMP4, LOC84518, LOC115265, LOC51255, ATP6V0B,

N4WBP5，GGTL3，MAGI-3，MLLT4，LUC7L，EROIL，MGC13114，MGC39807，CAPNS1，TRIM47，GPR34，KIAA1200，N4WBP5, GGTL3, MAGI-3, MLLT4, LUC7L, EROIL, MGC13114, MGC39807, CAPNS1, TRIM47, GPR34, KIAA1200,

N33，PSCD3，NSE1，BAL，C20orf24，MGC22805，KIAA1337，CDH11，LOC51248，KIAA1126，FLJ90119，PVRL2，ARHC，N33, PSCD3, NSE1, BAL, C20orf24, MGC22805, KIAA1337, CDH11, LOC51248, KIAA1126, FLJ90119, PVRL2, ARHC,

SSBP4，DNAJC1，E2IG5，FLJ10702，NUMBL，SET7，BR13，FLJ32069，FLJ20097，KIAA1870，C14orf31，TP531NP1，NCAG1，SSBP4, DNAJC1, E2IG5, FLJ10702, NUMBL, SET7, BR13, FLJ32069, FLJ20097, KIAA1870, C14orf31, TP531NP1, NCAG1,

GSH-2，FLJ21963，KIAA0599，MPP5，SCDGF-B，AXIN2，CGI-149，CG1-97，MGC19825，DNAJA4，SMOC2，MRPL27，GSH-2, FLJ21963, KIAA0599, MPP5, SCDGF-B, AXIN2, CGI-149, CG1-97, MGC19825, DNAJA4, SMOC2, MRPL27,

KIAA1542，ARHGEF5，CAMK2D，SLC21A11，FLJ37318，C20orf64，D1S155E，UNC84B，MGC26963，dJ55C23.6，GK001，KIAA1542, ARHGEF5, CAMK2D, SLC21A11, FLJ37318, C20orf64, D1S155E, UNC84B, MGC26963, dJ55C23.6, GK001,

CPNE4，MGC16491，FHOD2，HTPAP，KIAA2002，PRDM6，FGFR1，DKFZP564B1162，HLA-C，PRDX5，FLJ20623，CPNE4, MGC16491, FHOD2, HTPAP, KIAA2002, PRDM6, FGFR1, DKFZP564B1162, HLA-C, PRDX5, FLJ20623,

FLJ20719，C14orf47，MYBBP1A，RDH13，DPP3，PCDHB18，NOL6，JAM1，LOC54516，FLJ10210，NRXN3，MRPL53，FLJ20719, C14orf47, MYBBP1A, RDH13, DPP3, PCDHB18, NOL6, JAM1, LOC54516, FLJ10210, NRXN3, MRPL53,

KIAA1643，MGC15523，LOC115704，BR13，GTAR，KIAA1434，MGC33510，FRABIN，UBQLNI，MGC3195，FBXO32，KIAA1643, MGC15523, LOC115704, BR13, GTAR, KIAA1434, MGC33510, FRABIN, UBQLNI, MGC3195, FBXO32,

SMP1，FLJ10902，C1orf13，CGI-72，MGC45474，TRIM8，HM13，NFKBIE，FLJ22004，AD-003，MMP24，RBM8A，DNAJC5，SMP1, FLJ10902, C1orf13, CGI-72, MGC45474, TRIM8, HM13, NFKBIE, FLJ22004, AD-003, MMP24, RBM8A, DNAJC5,

C20orf169，NOR1，METL，MGC2747，FLJ14251，DKFZp451G182，KIAA1363，FLJ23393，RNF19，STK35，AMID，MGC4604，C20orf169, NOR1, METL, MGC2747, FLJ14251, DKFZp451G182, KIAA1363, FLJ23393, RNF19, STK35, AMID, MGC4604,

FL11，DKFZP566J2046，SNAP29，DKFZp547A023，DKFZp434F2322，SLC17A5，FLJ14117，MGC4342，SLC31A1，MGC2555，FL11, DKFZP566J2046, SNAP29, DKFZp547A023, DKFZp434F2322, SLC17A5, FLJ14117, MGC4342, SLC31A1, MGC2555,

KLF2，NKD2，SEC61A1，LOC91012，MSTP028，FLJ20421，MGC40555，KIAA1554，AD-003，SURF4，GALK1，FACL6，KLF2, NKD2, SEC61A1, LOC91012, MSTP028, FLJ20421, MGC40555, KIAA1554, AD-003, SURF4, GALK1, FACL6,

DKFZP434D146，GPT2，BRPF3，KIAA1165，SLC30A1，FLJ20542，KIAA1255，JUB，SYNPO2，SURF4，MGC2550，DKFZP434D146, GPT2, BRPF3, KIAA1165, SLC30A1, FLJ20542, KIAA1255, JUB, SYNPO2, SURF4, MGC2550,

LOC90507，SYNPO2，ARFGAP1，KIAA0599，DNAJB11，UBE2H，C20orf149，PHP14，FLJ23577，FLJ23654，LOC51290，LOC90507, SYNPO2, ARFGAP1, KIAA0599, DNAJB11, UBE2H, C20orf149, PHP14, FLJ23577, FLJ23654, LOC51290,

DJ667H12.2，FLJ23277，LOC115098，DKFZp547O146，LACTB，FLJ90575，NEK6，Cab45，MGC13045，SRA1，DPP9，SFRP2，DJ667H12.2, FLJ23277, LOC115098, DKFZp547O146, LACTB, FLJ90575, NEK6, Cab45, MGC13045, SRA1, DPP9, SFRP2,

LOC113179，KIAA1784，C20orf149，CGI-09，GBP2，PDK4，HRMT1L1，MGC33993，MESDC2，IDS，RDGBB，RPL17，LOC113179, KIAA1784, C20orf149, CGI-09, GBP2, PDK4, HRMT1L1, MGC33993, MESDC2, IDS, RDGBB, RPL17,

TEAD2，SEI1，C20orf58，HSPC210，KIAA1163，KIAA1223，RAB18，NFKBIA，SEPP1，B7-H3，MGC33607，CAB56184，TEAD2, SEI1, C20orf58, HSPC210, KIAA1163, KIAA1223, RAB18, NFKBIA, SEPP1, B7-H3, MGC33607, CAB56184,

SDCBP2，PCDH18，SPEC1，RAB18，SH120，MGC11102，MGC19825，LMLN，REN，CALM2，PPP1R14A，NDUFB9，SDCBP2, PCDH18, SPEC1, RAB18, SH120, MGC11102, MGC19825, LMLN, REN, CALM2, PPP1R14A, NDUFB9,

KIAA1026，MGC20486，FLJ30803，AKIP，LTB4DH，DKFZp547A023，C20orf167，FLJ31937，FLJ20186，APXL2，CFL2，CGI-KIAA1026, MGC20486, FLJ30803, AKIP, LTB4DH, DKFZp547A023, C20orf167, FLJ31937, FLJ20186, APXL2, CFL2, CGI-

20，KIAA1437，PVRL2，KIAA1295，KIAA1912，DC-TM4F2，CDW92，RPS27L，CAMK2D，RAB18，FLJ21415，MGC10999，20, KIAA1437, PVRL2, KIAA1295, KIAA1912, DC-TM4F2, CDW92, RPS27L, CAMK2D, RAB18, FLJ21415, MGC10999,

KIAA1896，KIAA1337，CGI-69，and STC1.KIAA1896, KIAA1337, CGI-69, and STC1.

                                          表7BForm 7B

                              未传代致瘤性细胞和HSC中相比下调的基因Down-regulated genes in unpassaged tumorigenic cells compared to HSC

HSPC053，HOXA9，SPINK2，HOXA9，MPL，KIAA0125，BEX1，FLJ14054，CD69，ANGPT1，AKR1C3，LAGY，TNFSF4，HSPC053, HOXA9, SPINK2, HOXA9, MPL, KIAA0125, BEX1, FLJ14054, CD69, ANGPT1, AKR1C3, LAGY, TNFSF4,

HLA-DQB1，ITM2A，KIT，GUCY1B3，PLAG1，PROML1，MYCN，MLCL，LYL1，MPO，HOXA10，PCDH9，，PLCL2，HLF，HLA-DQB1, ITM2A, KIT, GUCY1B3, PLAG1, PROML1, MYCN, MLCL, LYL1, MPO, HOXA10, PCDH9, PLCL2, HLF,

SV2，LOC81691，DLK1，HLF，ERG，SOCS2，MYB，PPM1F，PRSS2，BAALC，NPR3，EREG，MMRN，IQGAP2，C17，SV2, LOC81691, DLK1, HLF, ERG, SOCS2, MYB, PPM1F, PRSS2, BAALC, NPR3, EREG, MMRN, IQGAP2, C17,

MPHOSPH9，LOC51659，SELL，MEF2C，TEK，RAB38，FLJ10178，TRY6，NINJ2，FLJ22746，BM046，ICAM2，MLLT3，MPHOSPH9, LOC51659, SELL, MEF2C, TEK, RAB38, FLJ10178, TRY6, NINJ2, FLJ22746, BM046, ICAM2, MLLT3,

BCL11A，HMMR，NAP1L3，MPO，AREG，SATB1，LGN，FLJ10713，ERG，PAD15，IGHM，HLA-DQA1，SCHIP1，ARHGEF6，BCL11A, HMMR, NAP1L3, MPO, AREG, SATB1, LGN, FLJ10713, ERG, PAD15, IGHM, HLA-DQA1, SCHIP1, ARHGEF6,

GUCY1A3，TMSNB，TYMS，TAL1，MS4A3，GMFG，FL11，LPIN1，6-Sep，C20orf42，TACC3，LOC81558，MCM5，TRAITS，GUCY1A3, TMSNB, TYMS, TAL1, MS4A3, GMFG, FL11, LPIN1, 6-Sep, C20orf42, TACC3, LOC81558, MCM5, TRAITS,

IL8，CXCR4，KIAA0186，RetSDR2，RAMP，MGC2306，LGN，CDW52，HMGA2，PTGER4，NUDT11，ZNF198，PCDH9，IL8, CXCR4, KIAA0186, RetSDR2, RAMP, MGC2306, LGN, CDW52, HMGA2, PTGER4, NUDT11, ZNF198, PCDH9,

FLJ10468，PSIP2，CRHBP，ICAM3，IL12RB2，KIF4A，DKFZp761P1010，FLJ12428，GPR56，CXCL2，PRIM1，BIRC5，FLJ10468, PSIP2, CRHBP, ICAM3, IL12RB2, KIF4A, DKFZp761P1010, FLJ12428, GPR56, CXCL2, PRIM1, BIRC5,

PLAC8，TFPI，H3F3B，HBB，NEFH，LMO2，SV2B，ITM2A，BRRN1，MCM2，MLLT3，H2BFQ，DOCK2，UBCE71P4，PLAC8, TFPI, H3F3B, HBB, NEFH, LMO2, SV2B, ITM2A, BRRN1, MCM2, MLLT3, H2BFQ, DOCK2, UBCE71P4,

ZNFN1A1，BCL11A，DDO，NRIP1，TARBP1，HBB，KIAA1750，F2RL1，NRIP1，FLJ10719，CDC25A，VRK1，DUT，PIP5K1B，ZNFN1A1, BCL11A, DDO, NRIP1, TARBP1, HBB, KIAA1750, F2RL1, NRIP1, FLJ10719, CDC25A, VRK1, DUT, PIP5K1B,

NR4A2，BCL11A，BM039，HSPC022，6-Sep，TOP2A，PDE4B，GIT2，JAM2，KIAA1939，MAP4K1，RUNX3，SELP，ANKT，NR4A2, BCL11A, BM039, HSPC022, 6-Sep, TOP2A, PDE4B, GIT2, JAM2, KIAA1939, MAP4K1, RUNX3, SELP, ANKT,

B4GALT6，BCE-1，HBD，PECAM1，E2F3，FLT3，PIR51，TRAP-1，TFR2，P311，HSU79274，CLDN10，DNMT3B，CDC45L，B4GALT6, BCE-1, HBD, PECAM1, E2F3, FLT3, PIR51, TRAP-1, TFR2, P311, HSU79274, CLDN10, DNMT3B, CDC45L,

CDW52，PEL12，MGC861，C1orf29，BRCA1，HHEX，LBR，TOX，ITGA2B，FLJ11712，LOC81691，PPMIF，STAC，CRYGD，CDW52, PEL12, MGC861, C1orf29, BRCA1, HHEX, LBR, TOX, ITGA2B, FLJ11712, LOC81691, PPMIF, STAC, CRYGD,

MAD2L1，KIAA0379，ITGA4，PLAGL1，TAL1，PF4，ELMO1，ITPR1，RNU2，SNTB1，RAD54L，HCGIV.9，LRMP，BRDG1，MAD2L1, KIAA0379, ITGA4, PLAGL1, TAL1, PF4, ELMO1, ITPR1, RNU2, SNTB1, RAD54L, HCGIV.9, LRMP, BRDG1,

ZNF22，CABC1，TEC，NR4A1，FLJ20898，FLJ21276，FLJ10038，ITGA2B，ADA，SSBP2，RRM2，STMN1，PSIP2，DSIP1，ZNF22, CABC1, TEC, NR4A1, FLJ20898, FLJ21276, FLJ10038, ITGA2B, ADA, SSBP2, RRM2, STMN1, PSIP2, DSIP1,

NR3C1，RAD51，SCML2，STK17B，LCP2，MCM7，NT5M，FANCG，NR4A2，SCGF，KIAA0916，PRKCB1，STK18，PRSS21，NR3C1, RAD51, SCML2, STK17B, LCP2, MCM7, NT5M, FANCG, NR4A2, SCGF, KIAA0916, PRKCB1, STK18, PRSS21,

SEMA4D，KIAA0101，DLG7，FLJ10493，KOC1，PDZ-GEF1，ASB9，SCN9A，KIAA0820，FLJ23468，PTGS2，HIS1，GABPB2，SEMA4D, KIAA0101, DLG7, FLJ10493, KOC1, PDZ-GEF1, ASB9, SCN9A, KIAA0820, FLJ23468, PTGS2, HIS1, GABPB2,

KLHL3，PRKCB1，H1FX，PDZ-GEF1，TKT，AKAP7，MST4，PER1，CKAP2，GSTM5，KIAA0582，PRKCH，AMD1，AD024，KLHL3, PRKCB1, H1FX, PDZ-GEF1, TKT, AKAP7, MST4, PER1, CKAP2, GSTM5, KIAA0582, PRKCH, AMD1, AD024,

CD34，SLC27A2，FOXM1，RAGD，MEF2C，LOC51334，EDG6，HMGB2，FLJ22690，CPA3，ANP32B，GNA15，PRC1，CD34, SLC27A2, FOXM1, RAGD, MEF2C, LOC51334, EDG6, HMGB2, FLJ22690, CPA3, ANP32B, GNA15, PRC1,

CXCL3，SAH，CENPF，PRKACB，KIAA0092，RFC5，MAP4K1，SPN，SORL1，RPS21，ALDH1A1，VRP，TFEC，KIAA0769，CXCL3, SAH, CENPF, PRKACB, KIAA0092, RFC5, MAP4K1, SPN, SORL1, RPS21, ALDH1A1, VRP, TFEC, KIAA0769,

SERPINB1，CTSW，KNSL1，CBFA2T3，RNF2，KIAA0711，MSH5，CCNB2，PTPN7，FLJ22794，NASP，WBSCR5，RUNX3，SERPINB1, CTSW, KNSL1, CBFA2T3, RNF2, KIAA0711, MSH5, CCNB2, PTPN7, FLJ22794, NASP, WBSCR5, RUNX3,

CDC42，NR4A2，MCM6，FLJ10719，HLA-DQB1，C11orf8，BIRC5，NSBP1，PECAM1，WSX1，CCND2，E2F1，UPF3B，CDC42, NR4A2, MCM6, FLJ10719, HLA-DQB1, C11orf8, BIRC5, NSBP1, PECAM1, WSX1, CCND2, E2F1, UPF3B,

LOC129080，STAT5A，KIAA0471，SCARF1，KIAA0239，CASP2，PPBP，SFRS5，MCM5，SERP1NB1，HSPC157，LOC129080, STAT5A, KIAA0471, SCARF1, KIAA0239, CASP2, PPBP, SFRS5, MCM5, SERP1NB1, HSPC157,

DKFZp564B0769，PFAS，C4S-2，BANK，H2BFA，HNRPA1，MPHOSPH9，SMCY，NUDT1，KIAA0841，MFNG，HEC，VWF，DKFZp564B0769, PFAS, C4S-2, BANK, H2BFA, HNRPA1, MPHOSPH9, SMCY, NUDT1, KIAA0841, MFNG, HEC, VWF,

TUCAN，RAB33A，FLJ13949，HMMR，SRISNF2L，GNA11，H4FG，RTP801，DACH，KIAA0918，SYK，CKS2，SLA，TUCAN, RAB33A, FLJ13949, HMMR, SRISNF2L, GNA11, H4FG, RTP801, DACH, KIAA0918, SYK, CKS2, SLA,

HNRPDL，EHD3，SPN，TNFAIP3，MDM1，DJ434O14.3，NASP，PMSCL1，PLAGL1，RPIA，FLJ13912，FLJ20005，HERC1，HNRPDL, EHD3, SPN, TNFAIP3, MDM1, DJ434O14.3, NASP, PMSCL1, PLAGL1, RPIA, FLJ13912, FLJ20005, HERC1,

CDC2，DC11，ACYP1，TALDO1，MYB，TIF1，DKFZP564D0462，IL1B，ING3，AMT，FLJ20047，GGH，PLAGL1，PRKG2，CDC2, DC11, ACYP1, TALDO1, MYB, TIF1, DKFZP564D0462, IL1B, ING3, AMT, FLJ20047, GGH, PLAGL1, PRKG2,

DHFR，AND-1，ATP6V0A2，CDH7，RACGAP1，ITGB3BP，RPS14，TK1，POLA，FLJ20456，6-Sep，SMC4L1，RYBP，DHFR, AND-1, ATP6V0A2, CDH7, RACGAP1, ITGB3BP, RPS14, TK1, POLA, FLJ20456, 6-Sep, SMC4L1, RYBP,

CHAF1A，HCAP-G，EZH2，POLE2，USF2，PRO2198，BCL2，NUP98，ATP2A3，FLJ10604，AMD1，SMARCF1，IL3RA，CHAF1A, HCAP-G, EZH2, POLE2, USF2, PRO2198, BCL2, NUP98, ATP2A3, FLJ10604, AMD1, SMARCF1, IL3RA,

RUNX1，FLJ12673，KIAA0084，KIAA1157，HMGA1，COX11，HDGFRP3，SS-56，POLQ，GRB10，MSH5，DDX28，RRM1，RUNX1, FLJ12673, KIAA0084, KIAA1157, HMGA1, COX11, HDGFRP3, SS-56, POLQ, GRB10, MSH5, DDX28, RRM1,

CEB1，AS3，DNMT1，TCF8，C4ST，LSM5，TRIM22，KEO4，NR2C1，KIAA0092，KIAA0332，KIAA0308，PSIP1，RNF8，CEB1, AS3, DNMT1, TCF8, C4ST, LSM5, TRIM22, KEO4, NR2C1, KIAA0092, KIAA0332, KIAA0308, PSIP1, RNF8,

NR3C1，TAF5，TTK，RBM8A，MGC12760，KIAA0056，DHFR，ZFP36L2，RASGRP2，HE110，NAB1，KIAA0170，NAP1L2，NR3C1, TAF5, TTK, RBM8A, MGC12760, KIAA0056, DHFR, ZFP36L2, RASGRP2, HE110, NAB1, KIAA0170, NAP1L2,

KIAA0286，ABCF2，HYA22，PRKACB，LAIR1，24432，DCK，TFDP2，MGC2217，HOXA10，KIAA1028，DKC1，C11orf2，KIAA0286, ABCF2, HYA22, PRKACB, LAIR1, 24432, DCK, TFDP2, MGC2217, HOXA10, KIAA1028, DKC1, C11orf2,

C11orf21，SKP2，USP1，FUS2，DNAJC9，KIAA1110，GAB2，ZNEU1，M6A，DLEU1，MAC30，DUT，HNRPD，SIAHI，C11orf21, SKP2, USP1, FUS2, DNAJC9, KIAA1110, GAB2, ZNEU1, M6A, DLEU1, MAC30, DUT, HNRPD, SIAHI,

FLJ14280，KIAA0179，TRIP-Br2，DKFZp564B0769，TIEG，PTTG1，FANCA，ESPL1，ING1，BIN2，KIAA0721，HYAL3，FLJ14280, KIAA0179, TRIP-Br2, DKFZp564B0769, TIEG, PTTG1, FANCA, ESPL1, ING1, BIN2, KIAA0721, HYAL3,

CENPA，LRBA，MUTYH，CAPRI，PSMD11，FLJ11222，PDE4D，AKRIC2，BZW2，SLC27A2，ALDH5A1，BIN1，SLK，CENPA, LRBA, MUTYH, CAPRI, PSMD11, FLJ11222, PDE4D, AKRIC2, BZW2, SLC27A2, ALDH5A1, BIN1, SLK,

NFATC1，TFAM，MAPRE2，ABCC4，CA1，RBM15，PRSS3，PRV1，FEN1，PCNA，LOC58504，O1P5，SMC2L1，ITSN2，NFATC1, TFAM, MAPRE2, ABCC4, CA1, RBM15, PRSS3, PRV1, FEN1, PCNA, LOC58504, O1P5, SMC2L1, ITSN2,

TOP3A，FLJ23053，TIMM8A，APOBEC3G，TRIM9，RPA1，KNSL7，C5orf6，RBM12，MAC30，UBCE71P5，CUGBP2，TOP3A, FLJ23053, TIMM8A, APOBEC3G, TRIM9, RPA1, KNSL7, C5orf6, RBM12, MAC30, UBCE71P5, CUGBP2,

ARHGDIG，NRGN，SHCBP1，CGI-30，CDT1，DGKZ，RAC2，FL120272，C20orf42，SLA，MPP1，KIAA0682，ARHGDIG, NRGN, SHCBP1, CGI-30, CDT1, DGKZ, RAC2, FL120272, C20orf42, SLA, MPP1, KIAA0682,

DKFZP547E2110，ARHH，KIAA1172，KIAA0265，SOS2，HNRPA0，GIPC2，WASF1，MGC14258，HPRT1，KIAA0443，DKFZP547E2110, ARHH, KIAA1172, KIAA0265, SOS2, HNRPA0, GIPC2, WASF1, MGC14258, HPRT1, KIAA0443,

CD164，KIAA1466，FLJ23151，FLJ10450，DKFZP586A011，BUB1B，C20orf59，TFP1，KIAA0841，DATF1，SLC18A2，CD164, KIAA1466, FLJ23151, FLJ10450, DKFZP586A011, BUB1B, C20orf59, TFP1, KIAA0841, DATF1, SLC18A2,

MGC14258，CBFB，UBE1L，SNRK，MGC26766，RAD52，SNCA，CHES1，KHK，LRBA，CG018，MBNL，VAV1，BIN1，HIC2，MGC14258, CBFB, UBE1L, SNRK, MGC26766, RAD52, SNCA, CHES1, KHK, LRBA, CG018, MBNL, VAV1, BIN1, HIC2,

FLJ23018，HSU53209，ELA2，PTGER2，KIAA0555，CYF1P2，MBNL，CLC，AMPD2，CENTB1，PEPP2，ZFP36L2，CENPF，FLJ23018, HSU53209, ELA2, PTGER2, KIAA0555, CYF1P2, MBNL, CLC, AMPD2, CENTB1, PEPP2, ZFP36L2, CENPF,

LEPR，C5，FLJ12888，IGLL1，TLK1，AKR1C1，IAPP，TIMELESS，DNAJC6，PRO1331，TIF1，SF3B3，RES4-25，FLJ20641，LEPR, C5, FLJ12888, IGLL1, TLK1, AKR1C1, IAPP, TIMELESS, DNAJC6, PRO1331, TIF1, SF3B3, RES4-25, FLJ20641,

TPST2，CENTB1，DUT，CD244，EP400，ZWINT，SNCA，GJA4，AVP，MRPL16，MAN2A2，HADHSC，6-Sep，MAPK14，TPST2, CENTB1, DUT, CD244, EP400, ZWINT, SNCA, GJA4, AVP, MRPL16, MAN2A2, HADHSC, 6-Sep, MAPK14,

TAF1C，LY75，MELK，GMNN，NSMAF，BUB1，HGF，PRTN3，AK2，FLJ10335，SFRS5，ZNF215，FLJ12735，MGC5528，TAF1C, LY75, MELK, GMNN, NSMAF, BUB1, HGF, PRTN3, AK2, FLJ10335, SFRS5, ZNF215, FLJ12735, MGC5528,

GABPB1，GPIBB，MYOZ3，RAB6KIFL，RFC3，OXT，SMCUL1，Nup43，PDGFC，RRP4，HTR1F，HPS4，ICAM4，STRIN，GABPB1, GPIBB, MYOZ3, RAB6KIFL, RFC3, OXT, SMCUL1, Nup43, PDGFC, RRP4, HTR1F, HPS4, ICAM4, STRIN,

384D8-2，ANKRD6，ING4，JJAZ1，KIAA0916，FXYD6，KIAA0981，HSPC056，FLJ11294，SPAG5，HSPC047，WFDC1，384D8-2, ANKRD6, ING4, JJAZ1, KIAA0916, FXYD6, KIAA0981, HSPC056, FLJ11294, SPAG5, HSPC047, WFDC1,

ORC6L，ZAP，GAPCENA，LMNB2，MGC2603，POLQ，SFRS7，MYOM2，FLJ10156，WEE1，DPH2L1，MIRO-1，POLG2，ORC6L, ZAP, GAPCENA, LMNB2, MGC2603, POLQ, SFRS7, MYOM2, FLJ10156, WEE1, DPH2L1, MIRO-1, POLG2,

CHEK1，SRPR，ST7，NEK9，ITM2C，JIK，PAICS，KPNB1，CGI-32，FLJ20105，PTEN，CDC7L1，FLJ13262，ATPAF2，FGFR4，CHEK1, SRPR, ST7, NEK9, ITM2C, JIK, PAICS, KPNB1, CGI-32, FLJ20105, PTEN, CDC7L1, FLJ13262, ATPAF2, FGFR4,

STAG2，UBEIL，FLJ14007，KIAA0308，H2AFY，KIAA0451，FLJ21478，NFE2，GTL3，KATNB1，RIN3，ICAM2，CREB1，STAG2, UBEIL, FLJ14007, KIAA0308, H2AFY, KIAA0451, FLJ21478, NFE2, GTL3, KATNB1, RIN3, ICAM2, CREB1,

ABCB1，MGC4701，ATF1，LOC90355，FLJ10290，FLJ23392，FNBP1，SMARCE1，CES1，KIAA0419，FLJ20035，LOC51320，ABCB1, MGC4701, ATF1, LOC90355, FLJ10290, FLJ23392, FNBP1, SMARCE1, CES1, KIAA0419, FLJ20035, LOC51320,

PRDM2，TIMM9，RAD51，PPM1B，HELLS，CHD4，MORF，TRIP13，NTSR1，LPIN1，MAPRE2，ZNF278，HYA22，CG005，PRDM2, TIMM9, RAD51, PPM1B, HELLS, CHD4, MORF, TRIP13, NTSR1, LPIN1, MAPRE2, ZNF278, HYA22, CG005,

NPAT，MONDOA，LAPTM4B，RRM2，C20orf1，FLJ20010，PRKRIR，SFRS3，DKFZp5471014，MCM3，PCNT2，NAP1L1，NPAT, MONDOA, LAPTM4B, RRM2, C20orf1, FLJ20010, PRKRIR, SFRS3, DKFZp5471014, MCM3, PCNT2, NAP1L1,

FLJ23476，MYBPC2，PA26，C6orf32，MGC13024，OPA1，RBBP4，BIN1，CAMLG，cig5，PLA2G3，KIAA0592，FLJ20094，FLJ23476, MYBPC2, PA26, C6orf32, MGC13024, OPA1, RBBP4, BIN1, CAMLG, cig5, PLA2G3, KIAA0592, FLJ20094,

HNRPH3，GEMIN4，FLJ13386，TKT，DKFZP434B168，PMS1，FMR2，C21orf66，C19orf2，TFP1，DKFZP564O0523，LRMP，HNRPH3, GEMIN4, FLJ13386, TKT, DKFZP434B168, PMS1, FMR2, C21orf66, C19orf2, TFP1, DKFZP564O0523, LRMP,

PPP2R2B，ZNF135，ZNF198，FBL，SCGF，CEL，LRPPRC，FLJ12903，FLJ10858，KIAA1041，KIAA0800，PCDHA10，JRKL，PPP2R2B, ZNF135, ZNF198, FBL, SCGF, CEL, LRPPRC, FLJ12903, FLJ10858, KIAA1041, KIAA0800, PCDHA10, JRKL,

SUPT3H，ITPR1，POT1，C16orf5，CGI-48，FLJ22002，SFRS11，SYPL，MSH6，ZNF85，DLEU2，LIPT1，RFC4，FLJ10539，SUPT3H, ITPR1, POT1, C16orf5, CGI-48, FLJ22002, SFRS11, SYPL, MSH6, ZNF85, DLEU2, LIPT1, RFC4, FLJ10539,

LZTFL1，BM11，CSF1，COX11，UBE2C，LOC93349，ATP2A3，GPC5，F2R，RPL28，TGT，TCERG1，DDX34，LAMP2，CCNF，LZTFL1, BM11, CSF1, COX11, UBE2C, LOC93349, ATP2A3, GPC5, F2R, RPL28, TGT, TCERG1, DDX34, LAMP2, CCNF,

M96，CDC25C，LANPL，ADCYAPIR1，SLV39H1，FLJ14213，DKFZP434L0718，FLJ21269，PRAX-1，ANP32A，SRRM1，M96, CDC25C, LANPL, ADCYAPIR1, SLV39H1, FLJ14213, DKFZP434L0718, FLJ21269, PRAX-1, ANP32A, SRRM1,

CDC6，FANCE，H2AV，C6orf48，TSN，FBXW3，CEP1，ZNF161，SF3B3，CDC23，SFRS11，CYLN2，IMPDH2，PIGL，H2AFJ，CDC6, FANCE, H2AV, C6orf48, TSN, FBXW3, CEP1, ZNF161, SF3B3, CDC23, SFRS11, CYLN2, IMPDH2, PIGL, H2AFJ,

KL，TNFAIP3，MGC2306，Jade-1，CDKN3，FLJ10287，CSNK2A2，OPA1，TRAF5，RPP40，HTATIP2，ANP32A，WTAP，KL, TNFAIP3, MGC2306, Jade-1, CDKN3, FLJ10287, CSNK2A2, OPA1, TRAF5, RPP40, HTATIP2, ANP32A, WTAP,

ESRRB，LOC51185，MRE11A，H4FJ，KIAA0097，WAS，HMGB3，MCM10，NBR2，RPL3L，LAPTM4B，FLJ23277，ESRRB, LOC51185, MRE11A, H4FJ, KIAA0097, WAS, HMGB3, MCM10, NBR2, RPL3L, LAPTM4B, FLJ23277,

HSA250839，C19orf7，MGC19570，C6orf32，APEX1，KIAA1387，FHL3，CGI-49，TMPO，CGI-127，TBCID5，RBMX，SF3A3，HSA250839, C19orf7, MGC19570, C6orf32, APEX1, KIAA1387, FHL3, CGI-49, TMPO, CGI-127, TBCID5, RBMX, SF3A3,

FLJ10379，HADHSC，IGHG3，LOC254531，SFPQ，FL10154，DKFZP434H132，KPNB1，WHSC1，PRSS3，CCNB1，CYP3A7，FLJ10379, HADHSC, IGHG3, LOC254531, SFPQ, FL10154, DKFZP434H132, KPNB1, WHSC1, PRSS3, CCNB1, CYP3A7,

FLJ20244，RAB6IP1，SNRPA，LOC115648，BLM，FLJ20136，SYT11，CAT，USP15，PRPS2，UBE2D2，CENTB2，SRP72，FLJ20244, RAB6IP1, SNRPA, LOC115648, BLM, FLJ20136, SYT11, CAT, USP15, PRPS2, UBE2D2, CENTB2, SRP72,

TOPBP1，SIL，MAP2K5，SPG4，RENT2，SCAP1，GP1BA，DNAJC9，TPO，ZNF261，TOP2B，PDCD1，IPW，SNX26，PTTG3，TOPBP1, SIL, MAP2K5, SPG4, RENT2, SCAP1, GP1BA, DNAJC9, TPO, ZNF261, TOP2B, PDCD1, IPW, SNX26, PTTG3,

ENO2，CNR1，DDX11，CRLF3，KIAA0092，KIAA0433，NBS1，C20orf67，GP5，KIAA0101，BTBD3，GPRK6，TLK2，ENO2, CNR1, DDX11, CRLF3, KIAA0092, KIAA0433, NBS1, C20orf67, GP5, KIAA0101, BTBD3, GPRK6, TLK2,

FLJ20856，PKDI-like，RECQL5，ARHGEF9，FLJ11210，DKFZP5641052，PLCG2，BITE，HYPH，HNRPA1，ATP11B，LIG1，FLJ20856, PKDI-like, RECQL5, ARHGEF9, FLJ11210, DKFZP5641052, PLCG2, BITE, HYPH, HNRPA1, ATP11B, LIG1,

KIAA1473，PTER，PPP16B，FLJ10597，KCND1，FLJ22474，MTMR4，SMC5，FLJ20288，MED6，ULK1，DNM2，ZFHX1B，KIAA1473, PTER, PPP16B, FLJ10597, KCND1, FLJ22474, MTMR4, SMC5, FLJ20288, MED6, ULK1, DNM2, ZFHX1B,

LRP16，FLJ11184，RNF38，LOH11CR2A，NEDD4，AND-1，ITGA9，CDK2，PGDS，FLJ11896，FLJ13449，LOC93081，LRP16, FLJ11184, RNF38, LOH11CR2A, NEDD4, AND-1, ITGA9, CDK2, PGDS, FLJ11896, FLJ13449, LOC93081,

MRPS14，ANP32B，FLJ21272，KIAA0555，CDCA4，KIAA1966，FADS1，PRKCN，OGT，TRIP-Br2，KCNEIL，UQCRB，HIF1，MRPS14, ANP32B, FLJ21272, KIAA0555, CDCA4, KIAA1966, FADS1, PRKCN, OGT, TRIP-Br2, KCNEIL, UQCRB, HIF1,

SCA7，RAD51C，HDGFRP3，FLJ10565，HINT1，AKR1C1，PTBP2，TCF12，CG005，MPHOSPH9，KIAA0953，OSRF，SCA7, RAD51C, HDGFRP3, FLJ10565, HINT1, AKR1C1, PTBP2, TCF12, CG005, MPHOSPH9, KIAA0953, OSRF,

C14orf94，PNN，NGLY1，LILRA2，CD79B，LANCL1，C20orf16，CCNE2，MTCP1，PPAT，KIAA0800，KIAA1039，MGC5149，C14orf94, PNN, NGLY1, LILRA2, CD79B, LANCL1, C20orf16, CCNE2, MTCP1, PPAT, KIAA0800, KIAA1039, MGC5149,

FLJ22843，FLJ12610，MRPS31，C14orf2，RUFY2，NCOA61P，FBXO4，PRKAR2B，TOX，HBOA，PMPCB，LOC51275，GF11，FLJ22843, FLJ12610, MRPS31, C14orf2, RUFY2, NCOA61P, FBXO4, PRKAR2B, TOX, HBOA, PMPCB, LOC51275, GF11,

MGC21654，TGIF2，LARS，DKFZp547P234，NR4A1，KIAA0036，PHKA2，MYST1，HSA9761，AIP1，TFAM，CDC20，MGC21654, TGIF2, LARS, DKFZp547P234, NR4A1, KIAA0036, PHKA2, MYST1, HSA9761, AIP1, TFAM, CDC20,

CLNS1A，THY28，ZNF145，FLJ20509，FLJ10890，MAX，FLJ20312，ZNF305，C21orf45，ESPL1，ZNF292，VIP，FLJ13902，CLNS1A, THY28, ZNF145, FLJ20509, FLJ10890, MAX, FLJ20312, ZNF305, C21orf45, ESPL1, ZNF292, VIP, FLJ13902,

HA-1，ARTS-1，AS3，H4FI，THEA，FRAG1，DNA2L，KIAA0240，OIP2，ZNF16，GOLGIN-67，GPR44，MTHFD1，IMPA1，HA-1, ARTS-1, AS3, H4FI, THEA, FRAG1, DNA2L, KIAA0240, OIP2, ZNF16, GOLGIN-67, GPR44, MTHFD1, IMPA1,

GNB2L1，CNGB1，SYPL，PASK，PTDSS1，FLJ11342，MRPS31，CBX8，TTF2，DYRK1A，CR2，RANBP2，FLJ20003，GNB2L1, CNGB1, SYPL, PASK, PTDSS1, FLJ11342, MRPS31, CBX8, TTF2, DYRK1A, CR2, RANBP2, FLJ20003,

APOBEC3B，BCMSUNL，KIAA0725，PDE4D，PRH1，XPO1，CML2，HYA22，IDN3，KIAA0261，ZNF175，YARS，CDC6，APOBEC3B, BCMSUNL, KIAA0725, PDE4D, PRH1, XPO1, CML2, HYA22, IDN3, KIAA0261, ZNF175, YARS, CDC6,

MOAP1，GLRX，ATP2B2，PPAT，FLJ20530，ZFR，COIL，KIAA1100，PER1，PSTPIP2，TXNDC，PP2447，FLJ13197，CIAS1，MOAP1, GLRX, ATP2B2, PPAT, FLJ20530, ZFR, COIL, KIAA1100, PER1, PSTPIP2, TXNDC, PP2447, FLJ13197, CIAS1,

JMJ，SYT11，H2AV，SPS，CUL3，FLJ23306，SNRPD1，FLJ10876，NBR2，DKFZP434F0318，SP100，NIP30，BANP，SMC2L1，JMJ, SYT11, H2AV, SPS, CUL3, FLJ23306, SNRPD1, FLJ10876, NBR2, DKFZP434F0318, SP100, NIP30, BANP, SMC2L1,

GPR21，CSTF2T，HSA9761，SFPQ，EFNA2，GRB10，RPS20，KCNAB1，FLJ32069，PUM2，RPL17，FLJ20499，HGF，CCND3，GPR21, CSTF2T, HSA9761, SFPQ, EFNA2, GRB10, RPS20, KCNAB1, FLJ32069, PUM2, RPL17, FLJ20499, HGF, CCND3,

CTSG，ABCC1，PIAS1，PPARBP，DC13，SPHAR，SUSP1，C14orf10，NPFF，PFKFB1，PAPOLB，H2AFY，SPRR2C，STAG3，CTSG, ABCC1, PIAS1, PPARBP, DC13, SPHAR, SUSP1, C14orf10, NPFF, PFKFB1, PAPOLB, H2AFY, SPRR2C, STAG3,

C11orf8，D6S2654E，INVS，ANAPC1，GPHN，DKFZP564O043，TM7SF3，UBE2E1，NAP1L4，RASA1，MGC12909，DLAPH2，C11orf8, D6S2654E, INVS, ANAPC1, GPHN, DKFZP564O043, TM7SF3, UBE2E1, NAP1L4, RASA1, MGC12909, DLAPH2,

FA1M，UCHL1，C10orf2，NUMA1，FLJ10706，SSH3BP1，FLJ23560，2NF137，MTMR2，ZFD25，PIGN，KIAA0252，MEIS1，FA1M, UCHL1, C10orf2, NUMA1, FLJ10706, SSH3BP1, FLJ23560, 2NF137, MTMR2, ZFD25, PIGN, KIAA0252, MEIS1,

SSRP1，ZNF363，NUP50，FLJ10315，UNG，COL6A1，ZNF10，ILF3，DDX28，MGC4170，TSC22，MATR3，ARHGAP11A，SSRP1, ZNF363, NUP50, FLJ10315, UNG, COL6A1, ZNF10, ILF3, DDX28, MGC4170, TSC22, MATR3, ARHGAP11A,

LAG3，LOC51231，C21orf33，KIAA0376，ZNF42，RERE，GalNac-T10，NSBP1，CLEC2，RNPS1，MAP4K1，ADSL，SYNGR1，LAG3, LOC51231, C21orf33, KIAA0376, ZNF42, RERE, GalNac-T10, NSBP1, CLEC2, RNPS1, MAP4K1, ADSL, SYNGR1,

RPL22，FLJ10716，LHX6，FLJ10546，XRCC5，SP192，JJAZ1，INPP5D，HPIP，LOC57019，DKFZp434N062，DEK，EIF4ENIF1，RPL22, FLJ10716, LHX6, FLJ10546, XRCC5, SP192, JJAZ1, INPP5D, HPIP, LOC57019, DKFZp434N062, DEK, EIF4ENIF1,

ZFP36L2，FLJ13920，MDS1，KIAA0404，HMGB1，ILF3，SYNGR1，SIAH1，FADS2，KIAA1074，FLJ12788，TAF7，KCNA3，ZFP36L2, FLJ13920, MDS1, KIAA0404, HMGB1, ILF3, SYNGR1, SIAH1, FADS2, KIAA1074, FLJ12788, TAF7, KCNA3,

CL640，KHDRBS1，FLJ12377，ED1，MTCP1，FNBP1，EPS15，BHC80，CHD1L，DKFZP434L187，FLJ20477，SCOP，CL640, KHDRBS1, FLJ12377, ED1, MTCP1, FNBP1, EPS15, BHC80, CHD1L, DKFZP434L187, FLJ20477, SCOP,

KIAA0470，ME3，QK1，SALL2，SON，CSF3R，HDGFRP3，EIF2C1，P53AIP1，PCTK2，PAI-RBP1，ATRX，HTR2C，CHAF1B，KIAA0470, ME3, QK1, SALL2, SON, CSF3R, HDGFRP3, EIF2C1, P53AIP1, PCTK2, PAI-RBP1, ATRX, HTR2C, CHAF1B,

NXT2，Nbak2，CDC14B，CCBL1，GTF3C3，DNMT2，SLC24A1，AND-1，FLJ13373，SET，USP4，CRSP2，NFRKB，P2RX1，NXT2, Nbak2, CDC14B, CCBL1, GTF3C3, DNMT2, SLC24A1, AND-1, FLJ13373, SET, USP4, CRSP2, NFRKB, P2RX1,

SE70-2，CALCRL，DKFZP434D1335，OSBPL3，TUBA1，DKFZp434N062，DNAJC8，ALOX12，RTN3，KIAA0543，DNAJC8，SE70-2, CALCRL, DKFZP434D1335, OSBPL3, TUBA1, DKFZp434N062, DNAJC8, ALOX12, RTN3, KIAA0543, DNAJC8,

AFFX-r2-Bs-phe-M_at，AXOT，PSMAL/GCP III，WHSC2，DMRT1，T1C，AF311304，NPR3，C14orf93，FLJ10483，IMPACT，AFFX-r2-Bs-phe-M_at, AXOT, PSMAL/GCP III, WHSC2, DMRT1, T1C, AF311304, NPR3, C14orf93, FLJ10483, IMPACT,

TGIF2，TNS，CAPN3，ZNF292，FLJ22557，KIAA0036，CGI-79，H4FA，TFDP2，UBL3，SLC22A6，CGBP，SNRPD1，SCGF，TGIF2, TNS, CAPN3, ZNF292, FLJ22557, KIAA0036, CGI-79, H4FA, TFDP2, UBL3, SLC22A6, CGBP, SNRPD1, SCGF,

MRPS27，ZNF335，RBBP9，STK12，MAT2A，FLJ11175，KIAA0528，MXD3，CPSF4，HINT1，PP1H，GNAO1，BRD1，MRPS27, ZNF335, RBBP9, STK12, MAT2A, FLJ11175, KIAA0528, MXD3, CPSF4, HINT1, PP1H, GNAO1, BRD1,

KIAA0368，AP1S2，NAP1L1，ST3GALV1，ZNF287，CYP2C8，ZNF291，KIAA0582，GART，EPM2A，，，LOC51194，FLJ21269，KIAA0368, AP1S2, NAP1L1, ST3GALV1, ZNF287, CYP2C8, ZNF291, KIAA0582, GART, EPM2A,,, LOC51194, FLJ21269,

EMCN，MGC41924，USP2，HEMGN，MGC24665，ZNFN1A1，CDCA7，SHANK3，Evt1，CDH26，FLJ20171，C4ST3，EMCN, MGC41924, USP2, HEMGN, MGC24665, ZNFN1A1, CDCA7, SHANK3, Evt1, CDH26, FLJ20171, C4ST3,

MGC21854，ST6Ga111，CT2，WHIP，MGC16386，FLJ33957，BCL11A，FLJ33069，DKFZp762L0311，ZNF6，DACH，CENPH，MGC21854, ST6Ga111, CT2, WHIP, MGC16386, FLJ33957, BCL11A, FLJ33069, DKFZp762L0311, ZNF6, DACH, CENPH,

EHZF，NIN283，FLJ39957，DKFZP566N034，PTGS1，DKFZP586D0824，KIAA1218，MMP28，NID67，CYYR1，5OY11.1，EHZF, NIN283, FLJ39957, DKFZP566N034, PTGS1, DKFZP586D0824, KIAA1218, MMP28, NID67, CYYR1, 5OY11.1,

BIC，CDT1，FLJ14503，B3GNT5，SDPR，ITGA4，MGC16179，HOXA7，ROBO4，GNA11，DJ79P111，C1QTNF4，RAD52B，BIC, CDT1, FLJ14503, B3GNT5, SDPR, ITGA4, MGC16179, HOXA7, ROBO4, GNA11, DJ79P111, C1QTNF4, RAD52B,

K1AA1726，FLJ30046，ARHGAP9，PRDM16，FANCD2，C21orf91，UHRF1，OAZIN，FKSG14，NIN283，EPB41L5，RAB39B，K1AA1726, FLJ30046, ARHGAP9, PRDM16, FANCD2, C21orf91, UHRF1, OAZIN, FKSG14, NIN283, EPB41L5, RAB39B,

TFDP2，FLJ12994，PRKACB，FLJ32009，KLHL6，FLJ10493，KIAA0748，FLJ21986，NOG，GPR27，EPC1，STIP-1，CGI-105，TFDP2, FLJ12994, PRKACB, FLJ32009, KLHL6, FLJ10493, KIAA0748, FLJ21986, NOG, GPR27, EPC1, STIP-1, CGI-105,

MGC12935，FLJ20093，HSAJ1454，EVIN2，KIAA1554，MGC20262，FLJ20354，MGC8721，EK11，MAML3，SEPP1，TRB@，MGC12935, FLJ20093, HSAJ1454, EVIN2, KIAA1554, MGC20262, FLJ20354, MGC8721, EK11, MAML3, SEPP1, TRB@,

CHD2，MS12，DKFZP434A0131，KIAA1554，MGC20262，KIAA1798，TMPO，SYTL4，EHZF，KIAA1337，HNRPD，Rgr，CHD2, MS12, DKFZP434A0131, KIAA1554, MGC20262, KIAA1798, TMPO, SYTL4, EHZF, KIAA1337, HNRPD, Rgr,

FLJ00026，IRF5，MGC4832，MGC34827，PRAM-1，GAB3，ING3，MGC7036，EIIs1，DKFZP761M1511，PRO1635，ZNF367，FLJ00026, IRF5, MGC4832, MGC34827, PRAM-1, GAB3, ING3, MGC7036, EIIs1, DKFZP761M1511, PRO1635, ZNF367,

MYNN，SH2D3C，FLJ11220，HHGP，MCM10，GNG2，FLJ20280，FLJ11252，RPL13，YR-29，KIAA1805，FLJ14642，MYNN, SH2D3C, FLJ11220, HHGP, MCM10, GNG2, FLJ20280, FLJ11252, RPL13, YR-29, KIAA1805, FLJ14642,

FLJ12892，CGI-67，OSM，EIF3S6，DKFZp761D221，PAPOLA，MCLC，LOC159090，FLJ20280，KLF12，LOC144455，ALS2，FLJ12892, CGI-67, OSM, EIF3S6, DKFZp761D221, PAPOLA, MCLC, LOC159090, FLJ20280, KLF12, LOC144455, ALS2,

WHSC1，STRIN，UCC1，FANCA，PTPN22，KIAA1677，FLJ23563，MDS006，HMGB1，MGC10744，TIGA1，IL17D，SNURF，WHSC1, STRIN, UCC1, FANCA, PTPN22, KIAA1677, FLJ23563, MDS006, HMGB1, MGC10744, TIGA1, IL17D, SNURF,

LOC221002，CED-6，1-Sep，CGI-105，LOC134147，FLJ39370，DRLM，LOC85028，P66，CASP2，SLC25A21，MGC10966，LOC221002, CED-6, 1-Sep, CGI-105, LOC134147, FLJ39370, DRLM, LOC85028, P66, CASP2, SLC25A21, MGC10966,

FLJ32234，DCLRE1B，CSTF3，ATPAF1，FLJ00026，C6orf33，NY-REN-58，MGC35274，DKFZp571K0837，BRD7，FLJ32234, DCLRE1B, CSTF3, ATPAF1, FLJ00026, C6orf33, NY-REN-58, MGC35274, DKFZp571K0837, BRD7,

MGC27085，KIAA1084，DKFZp434G0920，MGC45962，MLL，CYYR1，KIAA1387，FLJ23306，AF15Q14，RAMP，CCNB1，MGC27085, KIAA1084, DKFZp434G0920, MGC45962, MLL, CYYR1, KIAA1387, FLJ23306, AF15Q14, RAMP, CCNB1,

HSPC063，FLJ11220，C6orf33，NHP2L1，DKFZp76IN1114，CGGBP1，USP16，KIAA1789，DKFZp434C1714，FLJ32194，HSPC063, FLJ11220, C6orf33, NHP2L1, DKFZp76IN1114, CGGBP1, USP16, KIAA1789, DKFZp434C1714, FLJ32194,

TIGD3，FLJ32549，MGC20496，LCX，ARHGAP9，STN2，MCM10，GPR114，PPIL3，MJD，UBE3B，WHSC1，LOC51234，TIGD3, FLJ32549, MGC20496, LCX, ARHGAP9, STN2, MCM10, GPR114, PPIL3, MJD, UBE3B, WHSC1, LOC51234,

CLLD8，C15orf15，TTC7L1，PRO2000，HEMGN，ELAVL4，KIAA1635，CLYBL，NLK，CLLD8，MDM4，MS12，ASE-1，LSR7，CLLD8, C15orf15, TTC7L1, PRO2000, HEMGN, ELAVL4, KIAA1635, CLYBL, NLK, CLLD8, MDM4, MS12, ASE-1, LSR7,

LOc146853，TIGD7，HELLS，LOC159090，TAF9L，DKFZp762O076，FLJ32370，WDR9，HRB2，TIGD2，GAJ，LOC51193，LOc146853, TIGD7, HELLS, LOC159090, TAF9L, DKFZp762O076, FLJ32370, WDR9, HRB2, TIGD2, GAJ, LOC51193,

FLJ13614，BAALc，KCNK17，DKFZp313A2432，ARRB1，DKFZp762N0610，DKFZp564B0769，MGC45866，CGI-30，FLJ13614, BAALc, KCNK17, DKFZp313A2432, ARRB1, DKFZp762N0610, DKFZp564B0769, MGC45866, CGI-30,

FLJ23277，ROCK1，TRA@，ARRB1，CUL5，DKFZP727C091，FLJ34817，FKBP5，FLJ00058，FLJ90013，FLJ11275，FLJ23277, ROCK1, TRA@, ARRB1, CUL5, DKFZP727C091, FLJ34817, FKBP5, FLJ00058, FLJ90013, FLJ11275,

KIAA1211，FLJ13215，HSA9761，EVIN2，DKFZP434C245，MGC16824，HSPC126，HSP70-4，LOC119392，FLJ35382，KIAA1211, FLJ13215, HSA9761, EVIN2, DKFZP434C245, MGC16824, HSPC126, HSP70-4, LOC119392, FLJ35382,

MMP28，ARIH2，SUV39H2，DKFZp761F0118，FLJ10997，NDUFB1，MNAB，MU，FRSB，KIAA1871，RARA，FLJ11712，MMP28, ARIH2, SUV39H2, DKFZp761F0118, FLJ10997, NDUFB1, MNAB, MU, FRSB, KIAA1871, RARA, FLJ11712,

MGC5306，FLJ30525，FLJ00005，LOc115330，AMBP，FLJ32942，LOC91768，PECI，KIAA1959，MGC10744，FLJ90013，MGC5306, FLJ30525, FLJ00005, LOc115330, AMBP, FLJ32942, LOC91768, PECI, KIAA1959, MGC10744, FLJ90013,

5OY11.1，LOC116349，TSGA14，KIAA1954，HSPC129，KIAA1194，KIAA1238，KHDRBS1，SNRPE，SGKL，FLJ31818，5OY11.1, LOC116349, TSGA14, KIAA1954, HSPC129, KIAA1194, KIAA1238, KHDRBS1, SNRPE, SGKL, FLJ31818,

CNOT6L，KIAA0853，MGC39650，FLJ22955，C11ORF30，CKLFSF7，CGI-30，GRCC8，AP3M1，MGC10946，CRSP6，AGS3，CNOT6L, KIAA0853, MGC39650, FLJ22955, C11ORF30, CKLFSF7, CGI-30, GRCC8, AP3M1, MGC10946, CRSP6, AGS3,

DKFZp564B0769，LOC81023，STAF65(gamma)，ZRF1，LOC63929，HYPC，LOC90507，bioref，FLJ21438，MGC22679，HPI-DKFZp564B0769, LOC81023, STAF65(gamma), ZRF1, LOC63929, HYPC, LOC90507, bioref, FLJ21438, MGC22679, HPI-

BP74，Jade-1，RGM，CYCS，EG1，C20orf92，TPC2，AUTS2，FLJ21918，ZNFN1A1，MAILDC6，AUTL1，TAGAP，STARD4，BP74, Jade-1, RGM, CYCS, EG1, C20orf92, TPC2, AUTS2, FLJ21918, ZNFN1A1, MAILDC6, AUTL1, TAGAP, STARD4,

TBRG1，FLJ20354，LSR7，RARA，FLJ14936，FLJ12975，KIAA0379，RIG-1，PPP2CA，MGC15548，HNRPC，ZNF265，TBRG1, FLJ20354, LSR7, RARA, FLJ14936, FLJ12975, KIAA0379, RIG-1, PPP2CA, MGC15548, HNRPC, ZNF265,

TRAP25，DKFZp564D177，MGC33864，HSPC129，PPHLN1，HSPC195，FLJ32020，WWP1，AKIP，TADA2L，TRAP25, DKFZp564D177, MGC33864, HSPC129, PPHLN1, HSPC195, FLJ32020, WWP1, AKIP, TADA2L,

DKFZP56411171，FIGNL1，GRP58，KIAA0141，LOc151648，FLJ20095，FLJ10997，KIAA1545，TIGD7，PRKRA，FLJ20060，DKFZP56411171, FIGNL1, GRP58, KIAA0141, LOc151648, FLJ20095, FLJ10997, KIAA1545, TIGD7, PRKRA, FLJ20060,

DKFZP434G156，FLJ14775，NAV1，RPLP1，B3GNT1，C21orf45，KIAA1586，ELD/OSA1，LOC51249，KIAA1982，FLJ23309，DKFZP434G156, FLJ14775, NAV1, RPLP1, B3GNT1, C21orf45, KIAA1586, ELD/OSA1, LOC51249, KIAA1982, FLJ23309,

ANAPCI，HINT1，MGC17919，TSGA14，DRLM，MCM6，KIAA1238，KPNA4，AFFX-r2-Bs-thRr-3s at.IGHG3，YARS，ANAPCI, HINT1, MGC17919, TSGA14, DRLM, MCM6, KIAA1238, KPNA4, AFFX-r2-Bs-thRr-3s at. IGHG3, YARS,

FLJ20309，LU，FLJ10407，MGC14797，KIAA1554，LOC115827，NRM，DNMT3A，MGC4308，KIAA1554，MGC41917，ATE1，FLJ20309, LU, FLJ10407, MGC14797, KIAA1554, LOC115827, NRM, DNMT3A, MGC4308, KIAA1554, MGC41917, ATE1,

TUFM，ROcKI，MATR3，KIAA1311，FGD3，FLJ10876，KIAA1337，ZNFN1A4，PRO2000，SCAP2，FBXO4，CNTN1，TUFM, ROcKI, MATR3, KIAA1311, FGD3, FLJ10876, KIAA1337, ZNFN1A4, PRO2000, SCAP2, FBXO4, CNTN1,

MYH11，TRNT1，TCF7L2，CDK5RAP2，DKFZp313A2432，GTF2H3，MGC14439，MGC4730，MGC19570，EIF2S3，RNF3，MYH11, TRNT1, TCF7L2, CDK5RAP2, DKFZp313A2432, GTF2H3, MGC14439, MGC4730, MGC19570, EIF2S3, RNF3,

MGC13204，CHES1，CNNM3，SFRS3，SMBP，TMF1，CSTF3，HBOA，CDCA1，FLJ32745，SPIN，WHSC1L1，MGC13204, CHES1, CNNM3, SFRS3, SMBP, TMF1, CSTF3, HBOA, CDCA1, FLJ32745, SPIN, WHSC1L1,

DKFZP56611024，FLJ14906，C20orf24，OSBPL7，NAALADASEL，HSA251708，KIAA0254，LOC144402，FLJ34231，DKFZP56611024, FLJ14906, C20orf24, OSBPL7, NAALADASEL, HSA251708, KIAA0254, LOC144402, FLJ34231,

KIAA1228，C20orf72，RANBP2，and NIP30.KIAA1228, C20orf72, RANBP2, and NIP30.

                                                 表7CTable 7C

                                传代的致瘤性细胞和HSC中相比上调的基因Up-regulated genes in passaged tumorigenic cells compared with HSCs

FN1，FN1，RAI3，KRT19，FN1，FN1，ITGB5，S100A8，S100P，CA12，TACSTD2，AGR2，S100A2，DC12，DSP，DUSP4，FN1, FN1, RAI3, KRT19, FN1, FN1, ITGB5, S100A8, S100P, CA12, TACSTD2, AGR2, S100A2, DC12, DSP, DUSP4,

FLJ20151，IGFBP3，S100A9，CXADR，CYR61，BIK，PTPRK，SERPINA3，ziziminl，CD24，SYN47，HRASLS3，LGALS3，FLJ20151, IGFBP3, S100A9, CXADR, CYR61, BIK, PTPRK, SERPINA3, ziziminl, CD24, SYN47, HRASLS3, LGALS3,

FLJ11619，LCN2，RARRES1，GOLPH2，HRY，TFF1，EFEMP1，STHM，IF127，SFN，MGC4309，ABCC3，DKFZp564A176，FLJ11619, LCN2, RARRES1, GOLPH2, HRY, TFF1, EFEMP1, STHM, IF127, SFN, MGC4309, ABCC3, DKFZp564A176,

CD24，MYO6，KRT7，MUC1，IER3，CTSL2，S100A11，MET，PRO1489，C8orf4，PPL，CD24，GPRC5B，S100A8，COBL，CD24, MYO6, KRT7, MUC1, IER3, CTSL2, S100A11, MET, PRO1489, C8orf4, PPL, CD24, GPRC5B, S100A8, COBL,

CDS1，TACSTD1，TACC2，KRT18，ILIR2，SOX9，SPUVE，CAV2，TSSC3，C3，CYPIB1，ITGB5，CD9，KRT6A，MAPK13，CDS1, TACSTD1, TACC2, KRT18, ILIR2, SOX9, SPUVE, CAV2, TSSC3, C3, CYPIB1, ITGB5, CD9, KRT6A, MAPK13,

ARHGAP8，CDKN2A，S100A10，SFN，RDHL，SOX9，CEACAM6，FLJ20273，MGP，CAV1，F3，TGFBI，LGALS1，MYO10，ARHGAP8, CDKN2A, S100A10, SFN, RDHL, SOX9, CEACAM6, FLJ20273, MGP, CAV1, F3, TGFBI, LGALS1, MYO10,

S100A14，INHBA，TM4SF1，CXCL1，TUBB，PPIC，FLJ10052，ILIRN，DPP7，FXYD3，GALNT3，KRT6A，ANXA2，ANXA2，S100A14, INHBA, TM4SF1, CXCL1, TUBB, PPIC, FLJ10052, ILIRN, DPP7, FXYD3, GALNT3, KRT6A, ANXA2, ANXA2,

FER1L3，ANXA9，TPD52L1，HRY，PTPN3，EFNA1，C8FW，CDH1，EPS8，CLDN4，PTPRF，CCND1，CALU，GALNAC4S-FER1L3, ANXA9, TPD52L1, HRY, PTPN3, EFNA1, C8FW, CDH1, EPS8, CLDN4, PTPRF, CCND1, CALU, GALNAC4S-

6ST，DKFZp56411922，ASS，CAP2，FARP1，CRIP1，LOC51760，HOXA1，MIG2，ANXA2P2，TGM2，MUC16，PAPSS2，SNK，6ST, DKFZp56411922, ASS, CAP2, FARP1, CRIP1, LOC51760, HOXA1, MIG2, ANXA2P2, TGM2, MUC16, PAPSS2, SNK,

RAI14，CAV1，COL4A5，C4.4A，PTGIS，KIAA1078，SLP1，SAR1，RARRES1，DUSP4，ANXA2，FLJ10901，CD24，KRT6B，RAI14, CAV1, COL4A5, C4.4A, PTGIS, KIAA1078, SLP1, SAR1, RARRES1, DUSP4, ANXA2, FLJ10901, CD24, KRT6B,

EPN3，ADAM9，EPHA2，TFAP2C，BMPR1A，PARVA，SERPINB5，ENAH，MARCKS，FAT，BF，TACC2，FLJ20171，EPN3, ADAM9, EPHA2, TFAP2C, BMPR1A, PARVA, SERPINB5, ENAH, MARCKS, FAT, BF, TACC2, FLJ20171,

NCKAP1，TONDU，P1GPC1，PARG1，EMS1，CTSL，LIF，EPB41L1，ISG20，ITPR3，LOC90957，CXCL5，PACE4，PHLDA1，NCKAP1, TONDU, P1GPC1, PARG1, EMS1, CTSL, LIF, EPB41L1, ISG20, ITPR3, LOC90957, CXCL5, PACE4, PHLDA1,

HN1，CXCL6，VIL2，C1orf34，GNG12，ALDH1A3，TJP1，TM4SF6，ROR1，FLJ20151，LGMN，DUSP5，IRS1，GFPT1，CD24，HN1, CXCL6, VIL2, C1orf34, GNG12, ALDH1A3, TJP1, TM4SF6, ROR1, FLJ20151, LGMN, DUSP5, IRS1, GFPT1, CD24,

ADM，GATA6，LAMC1，NRCAM，CRABP2，ARHE，MCP，YAP1，ADFP，CARD10，COL4A2，EDG2，PTGES，OSBPL10，ADM, GATA6, LAMC1, NRCAM, CRABP2, ARHE, MCP, YAP1, ADFP, CARD10, COL4A2, EDG2, PTGES, OSBPL10,

IGFBP3，KCNK1，RAB20，R1L，NFIB，EFEMP1，CTSH，PDXK，SGK，DEFB1，KRT17，RAB25，HUMPPA，C12orf5，DLG5，IGFBP3, KCNK1, RAB20, R1L, NFIB, EFEMP1, CTSH, PDXK, SGK, DEFB1, KRT17, RAB25, HUMPPA, C12orf5, DLG5,

KIAA0869，SLC1A1，PPP1R14B，KDELR3，RAB31，DDR1，TSTA3，CDH3，TFP12，PPAP2C，SLC12A8，TM4SFI，FLJ22662，KIAA0869, SLC1A1, PPP1R14B, KDELR3, RAB31, DDR1, TSTA3, CDH3, TFP12, PPAP2C, SLC12A8, TM4SFI, FLJ22662,

DDR1，S100A6，DD96，KIAA1078，VEGF，ARHGAP8，ELF3，RAB31，RIG，MAL，COL4A1，HBP17，LOC113146，ERBB3，DDR1, S100A6, DD96, KIAA1078, VEGF, ARHGAP8, ELF3, RAB31, RIG, MAL, COL4A1, HBP17, LOC113146, ERBB3,

RHCG，NR2F6，EMS1，MUC4，PLAB，STEAP，S100A7，NET1，FLJ11856，MGC5395，GPR48，DLAT，R1N2，NFIB，RHCG, NR2F6, EMS1, MUC4, PLAB, STEAP, S100A7, NET1, FLJ11856, MGC5395, GPR48, DLAT, R1N2, NFIB,

CEACAM6，CORO2A，TIMM17A，CLMN，FLJ13593，FARP1，E21G4，IL1RL1，DSTN，CYB5R2，TIMP2，KRT8，GFPT2，CEACAM6, CORO2A, TIMM17A, CLMN, FLJ13593, FARP1, E21G4, IL1RL1, DSTN, CYB5R2, TIMP2, KRT8, GFPT2,

POLR2J，SLC6A14，ANXA3，LAMBI，FLJ21918，MGC10796，EPB41L4B，G0S2，SDC4，CCL20，TLE1，LAMC2，NMU，POLR2J, SLC6A14, ANXA3, LAMBI, FLJ21918, MGC10796, EPB41L4B, G0S2, SDC4, CCL20, TLE1, LAMC2, NMU,

SPAG4，TRIM2，RAB31，EGFR，ZNF339，MGC35048，PLAT，PITX1，ZFP36L1，GMFB，PHLDA1，BNC，SLC11A2，LAMB3，SPAG4, TRIM2, RAB31, EGFR, ZNF339, MGC35048, PLAT, PITX1, ZFP36L1, GMFB, PHLDA1, BNC, SLC11A2, LAMB3,

TFP12，FLJ22408，SAT，LAMP1，POR，TGFA，MYO6，KCNMA1，TPM2，TUFT1，GPR87，BZW1，KDELR3，ANKRD3，TFP12, FLJ22408, SAT, LAMP1, POR, TGFA, MYO6, KCNMA1, TPM2, TUFT1, GPR87, BZW1, KDELR3, ANKRD3,

EGFR-RS，AKR1B10，RBP1，CDKN2A，CLDN1，AKAP12，SLC7A5，SEMA3C，ERBB2，GPR64，PLXNB1，COX5B，EGFR-RS, AKR1B10, RBP1, CDKN2A, CLDN1, AKAP12, SLC7A5, SEMA3C, ERBB2, GPR64, PLXNB1, COX5B,

MGC11242，FACL3，PPARD，PPAP2A，EMP2，CASK，MT1H，TMPRSS4，PDEF，KDELR2，FLJ21610，TMEM8，GSTT1，MGC11242, FACL3, PPARD, PPAP2A, EMP2, CASK, MT1H, TMPRSS4, PDEF, KDELR2, FLJ21610, TMEM8, GSTT1,

KREMEN2，ECT2，PFN2，MT1X，MT2A，HA1K1，CNN3，PTK2，IL1A，S100A13，NDRG1，MID1，TNFRSF11B，SOCS5，KREMEN2, ECT2, PFN2, MT1X, MT2A, HA1K1, CNN3, PTK2, IL1A, S100A13, NDRG1, MID1, TNFRSF11B, SOCS5,

MATN2，ME1，SEMA3F，ARHD，Pp35，ZNF144，MLPH，PDZK1，SCD，CRYAB，HSPC163，RRAD，IGSF3，PCB D，JTSN1，MATN2, ME1, SEMA3F, ARHD, Pp35, ZNF144, MLPH, PDZK1, SCD, CRYAB, HSPC163, RRAD, IGSF3, PCBD, JTSN1,

IL13RA1，UGCG，EDG2，ANXA8，SSSCA1，LAMA5，KIAA0436，KIAA0599，ENDOG，SLC6A8，CALD1，FLJ11183，IL13RA1, UGCG, EDG2, ANXA8, SSSCA1, LAMA5, KIAA0436, KIAA0599, ENDOG, SLC6A8, CALD1, FLJ11183,

MGC3101，UMPK，EFA6R，NQO1，PTK9，MT1L，ELF3，CST6，ST5，NETO2，KIAA0802，MYO1B，NOTCH3，PTK6，MGC3101, UMPK, EFA6R, NQO1, PTK9, MT1L, ELF3, CST6, ST5, NETO2, KIAA0802, MYO1B, NOTCH3, PTK6,

KIAA1416，MYO1C，SUCLG2，KRT17，RHBDL2，AMOTL2，COL7A1，IL20RA，CD14，CEBPD，SMARCA1，ESDN，KIAA1416, MYO1C, SUCLG2, KRT17, RHBDL2, AMOTL2, COL7A1, IL20RA, CD14, CEBPD, SMARCA1, ESDN,

TNFRSF6，FLJ20591，PEG10，FOXA1，KIAA1026，FLJ21870，PBEF，TOB1，AQP3，LISCH7，TGIF，MYO1B，MPZL1，DDR1，TNFRSF6, FLJ20591, PEG10, FOXA1, KIAA1026, FLJ21870, PBEF, TOB1, AQP3, LISCH7, TGIF, MYO1B, MPZL1, DDR1,

CP，IQGAP1，P4HA2，BMPR1A，NEBL，PLEK2，EPHB4，AK3，BHLHB3，IL6，TAZ，PLS3，OSR2，SH3YL1，NQO1，CP, IQGAP1, P4HA2, BMPR1A, NEBL, PLEK2, EPHB4, AK3, BHLHB3, IL6, TAZ, PLS3, OSR2, SH3YL1, NQO1,

PPAP2A，UP，SBB131，KDELR2，KIAA0790，FLJ10292，SLC2A1，AQP6，P2RY2，MTAP，FLJ10718，DAF，MOB，MKLN1，PPAP2A, UP, SBB131, KDELR2, KIAA0790, FLJ10292, SLC2A1, AQP6, P2RY2, MTAP, FLJ10718, DAF, MOB, MKLN1,

TM4SF6，SQSTM1，OCRL，C21orf97，NMB，FLJ23186，SDC1，RIS1，PTPRF，KLK10，SCEL，MGST3，CSTB，HOMER-3，TM4SF6, SQSTM1, OCRL, C21orf97, NMB, FLJ23186, SDC1, RIS1, PTPRF, KLK10, SCEL, MGST3, CSTB, HOMER-3,

PON2，CASK，SSH-3，DPP4，HSPB1，MGC2376，LOC92689，RARRES1，LTBP2，BNIP3，HMCS，TGM2，TNC，ITCH，PON2, CASK, SSH-3, DPP4, HSPB1, MGC2376, LOC92689, RARRES1, LTBP2, BNIP3, HMCS, TGM2, TNC, ITCH,

MRPS12，CTSB，SUCLG2，PP1C，SLC31A1，MGC14480，KIAA0440，EGFR，AK3，SRD5A1，FBP1，FLJI3984，UBE2H，MRPS12, CTSB, SUCLG2, PP1C, SLC31A1, MGC14480, KIAA0440, EGFR, AK3, SRD5A1, FBP1, FLJI3984, UBE2H,

H2BFL，MGC3103，NPD009，FCGBP，CDK5，ANG，TEAD3，DPP4，PRRG1，NQO1，KIAA0429，SUCLG2，IF2，ERO1L，H2BFL, MGC3103, NPD009, FCGBP, CDK5, ANG, TEAD3, DPP4, PRRG1, NQO1, KIAA0429, SUCLG2, IF2, ERO1L,

CLDN3，SERPINE1，SFN，FHL2，HS3ST1，PDE8A，CLDN8，BAP29，RRAS2，RPL5，PIG11，PPFIBP2，DNAJB2，RRAS2，CLDN3, SERPINE1, SFN, FHL2, HS3ST1, PDE8A, CLDN8, BAP29, RRAS2, RPL5, PIG11, PPFIBP2, DNAJB2, RRAS2,

NID2，TOPK，MRPL19，NT5E，FN1，KIAA0103，CED-6，MAP4K4，PRSS8，COL13A1，G1P2，ROR1，UGCG，BCAR3，ISG20，NID2, TOPK, MRPL19, NT5E, FN1, KIAA0103, CED-6, MAP4K4, PRSS8, COL13A1, G1P2, ROR1, UGCG, BCAR3, ISG20,

CYP24，L1M，LOC57228，SERPINE1，SLC7A8，TJP3，ESR1，NPAS2，CKAP4，CLDN7，UCHL3，KIAA0143，RBSK，FJX1，CYP24, L1M, LOC57228, SERPINE1, SLC7A8, TJP3, ESR1, NPAS2, CKAP4, CLDN7, UCHL3, KIAA0143, RBSK, FJX1,

NOL3，SLC39A4，FLJ12910，BN1P3，PLP2，FLJ22531，FLJ22028，JAM1，LMNA，KIAA0644，CUGBP1，VNN3，LAMC1，NOL3, SLC39A4, FLJ12910, BN1P3, PLP2, FLJ22531, FLJ22028, JAM1, LMNA, KIAA0644, CUGBP1, VNN3, LAMC1,

CX3CL1，THBS1，NUP50，SLC31A2，NNMT，THBS1，AMMECR1，KMO，MAPK13，KIAA1695，RCP，GTF21RD1，CX3CL1, THBS1, NUP50, SLC31A2, NNMT, THBS1, AMMECR1, KMO, MAPK13, KIAA1695, RCP, GTF21RD1,

ARPC1A，MMP7，DKFZP434E2135，IF2，GLDC，PRSS11，TJP1，ATF3，PAX8，IL13RA1，ATP6V1C1，TST，SHANK2，ARPC1A, MMP7, DKFZP434E2135, IF2, GLDC, PRSS11, TJP1, ATF3, PAX8, IL13RA1, ATP6V1C1, TST, SHANK2,

ANK1，CR1P2，ChGn，GAS2L1，EPHB3，N33，CD59，GEM，EIF5，CENTG2，OAZ3，ASPH，SRPK2，B3GNT3，EDNRA，ANK1, CR1P2, ChGn, GAS2L1, EPHB3, N33, CD59, GEM, EIF5, CENTG2, OAZ3, ASPH, SRPK2, B3GNT3, EDNRA,

HSPC159，BACE2，ATP6V1C1，DP1，EHD1，DNAJB1，YKT6，KLF8，DDEF2，SRD5A1，RALA，CYP1B1，GPNMB，HSPC159, BACE2, ATP6V1C1, DP1, EHD1, DNAJB1, YKT6, KLF8, DDEF2, SRD5A1, RALA, CYP1B1, GPNMB,

DKFZP564A022，FGFR3，ACP1，FLJ20366，TLR5，SCD，KIAA0882，KIAA1028，SC4MOL，MPZL1，RALGPS1A，SAR1，DKFZP564A022, FGFR3, ACP1, FLJ20366, TLR5, SCD, KIAA0882, KIAA1028, SC4MOL, MPZL1, RALGPS1A, SAR1,

PTCH，SDR1，PDE4A，CELSR1，F12，FGF2，GCNT3，SNCAIP，DDR1，PBEF，MMP14，EGLN1，ELOVL1，ADCY9，FST，PTCH, SDR1, PDE4A, CELSR1, F12, FGF2, GCNT3, SNCAIP, DDR1, PBEF, MMP14, EGLN1, ELOVL1, ADCY9, FST,

KIAA0716，HSPA1A，CNGA1，HNMT，KIAA0984，SIRPB2，HRH1，ITGA3，FASTK，LDLR，RGS20，MRPS17，ELMO3，KIAA0716, HSPA1A, CNGA1, HNMT, KIAA0984, SIRPB2, HRH1, ITGA3, FASTK, LDLR, RGS20, MRPS17, ELMO3,

APIM2，TEGT，SH3GLB1，SMARCA1，UNC84A，GJB3，CAST，DKFZP564F0522，SLC19A2，HK2，ID1，ARNTL2，EV15，APIM2, TEGT, SH3GLB1, SMARCA1, UNC84A, GJB3, CAST, DKFZP564F0522, SLC19A2, HK2, ID1, ARNTL2, EV15,

KLK11，KIAA0703，NPAS2，MELS2，CR1M1，GCLM，PARD3，EML1，RAD23B，APIM2，S100A1P，YWHAZ，PON2，KLK11, KIAA0703, NPAS2, MELS2, CR1M1, GCLM, PARD3, EML1, RAD23B, APIM2, S100A1P, YWHAZ, PON2,

MTCH2，FLJ23153，TUBB-5，CDH6，SCD，KRT5，RNASEH1，LHX1，UBE2D1，TMEF FI，MGC4171，PGM3，KLC2，TNF，MTCH2, FLJ23153, TUBB-5, CDH6, SCD, KRT5, RNASEH1, LHX1, UBE2D1, TMEF FI, MGC4171, PGM3, KLC2, TNF,

HSKM-B，IDH3A，KIAA0874，FLJ11773，PSMD5，HGD，PPPIR13B，TNFRSF12A，FLJI3841，MBLL39，SH3BP5，FLJ22418，HSKM-B, IDH3A, KIAA0874, FLJ11773, PSMD5, HGD, PPPIR13B, TNFRSF12A, FLJI3841, MBLL39, SH3BP5, FLJ22418,

CETN2，CAST，IF2，LLGL2，SPATA2，SYNGR2，SLC16AI，FBXO26，c1orf27，ITGB5，LOC113251，KIAA1029，FLJ20623，CETN2, CAST, IF2, LLGL2, SPATA2, SYNGR2, SLC16AI, FBXO26, c1orf27, ITGB5, LOC113251, KIAA1029, FLJ20623,

SELENBP1，PCDH1，DAG1，TMSB10，SUDD，STK17A，LAD1，SQSTM1，THBS1，ARNT2，CGI-115，TRIP13，DSTN，SELENBP1, PCDH1, DAG1, TMSB10, SUDD, STK17A, LAD1, SQSTM1, THBS1, ARNT2, CGI-115, TRIP13, DSTN,

CTNND1，SOX13，SFTPA2，SLC2A10，CGI-141，MT1G，COL4A6，CTNNAL1，RIL，IL1RAP，SNRPD3，MAOB，G1P3，CTNND1, SOX13, SFTPA2, SLC2A10, CGI-141, MT1G, COL4A6, CTNNAL1, RIL, IL1RAP, SNRPD3, MAOB, G1P3,

PIK3R3，FLJ21511，NAV2，CLDN3，VEGF，KIAAI609，MEF2A，SCARA3，CPD，FER1L3，KMO，NY-REN-45，JAG2，PIK3R3, FLJ21511, NAV2, CLDN3, VEGF, KIAAI609, MEF2A, SCARA3, CPD, FER1L3, KMO, NY-REN-45, JAG2,

OSBPL2，YIF1P，FLJ10055，PSMD12，GRIT， LOCII3251，FBXL2，PRSS16，PTPRG，FOXE1，EML1，GUK1，RHO6，TPBG，OSBPL2, YIF1P, FLJ10055, PSMD12, GRIT, LOCII3251, FBXL2, PRSS16, PTPRG, FOXE1, EML1, GUK1, RHO6, TPBG,

HRB，H_GS165L15.1，FLJ12571，MGC29643，SBB126，MARCKS，PSMB3，SLCCIIA2，FZD2，KIAA0220，TMEPAI，MTRR，HRB, H_GS165L15.1, FLJ12571, MGC29643, SBB126, MARCKS, PSMB3, SLCCIIA2, FZD2, KIAA0220, TMEPAI, MTRR,

HMGE，BCL6，STK39，CELSR2，KIAA0895，ACP1，E21G5，KDELR3，CYP-M，ANXA10，ANK3，CLIC4，KRTHB6，TSTA3，HMGE, BCL6, STK39, CELSR2, KIAA0895, ACP1, E21G5, KDELR3, CYP-M, ANXA10, ANK3, CLIC4, KRTHB6, TSTA3,

MLF1，TES，ASPH，PAPSS2，SLC20A2，RGS191P1，NF1B，NPD009，HOXB7，FLJ10134，APOE，KIAA1219，KIAA0173，MLF1, TES, ASPH, PAPSS2, SLC20A2, RGS191P1, NF1B, NPD009, HOXB7, FLJ10134, APOE, KIAA1219, KIAA0173,

PODXL，IGFBP1，HSPCA，MAK，C11orf5，H1G2，CR1M1，FKBP2，HSPAIB，FLJ20624，CPD，ITCH，ENSA，UNC84A，PODXL, IGFBP1, HSPCA, MAK, C11orf5, H1G2, CR1M1, FKBP2, HSPAIB, FLJ20624, CPD, ITCH, ENSA, UNC84A,

KIAA0062，EPPB9，FLJI0851，STK6，PSCA，PTP4A1，DNAJC3，FLJI3782，CKTSF1B1，UAP1，KRT15，AXL，HMGCS1，KIAA0062, EPPB9, FLJI0851, STK6, PSCA, PTP4A1, DNAJC3, FLJI3782, CKTSF1B1, UAP1, KRT15, AXL, HMGCS1,

GNPI，PRKCI，MGC5509，MAGED2，CD63，FLJ11856，ADAM10，KIAA0934，DXS9928E，SYNE-2，IFNGR1，SLC7A11，GNPI, PRKCI, MGC5509, MAGED2, CD63, FLJ11856, ADAM10, KIAA0934, DXS9928E, SYNE-2, IFNGR1, SLC7A11,

RIG，PP1057，LOXL2，SPOCK，PTPRF，PACSIN3，ATP11A，STK24，CAPN2，C4BPA，FLJI1149，TMP21，CYP2E1，RIG, PP1057, LOXL2, SPOCK, PTPRF, PACSIN3, ATP11A, STK24, CAPN2, C4BPA, FLJI1149, TMP21, CYP2E1,

COL4A1，PTP4A1，KIAA0937，PKP2，ARF4，KLF5，HSPA4，NPCIL1，ATP5J2，MSLN，TLE1，ARK5，SS18，SNARK，COL4A1, PTP4A1, KIAA0937, PKP2, ARF4, KLF5, HSPA4, NPCIL1, ATP5J2, MSLN, TLE1, ARK5, SS18, SNARK,

LOC56902，KIAA1630，JAG1，KIAA0843，CIS，MAP4K3，TAZ，PTHLH，RHEB2，NEDD5，HOXB7，MGC24447，EIF2AK3，LOC56902, KIAA1630, JAG1, KIAA0843, CIS, MAP4K3, TAZ, PTHLH, RHEB2, NEDD5, HOXB7, MGC24447, EIF2AK3,

UGTREL1，MIG2，ADK，GAL，FTH1，FTS，PEN-2，TNFRSF11B，CGI-148，MGC；1061，LAMP1，MGC39851，CPD，UGTREL1, MIG2, ADK, GAL, FTH1, FTS, PEN-2, TNFRSF11B, CGI-148, MGC; 1061, LAMP1, MGC39851, CPD,

MGC11061，NCOA3，CDC42BPB，C11orf24，MAP3K8，MGC3038，TRA@，1RS3L，CLTB，SC65，KIAA0471，PTS，POLR2K，MGC11061, NCOA3, CDC42BPB, C11orf24, MAP3K8, MGC3038, TRA@, 1RS3L, CLTB, SC65, KIAA0471, PTS, POLR2K,

CED-6，BLZF1，TRIM36，SPR，AP1S1，EVA1，LIMK1，TIMP1，KIAA0923，NDUFS8，EMP1，BFSP1，JAG1，GOCAPI，BID，CED-6, BLZF1, TRIM36, SPR, AP1S1, EVA1, LIMK1, TIMP1, KIAA0923, NDUFS8, EMP1, BFSP1, JAG1, GOCAPI, BID,

RIL，CGI-90，CLTB，RIG-1，ANGPTL4，ATP11A，ITGAV，IL1RAP，SH2D1A，FLJ22693，INSIG1，FKBP10，FLJ20847，RIL, CGI-90, CLTB, RIG-1, ANGPTL4, ATP11A, ITGAV, IL1RAP, SH2D1A, FLJ22693, INSIG1, FKBP10, FLJ20847,

DUSP14，VDR，IFRD1，TOMM22，POLR2K，IGFBP4，HSD11B2，PTHR2，PRE13，FLJ10769，AFAP，ENC1，MFN1，CD24，DUSP14, VDR, IFRD1, TOMM22, POLR2K, IGFBP4, HSD11B2, PTHR2, PRE13, FLJ10769, AFAP, ENC1, MFN1, CD24,

H2BFT，TRIM2，HIP2，JAG2，DAF，FLJ10099，CRK，YES1，DLG5，RARRES2，LIPG，APXL，FLJ20113，CYP51，CALM1，H2BFT, TRIM2, HIP2, JAG2, DAF, FLJ10099, CRK, YES1, DLG5, RARRES2, LIPG, APXL, FLJ20113, CYP51, CALM1,

MK167，PLS1，VIP32，WARS，ABCA1，RASAL1，CDC42EP4，MYO1D，CRA，H2BFB，KIAA0790，BOP1，TACSTD2，MK167, PLS1, VIP32, WARS, ABCA1, RASAL1, CDC42EP4, MYO1D, CRA, H2BFB, KIAA0790, BOP1, TACSTD2,

KPNA2，SGSH，RPP20，LAMP2，GRSF1，CBLC，ZNF165，SCAMp1，PLOD2，GSTM3，CLTB，C2orf6，MST1R，GSPT1，KPNA2, SGSH, RPP20, LAMP2, GRSF1, CBLC, ZNF165, SCAMp1, PLOD2, GSTM3, CLTB, C2orf6, MST1R, GSPT1,

CLCA2，SGCE，CHST3，CDC42EP4，NPC1，TPM4，HEBP2，WBSCR21，HMGCR，ARL7，FLJ20623，DHFR，FLJ23548，IL8，CLCA2, SGCE, CHST3, CDC42EP4, NPC1, TPM4, HEBP2, WBSCR21, HMGCR, ARL7, FLJ20623, DHFR, FLJ23548, IL8,

DKFZP564F013，SECTM1，RAD23B，CFLAR，POU2F3，ITPK1，IGSF4，CBX3，RHOBTB3，PDP，HSPA4，WFDC2，TRJM16，DKFZP564F013, SECTM1, RAD23B, CFLAR, POU2F3, ITPK1, IGSF4, CBX3, RHOBTB3, PDP, HSPA4, WFDC2, TRJM16,

ARHD，KIAA0632，TCN1，ITGB4，KIF5B，SGPL1，RAD1，EIF2S2，CYC1，IL1R1，HARC，KLAA0779，SLC25A13，PPARG，ARHD, KIAA0632, TCN1, ITGB4, KIF5B, SGPL1, RAD1, EIF2S2, CYC1, IL1R1, HARC, KLAA0779, SLC25A13, PPARG,

RAB17，PLEC1，DKFZP564A2416，C20orf97，DDX26，ALDH3A2，CGI-12，BAG3，EPB41L1，GS3955，FLJ20986，C14orf92，RAB17, PLEC1, DKFZP564A2416, C20orf97, DDX26, ALDH3A2, CGI-12, BAG3, EPB41L1, GS3955, FLJ20986, C14orf92,

PP35，BTF，KRT7，FLJ20457，G10，EPS8R2，LOC160313，MGC2376，KIAA0429，GOLGA2，GOSR2，COX17，FLJ21313，PP35, BTF, KRT7, FLJ20457, G10, EPS8R2, LOC160313, MGC2376, KIAA0429, GOLGA2, GOSR2, COX17, FLJ21313,

FLJ10300，EIF5，SKD3，ADK，NPEPL1，SLC35A3，FLJ20186，YWHAZ，UBE2A，CYB561，NR2F2，ELK1，FLJ13397，FLJ10300, EIF5, SKD3, ADK, NPEPL1, SLC35A3, FLJ20186, YWHAZ, UBE2A, CYB561, NR2F2, ELK1, FLJ13397,

LAMP2，SGSH，FDPS，FLJ10534，PIK3R3，SPINT1，FLJ11619，FLJ20989，AT1P1，SORD，PP，HCCS，SLC1A1，FLJ20739，LAMP2, SGSH, FDPS, FLJ10534, PIK3R3, SPINT1, FLJ11619, FLJ20989, AT1P1, SORD, PP, HCCS, SLC1A1, FLJ20739,

SLC6A8，RBBP8，GR1K3，CALU，KIAA0644，SAA2，KIAA0934，USPI8，TXNL2，FLJ10521，FBXO3，SSBP1，MGC3067，SLC6A8, RBBP8, GR1K3, CALU, KIAA0644, SAA2, KIAA0934, USPI8, TXNL2, FLJ10521, FBXO3, SSBP1, MGC3067,

CGI-100，MRPL13，PIG7，KIF3B，KIAA1735，DAAM1，ADAM17，IL5RA，TPD52L1，PPP2R3A，RAB9A，PAWR，HIPK3，CGI-100, MRPL13, PIG7, KIF3B, KIAA1735, DAAM1, ADAM17, IL5RA, TPD52L1, PPP2R3A, RAB9A, PAWR, HIPK3,

PPP3CB，EPHA1，GFPT1，KIAA0431，C7orfl4，BNIP1，LMCD1，ATP6V1G1，COPB2，KIAA0265，RPL5，FLJ20234，OBP2B，PPP3CB, EPHA1, GFPT1, KIAA0431, C7orfl4, BNIP1, LMCD1, ATP6V1G1, COPB2, KIAA0265, RPL5, FLJ20234, OBP2B,

MIR16，CTNNDI，ATP6V0E，DHCR24，FRK，MGC5178，IQGAP1，HFE，DKFZP434J214，ACTL7A，APBB2，LANO，PMM2，MIR16, CTNNDI, ATP6V0E, DHCR24, FRK, MGC5178, IQGAP1, HFE, DKFZP434J214, ACTL7A, APBB2, LANO, PMM2,

HMGE，ARHGEF4，NPTXI，CTSB，RPA3，NET-7，ARHGAP6，FLJ20637，FLRT3，FLJ10407，RTP801，NR6A1，NR5A2，HMGE, ARHGEF4, NPTXI, CTSB, RPA3, NET-7, ARHGAP6, FLJ20637, FLRT3, FLJ10407, RTP801, NR6A1, NR5A2,

PTPN12，ZNF217，TEB4，CALD1，HSPC111，DPI，SNA12，STS，ANXA4，BR1X，MGC16723，MCP，FLJ22055，C1orf28，PTPN12, ZNF217, TEB4, CALD1, HSPC111, DPI, SNA12, STS, ANXA4, BR1X, MGC16723, MCP, FLJ22055, C1orf28,

ACTN1，TMEM4，FLJ20401，SE57-1，SH3GLB1，CDYL，OAZIN，PRO1855，H41，RAB22A，FLJ10326，PEX13，SH3BP5，ACTN1, TMEM4, FLJ20401, SE57-1, SH3GLB1, CDYL, OAZIN, PRO1855, H41, RAB22A, FLJ10326, PEX13, SH3BP5,

M1F，SOAT1，MRS2L，CDC6，PEPP3，FLJ14675，TPD52，CTBP2，SP1NK1，PPP2R1B，SELT，TNFAIPI，1FRD1，SORT1，M1F, SOAT1, MRS2L, CDC6, PEPP3, FLJ14675, TPD52, CTBP2, SP1NK1, PPP2R1B, SELT, TNFAIPI, 1FRD1, SORT1,

ATP1B1，QSCN6，PDK1，SNX16，VIL2，PMM1，CIBI，FLJ22195，SLC27A5，PCNP，TNFRSF10B，CDR2，FLJ21657，MTX1，ATP1B1, QSCN6, PDK1, SNX16, VIL2, PMM1, CIBI, FLJ22195, SLC27A5, PCNP, TNFRSF10B, CDR2, FLJ21657, MTX1,

SLC38A1，BC-2，PEX3，C1AO1，PLXNB2，ROD1，RPL39L，TAFIB，ZF，C120rf22，DDX26，ME1，NPEPPS，DNAJB1，SLC38A1, BC-2, PEX3, C1AO1, PLXNB2, ROD1, RPL39L, TAFIB, ZF, C120rf22, DDX26, ME1, NPEPPS, DNAJB1,

SLC39A1，AT1P1，MGC2742，BBOX1，FAM3C，FBXL11，EGR1，LIN7C，UBE2G1，MCP，TMPRSS3，MARCKS，LOC56902，SLC39A1, AT1P1, MGC2742, BBOX1, FAM3C, FBXL11, EGR1, LIN7C, UBE2G1, MCP, TMPRSS3, MARCKS, LOC56902,

GRAF，ALS2CR3，KIAA0680，FZD6，SPON1，HSPC111，CCNBI，P2RX5，B4GALT4，GOLGA2，p47，KOC1，RAB2，GRAF, ALS2CR3, KIAA0680, FZD6, SPON1, HSPC111, CCNBI, P2RX5, B4GALT4, GOLGA2, p47, KOC1, RAB2,

TM4SF9，MGAT4A，HS2ST1，CD44，FLJ20315，TCFL4，PCMT1，BHLHB2，VRP，RBSK，FLJI0829，HES2，EKI1，ZRF1，TM4SF9, MGAT4A, HS2ST1, CD44, FLJ20315, TCFL4, PCMT1, BHLHB2, VRP, RBSK, FLJI0829, HES2, EKI1, ZRF1,

C2orF6，TUBGCP2，PFTK1，BZW1，CYR61，NOL3，PTGES，CG1-100，BM039，SCR1B，DDX3，SVIL，SMC6，NET-6，C2orF6, TUBGCP2, PFTK1, BZW1, CYR61, NOL3, PTGES, CG1-100, BM039, SCR1B, DDX3, SVIL, SMC6, NET-6,

KIAA1023，ATOX1，IER5，IL1R2，STX6，PKP3，PITX1，ETV2，MCCC2，MRPL33，MGC2494，BPGM，C22orf2，ACTR2，KIAA1023, ATOX1, IER5, IL1R2, STX6, PKP3, PITX1, ETV2, MCCC2, MRPL33, MGC2494, BPGM, C22orf2, ACTR2,

BCL10，TRAM，B7，FLJ12439，DKFZp564A176，PHKAI，SLC33A1，TGOLN2，HRC，LGALS8，FLJ22940，OBP2A，BCL10, TRAM, B7, FLJ12439, DKFZp564A176, PHKAI, SLC33A1, TGOLN2, HRC, LGALS8, FLJ22940, OBP2A,

STOML2，IFNGR1，POLR2J2，DKFZP586B0923，SLC2A4RG，NDUFA8，KIAA0964，FLJ11269，TMPRSS2，PLEKHA1，STOML2, IFNGR1, POLR2J2, DKFZP586B0923, SLC2A4RG, NDUFA8, KIAA0964, FLJ11269, TMPRSS2, PLEKHA1,

UGT2B28，ARL1，PFDN2，IGLJ3，FLJ23516，KIAA1609，WSB2，KIAA1598，YES1，KIAA0284，ATP6V1D，VMP1，C22orf5，UGT2B28, ARL1, PFDN2, IGLJ3, FLJ23516, KIAA1609, WSB2, KIAA1598, YES1, KIAA0284, ATP6V1D, VMP1, C22orf5,

HSPA6，MUC1，MAPK9，PARD3，APG12L，RAB5C，PAK6，LSM1，INS1G1，NDUFS6，ALDH3B2，TNFSF10，FLJ20275，HSPA6, MUC1, MAPK9, PARD3, APG12L, RAB5C, PAK6, LSM1, INS1G1, NDUFS6, ALDH3B2, TNFSF10, FLJ20275,

CHML，UBE2V1，IGF2R，JTGB5，SEC61G，LOC55831，OPTN，ORMDL2，GABRP，DPP3，FLJ20967，POP3，GPC1，CHML, UBE2V1, IGF2R, JTGB5, SEC61G, LOC55831, OPTN, ORMDL2, GABRP, DPP3, FLJ20967, POP3, GPC1,

ANXA2P3，PRDX4，CHPPR，DKFZp434G2311，LGALS3BP，UEV3，KRAS2，TM4SF11，FLJ10116，CTBP2，CALU，USP3，ANXA2P3, PRDX4, CHPPR, DKFZp434G2311, LGALS3BP, UEV3, KRAS2, TM4SF11, FLJ10116, CTBP2, CALU, USP3,

P4HA1，SLC22A1L，FER，SLC1A7，PCDHA12，ENC1，FLJ14251，PPP2R3A，FLJ20069，DDXx，STK6，PLA2G5，ZYG，P4HA1, SLC22A1L, FER, SLC1A7, PCDHA12, ENC1, FLJ14251, PPP2R3A, FLJ20069, DDXx, STK6, PLA2G5, ZYG,

PPF1A1，AFFX-HUMGAPDH/M331975at，AK1，GNA11，WWP1，HRY，SMURF1，FOP，DHCR7，GCSH，HDGF，NCBP1，PPF1A1, AFFX-HUMGAPDH/M331975at, AK1, GNA11, WWP1, HRY, SMURF1, FOP, DHCR7, GCSH, HDGF, NCBP1,

ETEA，KIAA1096，GMPS，TGFBR3，HSF2BP，ZFP103，CD44，C20orf24，PSEN2，PEX7，TNFRSF21，ARHGEF7，CD2AP，ETEA, KIAA1096, GMPS, TGFBR3, HSF2BP, ZFP103, CD44, C20orf24, PSEN2, PEX7, TNFRSF21, ARHGEF7, CD2AP,

ARF4，CHD1L，MGC8974，ZMPSTE24，PSMB5，ACR，GSK3B，NEDD4L，KPNA4，V1L2，CDC42EP2，UNC119，EPS8R1，ARF4, CHD1L, MGC8974, ZMPSTE24, PSMB5, ACR, GSK3B, NEDD4L, KPNA4, V1L2, CDC42EP2, UNC119, EPS8R1,

KIAA0143，FLJ22709，LOC55862，YWHAE，BAZ1A，WIT-1，IL13RAI，ITGB8，OS4，LRP3，DR1L1，FASN，TXN，RASAL2，KIAA0143, FLJ22709, LOC55862, YWHAE, BAZ1A, WIT-1, IL13RAI, ITGB8, OS4, LRP3, DR1L1, FASN, TXN, RASAL2,

NCOA3，JUP，AUH，NEK2，GEMIN6，PSMD11，RECQL，MAP7，SNX4，TPD52，KLK8，INPP5E，KIF1C，ORC5L，CDA，NCOA3, JUP, AUH, NEK2, GEMIN6, PSMD11, RECQL, MAP7, SNX4, TPD52, KLK8, INPP5E, KIF1C, ORC5L, CDA,

C20orf35，FLJ13189，B4GALT4，CDK5R1，Clorf16，ATP6VID，KIF5B，CTNND2，CGGBP1，SQLE，PTP4A1，CSNK2A1，C20orf35, FLJ13189, B4GALT4, CDK5R1, Clorf16, ATP6VID, KIF5B, CTNND2, CGGBP1, SQLE, PTP4A1, CSNK2A1,

LIFR，PLSCR1，SR1，CDC20，PSMB7，C20orf18，NAT1，KLK5，KPNA1，PELI1，TRIM29，YWHAZ，KLF4，FLJ21916，LTF，LIFR, PLSCR1, SR1, CDC20, PSMB7, C20orf18, NAT1, KLK5, KPNA1, PELI1, TRIM29, YWHAZ, KLF4, FLJ21916, LTF,

DAPK2，DHCR7，RNMT，RXRA，SPAG1，DDX21，CKTSFIB1，OXTR，KlA1096，COL16A1，CELSR2，KlAA0111，DAPK2, DHCR7, RNMT, RXRA, SPAG1, DDX21, CKTSFIB1, OXTR, KlA1096, COL16A1, CELSR2, KlAA0111,

TPARL，MLCB，STS，DKFZP586C1619，TPSB2，MEIS3，APBB2，HSPC121，ASK，ABCB6，RBMS2，DKFZp762N1910，TPARL, MLCB, STS, DKFZP586C1619, TPSB2, MEIS3, APBB2, HSPC121, ASK, ABCB6, RBMS2, DKFZp762N1910,

CCNE1，FLJ22347，TEAD4，PPIB，NDUFS8，TMG4，BUB1，RRAS2，NOC4，SSH-3，TAXlBP1，EPN2，ISGF3G，MRPL17，CCNE1, FLJ22347, TEAD4, PPIB, NDUFS8, TMG4, BUB1, RRAS2, NOC4, SSH-3, TAXlBP1, EPN2, ISGF3G, MRPL17,

AHNAK，TBL1X，EKI1，B4GALT1，SPHK1，PPIF，TXNDC4，DSC2，KIAA1096，SSR1，ATP9A，OSBPL1A，COX8，EIF2S1，AHNAK, TBL1X, EKI1, B4GALT1, SPHK1, PPIF, TXNDC4, DSC2, KIAA1096, SSR1, ATP9A, OSBPL1A, COX8, EIF2S1,

SIP1，ACPP，FLJ20085，SMARCA4，SSTR1，UNG2，C1GALT1，PRKCL2，CABYR，FLJ10232，SLC4A7，ARHGEF5，GLUD1，SIP1, ACPP, FLJ20085, SMARCA4, SSTR1, UNG2, C1GALT1, PRKCL2, CABYR, FLJ10232, SLC4A7, ARHGEF5, GLUD1,

MED8，MAP2K1，PPMIB，NET1，PPP2R3A，RHEB2，PME-1，FLJ20591，PLJ22595，SPS，CPSF5，MGC5466，SLC35A2，MED8, MAP2K1, PPMIB, NET1, PPP2R3A, RHEB2, PME-1, FLJ20591, PLJ22595, SPS, CPSF5, MGC5466, SLC35A2,

PLOD2，DKFZP434B103，APPBP2，TFIP11，FLJ10252，MRPS16，KCNK1，GOLGA5，PAIP1，CHPPR，PA200，APP，PLOD2, DKFZP434B103, APPBP2, TFIP11, FLJ10252, MRPS16, KCNK1, GOLGA5, PAIP1, CHPPR, PA200, APP,

FLJ23338，FLJ13852，RHEB2，PK428，BAIAP2，LAMC2，C7orf10，LANCL2，ITGB1，HCCS，TPM1，FACL3，MRPS15，FLJ23338, FLJ13852, RHEB2, PK428, BAIAP2, LAMC2, C7orf10, LANCL2, ITGB1, HCCS, TPM1, FACL3, MRPS15,

EPPB9，ITGB1，FLJ10199，CSPG6，COPS7A，KRTHA6，SGPL1，EML4，AHCYLI，TPD52，SHC1，EPLIN，TUBB1，GAS2L1，EPPB9, ITGB1, FLJ10199, CSPG6, COPS7A, KRTHA6, SGPL1, EML4, AHCYLI, TPD52, SHC1, EPLIN, TUBB1, GAS2L1,

MPZL1，IDH3A，CYP4B1，CGI-96，TM9SF2，FE1L4，C10of3，FLJ23537，LGALS8，P2RY6，ALDOA，PEX7，EBNA1BP2，MPZL1, IDH3A, CYP4B1, CGI-96, TM9SF2, FE1L4, C10of3, FLJ23537, LGALS8, P2RY6, ALDOA, PEX7, EBNA1BP2,

DKFZP566C134，NPEPPS，PDE4DIP，GSG1，FLJ20485，MTIF2，PCTAIRE2BP，FLJ23510，LAMP1，KIAA0020，GMFB，DKFZP566C134, NPEPPS, PDE4DIP, GSG1, FLJ20485, MTIF2, PCTAIRE2BP, FLJ23510, LAMP1, KIAA0020, GMFB,

ACTR2，HLCS，P4HB，CYCS，PSMD8，TIMM17A，MFTC，TXNL2，PNAS-4，CGI-60，PMP22，TONDU，GGPS1，FLJ20604，ACTR2, HLCS, P4HB, CYCS, PSMD8, TIMM17A, MFTC, TXNL2, PNAS-4, CGI-60, PMP22, TONDU, GGPS1, FLJ20604,

TAT，FLJ10803，CLN5，NRP2，RPN1，KIAA1718，CALM1，NOV，MAOA，TPS1，FLJ20555，KIAA0649，TSLL2，OSBPL11，TAT, FLJ10803, CLN5, NRP2, RPN1, KIAA1718, CALM1, NOV, MAOA, TPS1, FLJ20555, KIAA0649, TSLL2, OSBPL11,

TPM2，MRPL40，TCF-3，H2BFT，SLC4A7，SURF2，LZ16，KIAA0471，DPM1，DNAJA2，COG5，DKFZP434G2226，DC50，TPM2, MRPL40, TCF-3, H2BFT, SLC4A7, SURF2, LZ16, KIAA0471, DPM1, DNAJA2, COG5, DKFZP434G2226, DC50,

TCEB1，ACLY，DUSP3，ROD1，NCOA3，NFATC4，GAN，UNC84A，UCHL5，FLJ11850，RPP38，MYCBP，PDEF，TCEB1, ACLY, DUSP3, ROD1, NCOA3, NFATC4, GAN, UNC84A, UCHL5, FLJ11850, RPP38, MYCBP, PDEF,

DKFZP586N0721，KLJK6，TP11，PSMC2，SLC16A1，TEAD1，VEGF，NDUFS1，BS69，MAGEA3，TLE2，HSPC051，FN1，DKFZP586N0721, KLJK6, TP11, PSMC2, SLC16A1, TEAD1, VEGF, NDUFS1, BS69, MAGEA3, TLE2, HSPC051, FN1,

BAZ1A，FLJ22584，SEC23B，，，，NMES1，MAL2，PIGPC1，LOC55971，FLJ20171，ShrmL，LOC91523，FLJ22474，H19，BAZ1A, FLJ22584, SEC23B,,,, NMES1, MAL2, PIGPC1, LOC55971, FLJ20171, ShrmL, LOC91523, FLJ22474, H19,

RHPN2，MIG-6，NGEF，KIAA1165，YAP1，MGC4309，SYNE-1，CDKN2B，ENAH，CTL2，ALS2CR9，TMEPA1，IMUP，RHPN2, MIG-6, NGEF, KIAA1165, YAP1, MGC4309, SYNE-1, CDKN2B, ENAH, CTL2, ALS2CR9, TMEPA1, IMUP,

DKFZP564J0863，UGCG，MGC12335，ITGB6，CYP4X1，GLIS2，FLJ20273，FLJ31842，LOC55971，TMEPA1，SYT13，DKFZP564J0863, UGCG, MGC12335, ITGB6, CYP4X1, GLIS2, FLJ20273, FLJ31842, LOC55971, TMEPA1, SYT13,

SPUVE，KIAA1244，HSJ001348，MGC29643，BOK，TEM8，FLJ30532，LBP-32，DKFZP761L0424，FLJ23153，EDG3，SPUVE, KIAA1244, HSJ001348, MGC29643, BOK, TEM8, FLJ30532, LBP-32, DKFZP761L0424, FLJ23153, EDG3,

IL20RA，MYO5B，GJB2，MYEOV，PTK2，KIAA2028，SBB131，FLJ10052，AGR2，FGG，FAD104，LOC120224，CLDN1，IL20RA, MYO5B, GJB2, MYEOV, PTK2, KIAA2028, SBB131, FLJ10052, AGR2, FGG, FAD104, LOC120224, CLDN1,

LOC51760，IRX3，C20of100，CLDN12，MGC4734，ERO1L，FLJ40432，MGC33630，NTN4，KIAA1522，SLC4A11，ESDN，LOC51760, IRX3, C20of100, CLDN12, MGC4734, ERO1L, FLJ40432, MGC33630, NTN4, KIAA1522, SLC4A11, ESDN,

DKFZp434C0328，PTGFRN，EHF，MF12，PRO1489，TCEA3，GNG12，TMPRSS3，TEAD2，GJB6，ALS2CR9，DDEF1，CFL2，DKFZp434C0328, PTGFRN, EHF, MF12, PRO1489, TCEA3, GNG12, TMPRSS3, TEAD2, GJB6, ALS2CR9, DDEF1, CFL2,

LOC116238，KIAA1671，SDCCAG43，MGC35048，TOB1，LRG，DKFZp761P0423，C20orf129，SMOC2，FZD4，RDHL，LOC116238, KIAA1671, SDCCAG43, MGC35048, TOB1, LRG, DKFZp761P0423, C20orf129, SMOC2, FZD4, RDHL,

WNT7B，MGC14839，DJ667H12.2，TEAD1，RDHL FLJ14957，ZlC2，HSPC163，DLG5，FLJ14735，FLJ20048，WW45，WNT7B, MGC14839, DJ667H12.2, TEAD1, RDHL FLJ14957, ZlC2, HSPC163, DLG5, FLJ14735, FLJ20048, WW45,

FLJ90440，LOC92689，DAG1，LOC55971，B4GALT1，HAS3，PlGR，SNX9，AK2，PRO2605，UGCGL2，CDH24，GFRA3，FLJ90440, LOC92689, DAG1, LOC55971, B4GALT1, HAS3, PlGR, SNX9, AK2, PRO2605, UGCGL2, CDH24, GFRA3,

FLJ13593，CP，CRBPIV，FHOD2，MGC26963，LOC129642，UACA，YAP1，FLJ23420，IL28RA，PSA，DKFZp434D0215，FLJ13593, CP, CRBPIV, FHOD2, MGC26963, LOC129642, UACA, YAP1, FLJ23420, IL28RA, PSA, DKFZp434D0215,

PPPIR14C，PTGFRN，E21G5，C14orf31，FLJ10052，BCAR1，MGC22805，DKFZp434G171，MGC11034，KIAA1870，PPPIR14C, PTGFRN, E21G5, C14orf31, FLJ10052, BCAR1, MGC22805, DKFZp434G171, MGC11034, KIAA1870,

FLJ22415，FLJ34633，GPR54，CHDH，FST，KIAA1708，UBE2H，DDEF1，WASL，FLJ14408，CXCL16，PARVA，FLJ22415, FLJ34633, GPR54, CHDH, FST, KIAA1708, UBE2H, DDEF1, WASL, FLJ14408, CXCL16, PARVA,

DKFZP434H0820，CASPR3，RAB10，PDP，ANLN，FLJ25157，NETO2，OLD35，UBQLN1，LOC58489，FLJ23867，E21G5，DKFZP434H0820, CASPR3, RAB10, PDP, ANLN, FLJ25157, NETO2, OLD35, UBQLN1, LOC58489, FLJ23867, E21G5,

ATP11A，CD44，DNAH5，LOC128153，PHLDA1，IPP，DUSP16，COL12A1，MGST1，PLEKHA1，KIAA2025，LTB4DH，ATP11A, CD44, DNAH5, LOC128153, PHLDA1, IPP, DUSP16, COL12A1, MGST1, PLEKHA1, KIAA2025, LTB4DH,

FLJ20739，FLJ22174，MGC24180，DKFZp761N0624，IRAK2，ALS2CR9，MGC39329，AKAP2，C14orf50，MGST1，UGCGL1，FLJ20739, FLJ22174, MGC24180, DKFZp761N0624, IRAK2, ALS2CR9, MGC39329, AKAP2, C14orf50, MGST1, UGCGL1,

KLK7，FLJ31937，DIRC2，FLJ10035，MGC11034，SOX7，PARVA，LOC139231，GPCR1，SDCCAG28，GPR92，LOC147184，KLK7, FLJ31937, DIRC2, FLJ10035, MGC11034, SOX7, PARVA, LOC139231, GPCR1, SDCCAG28, GPR92, LOC147184,

LOC113026，MGC14798，L0C147700，DKFZP434A1315，FLJ10702，LTB4DH，PYPAF3，RBMS1，SLC30A1，MTA3，ARL8，LOC113026, MGC14798, L0C147700, DKFZP434A1315, FLJ10702, LTB4DH, PYPAF3, RBMS1, SLC30A1, MTA3, ARL8,

KIAA1688，RASAL2，PDK1，XPR1，SULF2.，STEAP2，H41，METL，FBXO32，TLE1，DDEF1，GPT2，MRPL30，FIJ14117，KIAA1688, RASAL2, PDK1, XPR1, SULF2., STEAP2, H41, METL, FBXO32, TLE1, DDEF1, GPT2, MRPL30, FIJ14117,

DKFZp434E2321，MGC26963，SAT，ORFI-FL49，GRP58，MGC33662，NT5E，FLJ31052，RNAC，CGI-85，CTL2，STC1，SCD，DKFZp434E2321, MGC26963, SAT, ORFI-FL49, GRP58, MGC33662, NT5E, FLJ31052, RNAC, CGI-85, CTL2, STC1, SCD,

DKFZP434K0427，SCARA3，MGC14128，BCCIP，MGC3195，TGFBR3，PXMP4，KIAA1500，Spir-1，ARHGEF12，DKFZP434K0427, SCARA3, MGC14128, BCCIP, MGC3195, TGFBR3, PXMP4, KIAA1500, Spir-1, ARHGEF12,

DKFZP434A0225，LOC55829，C20orf24，HSPC242，CAMK2D，FAD104，ZD52F10，HS6ST2，HLCS，FLRT3，SDCCAG28，DKFZP434A0225, LOC55829, C20orf24, HSPC242, CAMK2D, FAD104, ZD52F10, HS6ST2, HLCS, FLRT3, SDCCAG28,

KLF15，C20orf139，FLJ39155，MGC1314，C20orf24，FLJ14511，CGI-20，EDG8，MGC10765，C7orf3，MGC14801，FLJ10697，KLF15, C20orf139, FLJ39155, MGC1314, C20orf24, FLJ14511, CGI-20, EDG8, MGC10765, C7orf3, MGC14801, FLJ10697,

ATP1B1，EHF，JUB，FLJ11200，MacGAP，H4FH，MGC11102，RORC，COL12A1，PRO1853，MGC13096，SPTB，FLJ32115，ATP1B1, EHF, JUB, FLJ11200, MacGAP, H4FH, MGC11102, RORC, COL12A1, PRO1853, MGC13096, SPTB, FLJ32115,

DKFZP566F084，SEMA4B，DKFZP434A0225，BTC，PCDHB14，CGI-09，EMS1，PCDHB16，KIAA1384，SCEL，GRP58，DKFZP566F084, SEMA4B, DKFZP434A0225, BTC, PCDHB14, CGI-09, EMS1, PCDHB16, KIAA1384, SCEL, GRP58,

KIAA1357，CAC-1，SURF4，FLJ11011，LMLN，ARL6IP2，OCLN，C17orf28，INPP4B，C14orf31，FLJ22558，FLJ10116，KIAA1357, CAC-1, SURF4, FLJ11011, LMLN, ARL6IP2, OCLN, C17orf28, INPP4B, C14orf31, FLJ22558, FLJ10116,

KIAA1363，DAB21P，MGC35352，GK001，PDGFA，SNX8，MGC22805，LOC114990，ELP2，CXADR，LOC120224，KIAA1363, DAB21P, MGC35352, GK001, PDGFA, SNX8, MGC22805, LOC114990, ELP2, CXADR, LOC120224,

ST6GalNAcI，MGC35403，MGC39350，KPNB2，DSCR1L2，FLJ20333，PPP1R1B，ElF2C2，PX19，BPNT1，AD-003，LACTB，ST6GalNAcI, MGC35403, MGC39350, KPNB2, DSCR1L2, FLJ20333, PPP1R1B, ElF2C2, PX19, BPNT1, AD-003, LACTB,

FLJ36445，ULBP2，GUK1，KIAA1321，SPP2，CRB3，FLJ90586，NDUFB9，PDK4，FLJ30973，HSPC228，MacGAP，DEFB118，FLJ36445, ULBP2, GUK1, KIAA1321, SPP2, CRB3, FLJ90586, NDUFB9, PDK4, FLJ30973, HSPC228, MacGAP, DEFB118,

DKFZp761K2222，ASPH，MGC45474，UBQLN1，TRAF4，DKFZp761K2222，DJ667H12.2，AFFX-DKFZp761K2222, ASPH, MGC45474, UBQLN1, TRAF4, DKFZp761K2222, DJ667H12.2, AFFX-

HUMGAPDH/M33197_5_at，C12orf22，RHOBTB3，MGc33974，KPNB2，C9orf5，FLJ32421，FLJ25604，COQ4，FLJ20281，HUMGAPDH/M33197_5_at, C12orf22, RHOBTB3, MGc33974, KPNB2, C9orf5, FLJ32421, FLJ25604, COQ4, FLJ20281,

FLJ13391，TEAD2，ELL2，RPS3A，FLJ33516，ESPN，DKFZP434A0225，KIAA1684，TRA@，SEC61A1，DKFZP434K0427，FLJ13391, TEAD2, ELL2, RPS3A, FLJ33516, ESPN, DKFZP434A0225, KIAA1684, TRA@, SEC61A1, DKFZP434K0427,

PRIC285，KIAA1870，AMN，LOC151242，FLJ20686，FLJ10210，FLJ22415，MGC19764，CGI-97，CDW92，NAT5，KIAA1126，PRIC285, KIAA1870, AMN, LOC151242, FLJ20686, FLJ10210, FLJ22415, MGC19764, CGI-97, CDW92, NAT5, KIAA1126,

CLMN，RAB18，MRPS15，JAM1，TEAD2，ENAH，KIAA1228，ACTR3，PCDHA10，ATP5A1，GNPNAT1，CL25084，CLMN, RAB18, MRPS15, JAM1, TEAD2, ENAH, KIAA1228, ACTR3, PCDHA10, ATP5A1, GNPNAT1, CL25084,

LOC51260，CNN3，TFDP1，FLJ31528，KIAA1434，FLJ10902，MGC14289，GGTL3，SYTL2，MGC21874，TIM50L，PHCA，LOC51260, CNN3, TFDP1, FLJ31528, KIAA1434, FLJ10902, MGC14289, GGTL3, SYTL2, MGC21874, TIM50L, PHCA,

PSCD3，KIAA1026，INADL DNAJC5，AD037，FLJ11046，KIAA1804，KIAA1337，PPARD，KIF1B，MIR16，ROD1，PSCD3, KIAA1026, INADL DNAJC5, AD037, FLJ11046, KIAA1804, KIAA1337, PPARD, KIF1B, MIR16, ROD1,

SLC2A13，CFL2，GDF1，MRPL36，SLC26A9，LOC51290，CABYR，HSPC159，SPPL2A，ABCC3，BTBD6，SMURF2，STK35，SLC2A13, CFL2, GDF1, MRPL36, SLC26A9, LOC51290, CABYR, HSPC159, SPPL2A, ABCC3, BTBD6, SMURF2, STK35,

CGI-85，ZAK，DKFZp434B1231，KCNK6，PCDHB2，Spir-1，KIAA0146，ZNF265，COPZ1，FLJ20421，C11orf15，CGI-85, ZAK, DKFZp434B1231, KCNK6, PCDHB2, Spir-1, KIAA0146, ZNF265, COPZ1, FLJ20421, C11orf15,

DKFZp761D0614，KRT19，RAB23，MGC16491，FLJ40432，MGC10981，C20orf45，CTEN，MGC30022，NUCKS，MGC13251，DKFZp761D0614, KRT19, RAB23, MGC16491, FLJ40432, MGC10981, C20orf45, CTEN, MGC30022, NUCKS, MGC13251,

MRPL27，FLJ90586，MGC16028，FLJ90165，SHMT1，FLJ14525，BACE2，ABL1M2，FLJ20719，SCGB3A1，MGC2477，MRPL27, FLJ90586, MGC16028, FLJ90165, SHMT1, FLJ14525, BACE2, ABL1M2, FLJ20719, SCGB3A1, MGC2477,

FLJ20038，MGC29643，FLJ30829，C20orf155，PGK1，FLJ37440，RBM8A，FBXO22，KIAA1219，KIAA1200，KIF3B，FLJ20038, MGC29643, FLJ30829, C20orf155, PGK1, FLJ37440, RBM8A, FBXO22, KIAA1219, KIAA1200, KIF3B,

MGC19825，AK5，C22orf20，FLJ10378，INADL，HSPCA，EIF5A2，RAB18，BCL2L13，MBC3205，UBE2H，FLJ20354，MGC19825, AK5, C22orf20, FLJ10378, INADL, HSPCA, EIF5A2, RAB18, BCL2L13, MBC3205, UBE2H, FLJ20354,

SLC5A7，FLJ30532，C14orf47，TMP1T，EHD4，FLJ13089，MGC17299，IDS，CED-6，MGC27277，LOC137392，FXYD6，SLC5A7, FLJ30532, C14orf47, TMP1T, EHD4, FLJ13089, MGC17299, IDS, CED-6, MGC27277, LOC137392, FXYD6,

MGC22825，CPM，SNX9，MGC19764，TLR7，FENS-1，SDCBP2，NUDT5，MGC11102，SEC24A，CG1-141，NKD2，EFG1，MGC22825, CPM, SNX9, MGC19764, TLR7, FENS-1, SDCBP2, NUDT5, MGC11102, SEC24A, CG1-141, NKD2, EFG1,

ANAPC11，MYO5B，MGC14833，LOC85B65，EPB41L4B，FLJ21415，KCNC4，GSBS，TEAD2，LOC115548，MAGI-3，C9orf5，ANAPC11, MYO5B, MGC14833, LOC85B65, EPB41L4B, FLJ21415, KCNC4, GSBS, TEAD2, LOC115548, MAGI-3, C9orf5,

CLONE24922，MRPS15，RGNEF，CORTBP2，FLJ20354，HSPC121，NOC4，KIAA1673，MGC14595，MGC2560，MGC2408，CLONE24922, MRPS15, RGNEF, CORTBP2, FLJ20354, HSPC121, NOC4, KIAA1673, MGC14595, MGC2560, MGC2408,

MRPL14，APOA1BP，FLJ14681，MGC13102，KIAA1437，KIAA1126，MGC13034，CSEN，SH120，VIP，PRO2000，SLC31A1，MRPL14, APOA1BP, FLJ14681, MGC13102, KIAA1437, KIAA1126, MGC13034, CSEN, SH120, VIP, PRO2000, SLC31A1,

AD-003，CALM2，HT002，RAP2A，EML4，WDR5，MPP5，LOC90990，MGC2560，FLJ14431，ARHGEF5，HCC8，TCEB2，AD-003, CALM2, HT002, RAP2A, EML4, WDR5, MPP5, LOC90990, MGC2560, FLJ14431, ARHGEF5, HCC8, TCEB2,

FLJ13187，FLJ90575，FLJ10525，FLJ23393，HOXB9，LOC84661，dJ55C23.6，HFE，MGC13040，WDR20，MRPL4，FLJ25604，FLJ13187, FLJ90575, FLJ10525, FLJ23393, HOXB9, LOC84661, dJ55C23.6, HFE, MGC13040, WDR20, MRPL4, FLJ25604,

DKFZP566C134，LOC55871，CGI-99，MRPS23，MRPL47，MGC13045，ERK8，KIAA1500，HPS3，CRYPT1C，SBB131，DKFZP566C134, LOC55871, CGI-99, MRPS23, MRPL47, MGC13045, ERK8, KIAA1500, HPS3, CRYPT1C, SBB131,

MGC14353，CGI-20，FHOD2，PPP1R14A，REPS1，MAPKAP1，V-1，FBXO25，BNIP-S，MGC13114，EKN1，GPR24，RCP，MGC14353, CGI-20, FHOD2, PPP1R14A, REPS1, MAPKAP1, V-1, FBXO25, BNIP-S, MGC13114, EKN1, GPR24, RCP,

FLJ12806，MGC2747，OBP2A，HM13，C21orf97，FLJ14909，C9orf10，STYX，THOC3，RDGBB，PFKFB4，FLJ21924，FLJ12806, MGC2747, OBP2A, HM13, C21orf97, FLJ14909, C9orf10, STYX, THOC3, RDGBB, PFKFB4, FLJ21924,

KIAA1295，ZDHHC9，STXBP5，RPE，UBE2H，PCDHB18，FLJ20303，NPD007，N4WBP5，FLJ20333，FLJ12747，SURF4，KIAA1295, ZDHHC9, STXBP5, RPE, UBE2H, PCDHB18, FLJ20303, NPD007, N4WBP5, FLJ20333, FLJ12747, SURF4,

C20orf45，FLJ12787，LOC90507，FLJ10839，EPB41L4B，FLJ37953，BAP29，MRPL50，MGC10999，C9orf5，TBDN100，C20orf45, FLJ12787, LOC90507, FLJ10839, EPB41L4B, FLJ37953, BAP29, MRPL50, MGC10999, C9orf5, TBDN100,

STK35，FRABIN，JUB，PRO2714，MLLT4，MGC40214，CPNE4，FLJ22233，MIZIP，MGC14859，MRPS24，HPS3，FLJ23841，STK35, FRABIN, JUB, PRO2714, MLLT4, MGC40214, CPNE4, FLJ22233, MIZIP, MGC14859, MRPS24, HPS3, FLJ23841,

FLJ23577，HSPCA，MRPS10，FLJ14251，SSR3，MGC13186，KIAA1453，HN1，HOOK3，ATP1B3，MRPL50，MAP4K1，FLJ23577, HSPCA, MRPS10, FLJ14251, SSR3, MGC13186, KIAA1453, HN1, HOOK3, ATP1B3, MRPL50, MAP4K1,

LOC90120，D1S155E，DKFZP564O0463，FLJ23816，CFTR，MGC40555，MGC20781，FLJ20085，NOPE，FLJ14825，MSP，LOC90120, D1S155E, DKFZP564O0463, FLJ23816, CFTR, MGC40555, MGC20781, FLJ20085, NOPE, FLJ14825, MSP,

LMO7，C7orf2，MRPL32，FLJ10074，MAK3P，KRT61RS，DKFZp547A023，SAMHD1，HSPC043，FLJ10597，FACL6，LGR6，LMO7, C7orf2, MRPL32, FLJ10074, MAK3P, KRT61RS, DKFZp547A023, SAMHD1, HSPC043, FLJ10597, FACL6, LGR6,

SORCS2，MGC4840，RAB35，MGC10911，and MLL3.SORCS2, MGC4840, RAB35, MGC10911, and MLL3.

                                               表7DTable 7D

                                传代的致瘤性细胞和HSC中相比下调的基因Down-regulated genes in passaged tumorigenic cells compared to HSCs

MEF2C，HSPC053，HOXA9，PRG1，RetSDR2，GMFG，AIF1，A1F1，HLA-DPB1，PLCL2，ICAM2，HLA-DPA1，PTPRC，MEF2C, HSPC053, HOXA9, PRG1, RetSDR2, GMFG, AIF1, A1F1, HLA-DPB1, PLCL2, ICAM2, HLA-DPA1, PTPRC,

SPINK2，SPARC，CUGBP2，PTGER4，CECR1，CDW52，CCND2，LYZ，SELL，CD69，HOXA9，ITM2A，HLA-DQB1，ITM2B，SPINK2, SPARC, CUGBP2, PTGER4, CECR1, CDW52, CCND2, LYZ, SELL, CD69, HOXA9, ITM2A, HLA-DQB1, ITM2B,

LYL1，KIAA0125，LMO2，ARHGEF6，KIAA0084，MPL，RGS2，LAGY，QKJ，EV12B，ZNFN1A1，DOCK2，HLA-DRB3，LYL1, KIAA0125, LMO2, ARHGEF6, KIAA0084, MPL, RGS2, LAGY, QKJ, EV12B, ZNFN1A1, DOCK2, HLA-DRB3,

NAP1L3，HLA-DPA1，KIT，HF1，HLF，LST1，ANGPT1，CD53，LST1，FLJ14054，SELPLG，LST1，BM046，TUBA3，HLA-NAP1L3, HLA-DPA1, KIT, HF1, HLF, LST1, ANGPT1, CD53, LST1, FLJ14054, SELPLG, LST1, BM046, TUBA3, HLA-

DQA1，BCE-1，CDW52，FLJ10178，PRKACB，PRKCB1，IQGAP2，CHES1，GUCY1B3，PSCDBP，HLA-DRA，LAPTM5，DQA1, BCE-1, CDW52, FLJ10178, PRKACB, PRKCB1, IQGAP2, CHES1, GUCY1B3, PSCDBP, HLA-DRA, LAPTM5,

PRG1，MEF2C，SLC2A5，LST1，FHL1，MAP4K1，TNFSF4，PLAC8，HLA-DQB1，IGFBP7，PCDH9，MAP4K1，EV12A，PRG1, MEF2C, SLC2A5, LST1, FHL1, MAP4K1, TNFSF4, PLAC8, HLA-DQB1, IGFBP7, PCDH9, MAP4K1, EV12A,

SATB1，MLC1，SSBP2，FL11，CLIC2，CLECSF2，LY75，NDN，HLA-DRB1，FLJ21276，DLK1，GLUL，NUDT11，BEX1，SATB1, MLC1, SSBP2, FL11, CLIC2, CLECSF2, LY75, NDN, HLA-DRB1, FLJ21276, DLK1, GLUL, NUDT11, BEX1,

SH3BGRL，PRKCB1，MPHOSPH9，LST1，HLA-DQB1，FLJ22690，UQCRH，FLJ22746，HLA-DRB3，SLC2A3，NPIP，SH3BGRL, PRKCB1, MPHOSPH9, LST1, HLA-DQB1, FLJ22690, UQCRH, FLJ22746, HLA-DRB3, SLC2A3, NPIP,

BCL11A，MPO，RUNX3，ERG，SV2，HLF，MMRN，CYF1P2，HLA-DRB4，PECAM1，CORO1A，MOXK2，SEPP1，BAALC，6-BCL11A, MPO, RUNX3, ERG, SV2, HLF, MMRN, CYF1P2, HLA-DRB4, PECAM1, CORO1A, MOXK2, SEPP1, BAALC, 6-

Sep，ITM2B，LCP2，PEL12，C17，IGHM，LRMP，PPP1R16B，HLA-DRB5，HBB，DJ971N18.2，LOCC51186，SCGF，ERG，Sep, ITM2B, LCP2, PEL12, C17, IGHM, LRMP, PPP1R16B, HLA-DRB5, HBB, DJ971N18.2, LOCC51186, SCGF, ERG,

LAPTM5，P311，SAMSN1，ITGA4，DJ434O14.3，IGFBP7，TFEC，HA-1，MAGED1，HSPC022，FNBP1，TCF8，ELMO1，LAPTM5, P311, SAMSN1, ITGA4, DJ434O14.3, IGFBP7, TFEC, HA-1, MAGED1, HSPC022, FNBP1, TCF8, ELMO1,

CUGBP2，NGFRAP1，P1P5K1B，DDO，MLLT3，ALCAM，NPR3，CMRF-35H，DPYD，PLAG1，BIN2，ITM2A，MYCN，CUGBP2, NGFRAP1, P1P5K1B, DDO, MLLT3, ALCAM, NPR3, CMRF-35H, DPYD, PLAG1, BIN2, ITM2A, MYCN,

GSPT2，LXN，ALEX1，PIK3CD，ADAM28，PLAGL1，FLT3，WBSCR5，C6orf37，GUCYIA3，CD74，KIAA0053，TRAITS，GSPT2, LXN, ALEX1, PIK3CD, ADAM28, PLAGL1, FLT3, WBSCR5, C6orf37, GUCYIA3, CD74, KIAA0053, TRAITS,

HLA-DQB1，MGC2306，ICAM3，PTGS2，H3F3B，TCF4，SNCA，FLJ10713，PROML1，TEK，APOBEC3G，PRO1635，HLA-E，HLA-DQB1, MGC2306, ICAM3, PTGS2, H3F3B, TCF4, SNCA, FLJ10713, PROML1, TEK, APOBEC3G, PRO1635, HLA-E,

JAM3，UBE1L，BCL11A，GNA11，LHFP，LST1，CDH2，MYB，FLJ10462，ZFHX1B，CBFA2T3，TMSNB，HLA-DMA，PLCB1，JAM3, UBE1L, BCL11A, GNA11, LHFP, LST1, CDH2, MYB, FLJ10462, ZFHX1B, CBFA2T3, TMSNB, HLA-DMA, PLCB1,

SOCS2，CG018，PDE4B，MHC2TA，PAD15，USF2，CUGBP2，VIM，HLA-DRB6，TFP1，BIRC1，PTGS1，HFL2，SCDGF-B，SOCS2, CG018, PDE4B, MHC2TA, PAD15, USF2, CUGBP2, VIM, HLA-DRB6, TFP1, BIRC1, PTGS1, HFL2, SCDGF-B,

LSP1，NRLN1，MPO，KIAA1939，PTGS1，MS4A3，HP1P，FLJ20220，HLA-DPA1，NCF4，MAPRE2，ZFP，BANK，TOX，LSP1, NRLN1, MPO, KIAA1939, PTGS1, MS4A3, HP1P, FLJ20220, HLA-DPA1, NCF4, MAPRE2, ZFP, BANK, TOX,

CXCR4，IGHM，RUNX3，HCLS1，LOC81558，ARHGD1B，TRO，SCHIP1，CRHBP，KIAA1750，BCL2，FLJ20950，FLJ10097，CXCR4, IGHM, RUNX3, HCLS1, LOC81558, ARHGD1B, TRO, SCHIP1, CRHBP, KIAA1750, BCL2, FLJ20950, FLJ10097,

DAB2，BASP1，JAM2，FLJ216l6，HHEX，ITM2C，SPRY1，SERPING1，SLA，EB12，ZNF42，DSIP1，FLJ10038，PECAM1，6-DAB2, BASP1, JAM2, FLJ216l6, HHEX, ITM2C, SPRY1, SERPING1, SLA, EB12, ZNF42, DSIP1, FLJ10038, PECAM1, 6-

Sep，CASP1，RB1，TACC3，13CDNA73，6-Sep，MAPRE2，FCER1A，BTK，LOH11CR2A，LRMP，PLAGL1，MICAL，TCF4，Sep, CASP1, RB1, TACC3, 13CDNA73, 6-Sep, MAPRE2, FCER1A, BTK, LOH11CR2A, LRMP, PLAGL1, MICAL, TCF4,

CLGN，HIFX，WASPIP，LAIR1，ZNF175，INSR，FLJ20456，C11orf8，KIAA0443，AKAP7，TAL1，HLA-DRA，HRB2，PLEK，CLGN, HIFX, WASPIP, LAIR1, ZNF175, INSR, FLJ20456, C11orf8, KIAA0443, AKAP7, TAL1, HLA-DRA, HRB2, PLEK,

RAGD，PLAGL1，ALDH1A1，B4GALT6，GLIPR1，GAB2，KIAA1157，PPM1F，WAS，SETBP1，MUF1，C6orf32，MYOZ3，RAGD, PLAGL1, ALDH1A1, B4GALT6, GLIPR1, GAB2, KIAA1157, PPM1F, WAS, SETBP1, MUF1, C6orf32, MYOZ3,

TUCAN，RNU2，KLHL3，TSC，PKIA，MLLT3，NEFH，DKFZp564B0769，PPM1F，SNTB1，PCDH9，CRYGD，MPP1，ABCB1，TUCAN, RNU2, KLHL3, TSC, PKIA, MLLT3, NEFH, DKFZp564B0769, PPM1F, SNTB1, PCDH9, CRYGD, MPP1, ABCB1,

KIAA1110，ALEX3，ATP2A3，KIAA0308，MAGEH1，BIMLEC，CTSW，SORL1，FLJ20898，MCM5，CD244，PPP1R16B，KIAA1110, ALEX3, ATP2A3, KIAA0308, MAGEH1, BIMLEC, CTSW, SORL1, FLJ20898, MCM5, CD244, PPP1R16B,

MAGEDI，ASC，GIPC2，RASSF2，LOC81691，SCGF，PTEN，24432，STAT5A，6-Sep，SLC24A1，UBE1L，CD83，TAHCCP1，MAGEDI, ASC, GIPC2, RASSF2, LOC81691, SCGF, PTEN, 24432, STAT5A, 6-Sep, SLC24A1, UBE1L, CD83, TAHCCP1,

GNA15，NR3C2，KIAA0053，INPP5D，CPA3，GYPC，SYK，PRKACB，RUNX1，RIN3，TRB@，NP1P，CABC1，HLA-B，PGDS，GNA15, NR3C2, KIAA0053, INPP5D, CPA3, GYPC, SYK, PRKACB, RUNX1, RIN3, TRB@, NP1P, CABC1, HLA-B, PGDS,

CD34，SPN，LOC58504，MAGEL2，TBXAS1，MFNG，LOC91316，TRAP-1，RECK，TCCEA2，FLJ20136，ARHGAP6，AMT，CD34, SPN, LOC58504, MAGEL2, TBXAS1, MFNG, LOC91316, TRAP-1, RECK, TCCEA2, FLJ20136, ARHGAP6, AMT,

CAT，ADARB1，PTEN，LCP1，CCL3，SCN9A，RASGRP2，DKFZP58612223，SS-56，SLA，C4S-2，PDGFC，LILRA2，RAGD，CAT, ADARB1, PTEN, LCP1, CCL3, SCN9A, RASGRP2, DKFZP58612223, SS-56, SLA, C4S-2, PDGFC, LILRA2, RAGD,

HNRPDL，ZNF288，ITGA2B，LOC81691，HBD，SELP，C6orf32，PDZ-GEF1，CPT1A，KLF2，ZNF198，TACC1，HBB，BI，HNRPDL, ZNF288, ITGA2B, LOC81691, HBD, SELP, C6orf32, PDZ-GEF1, CPT1A, KLF2, ZNF198, TACC1, HBB, BI,

CIAS1，HNRPA0，HLA-DQA1，KIAA0308，MYO1F，PRO1331，RAB33A，TNS，NAP1L2，CERK，MGC4170，ADA，CIAS1, HNRPA0, HLA-DQA1, KIAA0308, MYO1F, PRO1331, RAB33A, TNS, NAP1L2, CERK, MGC4170, ADA,

RNASE3，NFE2，ANKRRD6，AKR1C3，CDC42，H1S1，TR1M22，B1N1，ICAM4，IL12RB2，CSF2RB，EPB41L3，BRDG1，RNASE3, NFE2, ANKRRD6, AKR1C3, CDC42, H1S1, TR1M22, B1N1, ICAM4, IL12RB2, CSF2RB, EPB41L3, BRDG1,

TMRC5，CIRBP，RPLP2，AMPD2，SFRS7，EDG6，BRCA1，MSN，HLA-DQBI，C5orf5，GSTM5，ITPR1，IL16，AIF1，TMRC5, CIRBP, RPLP2, AMPD2, SFRS7, EDG6, BRCA1, MSN, HLA-DQBI, C5orf5, GSTM5, ITPR1, IL16, AIF1,

NFATC1，LILRB2，FGF23，STAC，RPL22，PTEN，LRBA，PFAS，CGI-116，DKFZP586A0522，MGC13024，GALC，ABCG1，NFATC1, LILRB2, FGF23, STAC, RPL22, PTEN, LRBA, PFAS, CGI-116, DKFZP586A0522, MGC13024, GALC, ABCG1,

MGC45806，ELF1，SAP18，ALDH5A1，ELA2，GATM，CHC1L，KIAA0918，LOC51334，FOSB，PRO2198，TEC，SLC1A4，MGC45806, ELF1, SAP18, ALDH5A1, ELA2, GATM, CHC1L, KIAA0918, LOC51334, FOSB, PRO2198, TEC, SLC1A4,

CAD，KIAA1028，VAV1，LOC57100，C11orf21，SLC1A4，TRPV2，EPB41L2，FBN1，CD48，GIT2，CSF3R，DNAJC6，BIN1，CAD, KIAA1028, VAV1, LOC57100, C11orf21, SLC1A4, TRPV2, EPB41L2, FBN1, CD48, GIT2, CSF3R, DNAJC6, BIN1,

KIAA0582，ARL4，SH3BGRL，GLS，FXYD6，PF4，SCGF，NEK9，PKD2，MATK，B1N1，NSBP1，MSH5，PRKG2，NT5M，KIAA0582, ARL4, SH3BGRL, GLS, FXYD6, PF4, SCGF, NEK9, PKD2, MATK, B1N1, NSBP1, MSH5, PRKG2, NT5M,

PML，CD37，SF3A2，PLSCR4，CSK，HA-1，NUDT1，SIAH1，MEIS1，IGLJ3，HLX1，SV2B，DKFZP58612223，KEO4，ENPP2，PML, CD37, SF3A2, PLSCR4, CSK, HA-1, NUDT1, SIAH1, MEIS1, IGLJ3, HLX1, SV2B, DKFZP58612223, KEO4, ENPP2,

CTSF，IL1B，PSMB10，IL1B，ZFP36L2，SFPQ，FLJ1175，ATP2A3，STK10，FLJ22021，MYOM2，PTENP1，MGC861，CTSF, IL1B, PSMB10, IL1B, ZFP36L2, SFPQ, FLJ1175, ATP2A3, STK10, FLJ22021, MYOM2, PTENP1, MGC861,

HERC1，Jade-1，BTEB1，KIAA1102，NPTX2，UCHL1，LYN，COL5A1，ZNF215，MGC2217，SRISNF2L，LOH11CRZA，HERC1, Jade-1, BTEB1, KIAA1102, NPTX2, UCHL1, LYN, COL5A1, ZNF215, MGC2217, SRISNF2L, LOH11CRZA,

RERE，COL5A1，RAP1B，CLDN15，VWF，HHEX，SMARCA2，SMCY，UBCE71P4，LOC115207，KPNB1，ZNF22，STOM，RERE, COL5A1, RAP1B, CLDN15, VWF, HHEX, SMARCA2, SMCY, UBCE71P4, LOC115207, KPNB1, ZNF22, STOM,

C16orf5，ICAM2，KIAA1102，CENTB1，DKFZP434C171，ITGAM，TFP1，CASP1，CLN2，TAL1，AASS，SAH，FLJ11712，C16orf5, ICAM2, KIAA1102, CENTB1, DKFZP434C171, ITGAM, TFP1, CASP1, CLN2, TAL1, AASS, SAH, FLJ11712,

FXYD5，KIAA0303，FBXL5，SFRS5，FNBP1，FLJ11749，MAGE-E1，SNRK，SPN，CTSS，SIAT1，SCARF1，HSPC047，CD38，FXYD5, KIAA0303, FBXL5, SFRS5, FNBP1, FLJ11749, MAGE-E1, SNRK, SPN, CTSS, SIAT1, SCARF1, HSPC047, CD38,

VAMP5，SF3B3，FLJ10374，FHL1，PTPRCAP，LRBA，DUSP6，PTPRC，KIAA0092，PLA2G4A，RBM5，FLJ21478，PLCB2，VAMP5, SF3B3, FLJ10374, FHL1, PTPRCAP, LRBA, DUSP6, PTPRC, KIAA0092, PLA2G4A, RBM5, FLJ21478, PLCB2,

GOLGIN-67，RBM8A，OXCT，HEM1，DUSP6，CR11，RAB61P1，IMPDH2，C21orf33，LOC93349，EMP3，NASP，MGC40204，GOLGIN-67, RBM8A, OXCT, HEM1, DUSP6, CR11, RAB61P1, IMPDH2, C21orf33, LOC93349, EMP3, NASP, MGC40204,

PTGER2，COL5A1，SPARC，NISCH，SIGLEC5，CSTF2T，HGF，SNX10，DACH，NINJ2，MGC12760，KIAA1332，NPIP，PTGER2, COL5A1, SPARC, NISCH, SIGLEC5, CSTF2T, HGF, SNX10, DACH, NINJ2, MGC12760, KIAA1332, NPIP,

KIAA0379，LYN，H2AFY，PACAP，PLCG2，PDE4D，LOC129080，FLJ11753，KIAA0447，BCL2A1，FUS2，PTPN7，WASF1，KIAA0379, LYN, H2AFY, PACAP, PLCG2, PDE4D, LOC129080, FLJ11753, KIAA0447, BCL2A1, FUS2, PTPN7, WASF1,

ZNF42，C18orf1，UROD，KIAA0303，NRGN，RNASE2，FLJ23056，FYN，DEFCAP，PTPN22，MAPKAPK3，ZFP36L2，AF1Q，ZNF42, C18orf1, UROD, KIAA0303, NRGN, RNASE2, FLJ23056, FYN, DEFCAP, PTPN22, MAPKAPK3, ZFP36L2, AF1Q,

NCF4，CDH7，DJ971N182，PA26，ANXA6，PHGDH，MCL1，LEPROTL1，HUMMHCW1A，TNFRSF14，STK17B，CG149，NCF4, CDH7, DJ971N182, PA26, ANXA6, PHGDH, MCL1, LEPROTL1, HUMMHCW1A, TNFRSF14, STK17B, CG149,

MGC14258，PSIP2，CRJ1，FLJ35827，CCRL2，PTPRN2，CES1，SCA1，FLJ21865，KIAA0798，B1A2，HLA-DQB1，UCP2，MGC14258, PSIP2, CRJ1, FLJ35827, CCRL2, PTPRN2, CES1, SCA1, FLJ21865, KIAA0798, B1A2, HLA-DQB1, UCP2,

DPYSL2，FLJ11259，FLJ20312，KIAA0240，GTL3，C6orf48，AK2，TFR2，FLJ13949，MAX，CHKL，FLJ12668，ALDH2，DPYSL2, FLJ11259, FLJ20312, KIAA0240, GTL3, C6orf48, AK2, TFR2, FLJ13949, MAX, CHKL, FLJ12668, ALDH2,

NUCB2，HPIP，RNF8，C1orf21，AS3，ZNEU1，FLJ11323，FLJ23506，LOC115648，KCND1，STMN1，BTN3A3，MAP4K1，NUCB2, HPIP, RNF8, C1orf21, AS3, ZNEU1, FLJ11323, FLJ23506, LOC115648, KCND1, STMN1, BTN3A3, MAP4K1,

ALG12，ATP5G2，PET112L，TIAF1，KIAA1043，TRPC1，THY28，SYT11，HSU79274，PRPF8，CLC，PCNT2，H2AFY，ALG12, ATP5G2, PET112L, TIAF1, KIAA1043, TRPC1, THY28, SYT11, HSU79274, PRPF8, CLC, PCNT2, H2AFY,

DAPK1，CCL4，RPL28，IFRG28，CCND3，C14orf94，MGC3035，6-Sep，GNB5，KIAA0916，EIF3S7，LENG4，FACL5，AP1S2，DAPK1, CCL4, RPL28, IFRG28, CCND3, C14orf94, MGC3035, 6-Sep, GNB5, KIAA0916, EIF3S7, LENG4, FACL5, AP1S2,

MCM5，DKFZp434N062，A1P1，PROS1，CIRBP，REC8，SLK，C11orf2，dJ222E13.1，H2AV，NEK1，BNIP2，FLJ13197，ITGA4，MCM5, DKFZp434N062, A1P1, PROS1, CIRBP, REC8, SLK, C11orf2, dJ222E13.1, H2AV, NEK1, BNIP2, FLJ13197, ITGA4,

FLJ21269，KIAA0708，IMPA1，FLJ12750，SLC18A2，EMR1，KIAA0239，RPS9，ARHH，MCJ，ALTE，KCNE1L，ABCB1，FLJ21269, KIAA0708, IMPA1, FLJ12750, SLC18A2, EMR1, KIAA0239, RPS9, ARHH, MCJ, ALTE, KCNE1L, ABCB1,

RPL22，KIAA0841，LOC58486，SNX26，ADAMTS1，USP4，STXBP1，ITGA2B，C5orf6，RBM10，FLJ21439，KHK，OS4，RPL22, KIAA0841, LOC58486, SNX26, ADAMTS1, USP4, STXBP1, ITGA2B, C5orf6, RBM10, FLJ21439, KHK, OS4,

MAPK14，NIP30，KIAA0471，SLC16A7，RIN3，DDX28，HPIP，RNASE6，ADSL，ARHG，GNG7，HLA-C，RHOBTB1，MAPK14, NIP30, KIAA0471, SLC16A7, RIN3, DDX28, HPIP, RNASE6, ADSL, ARHG, GNG7, HLA-C, RHOBTB1,

CACNB2，DATF1，PDZ-GEF1，RPL13，TALDO1，DGKG，FLJ22794，PTPN6，SYT11，C5，FLJ22349，FGFR4，CGBP，PROL2，CACNB2, DATF1, PDZ-GEF1, RPL13, TALDO1, DGKG, FLJ22794, PTPN6, SYT11, C5, FLJ22349, FGFR4, CGBP, PROL2,

LARS，RPL3，JIK，MGC45806，MGC2488，MGC2752，TYMS，PECAM1，NSMAF，ABCC1，LEPR，MYB，LAIR1，LOC57209，LARS, RPL3, JIK, MGC45806, MGC2488, MGC2752, TYMS, PECAM1, NSMAF, ABCC1, LEPR, MYB, LAIR1, LOC57209,

EP400，ALCAM，ZNF187，FLJ13386，KPNB1，LTA4H，HGF，PP1628，NRIP1，GNAO1，IL3RA，CD79B，CENTB1，ZNF261，EP400, ALCAM, ZNF187, FLJ13386, KPNB1, LTA4H, HGF, PP1628, NRIP1, GNAO1, IL3RA, CD79B, CENTB1, ZNF261,

ST18，FGF9，CDK10，RA117，STARD5，OXT，PML，KATNB1，ASMTL，NEDD4，ACTA2，MBNL，FLJ31821，PER1，ST18, FGF9, CDK10, RA117, STARD5, OXT, PML, KATNB1, ASMTL, NEDD4, ACTA2, MBNL, FLJ31821, PER1,

MOAP1，DCK，DXS1283E，SNCA，AD7C-NTP，MYBPC2，STX8，ATPAF2，ACYP1，RAD51L1，CL1PR-59，FACL4，AASS，MOAP1, DCK, DXS1283E, SNCA, AD7C-NTP, MYBPC2, STX8, ATPAF2, ACYP1, RAD51L1, CL1PR-59, FACL4, AASS,

RAC2，MGC2306，SLC27A2，FLI2318，RGS1，NAP1L1，ELAC2，LOC51185，SGKL，PCDH16，TRAF5，KIAA0682，DGKZ，RAC2, MGC2306, SLC27A2, FLI2318, RGS1, NAP1L1, ELAC2, LOC51185, SGKL, PCDH16, TRAF5, KIAA0682, DGKZ,

FLJ10539，P1GN，FLJ10647，NCOA1，LBR，GF11，MAN2A2，KRTAP2-4，HLA-C，FLJ35827，PCDHA10，HLA-A，APLP2，FLJ10539, P1GN, FLJ10647, NCOA1, LBR, GF11, MAN2A2, KRTAP2-4, HLA-C, FLJ35827, PCDHA10, HLA-A, APLP2,

SFRS5，FLJ13262，WTAP，EFNA2，C12orf8，CCND2，PTPRC，MPPE1，HMGA2，CLK2，SWAP70，PRO1843，FLJ14280，SFRS5, FLJ13262, WTAP, EFNA2, C12orf8, CCND2, PTPRC, MPPE1, HMGA2, CLK2, SWAP70, PRO1843, FLJ14280,

FLJ23277，KIAA1172，PRCP，MADD，SMARCA2，WASF2，MGC5149，CDC42，PLEK，SMARCF1，RCD-8，ATP9B，IHPK2，FLJ23277, KIAA1172, PRCP, MADD, SMARCA2, WASF2, MGC5149, CDC42, PLEK, SMARCF1, RCD-8, ATP9B, IHPK2,

IGHG3，DHRS4，EEF2，QARS，KIAA0841，ADRA2A，RPL29，GCNT1，UBL3，GRB10，IMP-2，ABCA5，HSPC157，IGHG3, DHRS4, EEF2, QARS, KIAA0841, ADRA2A, RPL29, GCNT1, UBL3, GRB10, IMP-2, ABCA5, HSPC157,

TNFRSF5，H2AV，IM4，TBXA2R，SLC1A4，RPS6KA5，IGLL1，MGC8721，PEPP2，USP7，PSMB8，ARHGDIG，HLA-A，TNFRSF5, H2AV, IM4, TBXA2R, SLC1A4, RPS6KA5, IGLL1, MGC8721, PEPP2, USP7, PSMB8, ARHGDIG, HLA-A,

RBM10，NAP1L1，KIAA1393，AVP，KIAA1018，RPL28，RES4-22，NAP1L1，ST13，KIAA0186，MBNL，HEXA，KIAA0555，RBM10, NAP1L1, KIAA1393, AVP, KIAA1018, RPL28, RES4-22, NAP1L1, ST13, KIAA0186, MBNL, HEXA, KIAA0555,

FLJ20189，MN1，TSPYL，USF2，APLP2，ZNF135，HPS1，RPS21，MAP2K5，HSD17B8，PROSC，NAPIL1，DUT，KIM0170，FLJ20189, MN1, TSPYL, USF2, APLP2, ZNF135, HPS1, RPS21, MAP2K5, HSD17B8, PROSC, NAPIL1, DUT, KIM0170,

TPK1，NY-REN-34，RBIG1，IL16，AKR7A2，STK10，PRP17，WWP2，PTD015，CAPR1，ARHGAP8，FLJ20856，APPBP2，TPK1, NY-REN-34, RBIG1, IL16, AKR7A2, STK10, PRP17, WWP2, PTD015, CAPR1, ARHGAP8, FLJ20856, APPBP2,

LRRN1，MDM1，HLA-DMB，CGI-30，COX11，DDX28，ACK1，TM7SF3，FLJ23554，SDCCAG8，FLJ20094，MMP28，LRRN1, MDM1, HLA-DMB, CGI-30, COX11, DDX28, ACK1, TM7SF3, FLJ23554, SDCCAG8, FLJ20094, MMP28,

MUTYH，CA1，AKR7A2，WDR6，DYRKIA，DPH2L1，RBPMS，FLJ20005，MAP2K5，C4ST，FLJ22059，FLJ20202，H2BFQ，MUTYH, CA1, AKR7A2, WDR6, DYRKIA, DPH2L1, RBPMS, FLJ20005, MAP2K5, C4ST, FLJ22059, FLJ20202, H2BFQ,

CAMLG，CHAFIA，ABLIMI，MAPK11，RAP140，DUT，ITSN2，EHHADH，DKFZP547E2110，H2AFJ，MGC4659，RPL13，CAMLG, CHAFIA, ABLIMI, MAPK11, RAP140, DUT, ITSN2, EHHADH, DKFZP547E2110, H2AFJ, MGC4659, RPL13,

KCNA3，BC008967，CASP1，NMI，NBEA，NUMA1，DEF6，PRAX-1，TBC1D5，KIAA0332，NEWlCP，KIAA0769，CENTB2，KCNA3, BC008967, CASP1, NMI, NBEA, NUMA1, DEF6, PRAX-1, TBC1D5, KIAA0332, NEWlCP, KIAA0769, CENTB2,

CK1P-1，EIF4A2，OAZ，ARH，KIAA0467，C19orf7，KCNAB2，TTLL1，FLJ10597，SF3A2，FLJ11222，PSTPIP2，BCL11A，CK1P-1, EIF4A2, OAZ, ARH, KIAA0467, C19orf7, KCNAB2, TTLL1, FLJ10597, SF3A2, FLJ11222, PSTPIP2, BCL11A,

SPHAR，GLIPR1，KIAA0555，MMP2，EIF4A1，STOM，ALOX12，FLJ11588，RBAF600，PROSC，CG005，VILL，FLJ12707，SPHAR, GLIPR1, KIAA0555, MMP2, EIF4A1, STOM, ALOX12, FLJ11588, RBAF600, PROSC, CG005, VILL, FLJ12707,

M6A，TCIRG1，HTR1F，RICH1，F13A1，CACNA2D3，RRP4，TAF7，ZNF134，HSU53209，LZTFL1，TKT，LILRA2，ZNF302，M6A, TCIRG1, HTR1F, RICH1, F13A1, CACNA2D3, RRP4, TAF7, ZNF134, HSU53209, LZTFL1, TKT, LILRA2, ZNF302,

FLJ13114，ZNF177，PURA，DKFZp5471014，TXN2，TLR3，BHC80，MGC5139，PTPNS1，ZNF145，THTPA，BTBD3，FLJ13114, ZNF177, PURA, DKFZp5471014, TXN2, TLR3, BHC80, MGC5139, PTPNS1, ZNF145, THTPA, BTBD3,

MDS010，KIAA0924，ZNF292，ITGB2，TJP4，GPRK6，CYLN2，ENPP4，ALB，RPS20，FOXOIA，ADH5，CTSS，FLJ23221，MDS010, KIAA0924, ZNF292, ITGB2, TJP4, GPRK6, CYLN2, ENPP4, ALB, RPS20, FOXOIA, ADH5, CTSS, FLJ23221,

C11orf8，TNFSF13，TOLLIP，KIAA1449，HINT1，GLTSCR2，KIAA1052，FLJ10260，RAB3GAP，HINT1，TAPBP，CHD5，C11orf8, TNFSF13, TOLLIP, KIAA1449, HINT1, GLTSCR2, KIAA1052, FLJ10260, RAB3GAP, HINT1, TAPBP, CHD5,

LOC57406，TP53TG1，SRP46，MS4A4A，NUP62，P1M1，ZNF42，COG4，ADPRTL1，ZNF289，CATSPER2，TXNIP，PDE4D1P，LOC57406, TP53TG1, SRP46, MS4A4A, NUP62, P1M1, ZNF42, COG4, ADPRTL1, ZNF289, CATSPER2, TXNIP, PDE4D1P,

HSA250839，FUT4，HSPA1L，GALT，MGC4278，APEX1，FN5，STRIN，USP11，SPP1，NPFF，CEP1，GAPCENA，HLA-E，HSA250839, FUT4, HSPA1L, GALT, MGC4278, APEX1, FN5, STRIN, USP11, SPP1, NPFF, CEP1, GAPCENA, HLA-E,

SCAND2，CG005，VRP，BRAP，GPR56，MLH1，GPR105，OGT，ClR，BTN3A1，FLJ14107，PACS1，MGC26766，FLJ22378，SCAND2, CG005, VRP, BRAP, GPR56, MLH1, GPR105, OGT, ClR, BTN3A1, FLJ14107, PACS1, MGC26766, FLJ22378,

APOBEC3C，CG005，CA11，QDPR，DUT，ALDH6A1，FLJ10450，BST1，NGLY1，FLJ12057，FECH，ZNF137，SERPINB1，APOBEC3C, CG005, CA11, QDPR, DUT, ALDH6A1, FLJ10450, BST1, NGLY1, FLJ12057, FECH, ZNF137, SERPINB1,

EZH1，cASP1，MGC3265，CXorf9，TRG@，DKFZp564B0769，KIAA0616，D1S155E，MN7，C18orf1，NSBP1，NXF1，FHL1，EZH1, cASP1, MGC3265, CXorf9, TRG@, DKFZp564B0769, KIAA0616, D1S155E, MN7, C18orf1, NSBP1, NXF1, FHL1,

TOP3A，TARBP1，KIAA0766，RRAS，SEMA4D，CEBPA，TIP120A，IL15，HADHSC，H1RIP3，CTBP1，DVL2，RBM12，TOP3A, TARBP1, KIAA0766, RRAS, SEMA4D, CEBPA, TIP120A, IL15, HADHSC, H1RIP3, CTBP1, DVL2, RBM12,

RAD54L，NYD-SP15，PHC1，KIAA1042，IGL@，NPR3，HRMT1L1，FLJ20551，MYST1，LOC51231，TCF12，KIAA0543，RAD54L, NYD-SP15, PHC1, KIAA1042, IGL@, NPR3, HRMT1L1, FLJ20551, MYST1, LOC51231, TCF12, KIAA0543,

MKPX，LOC51157，SYNGR1，AKR1A1，SCOP，LRRN1，FY，AMY1A，PHEMX，KIAA0930，MAP3K3，FLJ10631，ZNF85，MKPX, LOC51157, SYNGR1, AKR1A1, SCOP, LRRN1, FY, AMY1A, PHEMX, KIAA0930, MAP3K3, FLJ10631, ZNF85,

APOL3，MAPK12，TRG@，POLD1，LDOC1，POLA，TPST2，WASF3，RPL11，MKL1，FLJ22242，PTPRM，AMHR2，APOL3, MAPK12, TRG@, POLD1, LDOC1, POLA, TPST2, WASF3, RPL11, MKL1, FLJ22242, PTPRM, AMHR2,

FLJ20288，TERF2，DOK4，KCNAB1，D1SC1，FLJ22494，LOC91316，VIP，POLR2A，RGS19，C12orf6，RPS9，LIG1，NASP，FLJ20288, TERF2, DOK4, KCNAB1, D1SC1, FLJ22494, LOC91316, VIP, POLR2A, RGS19, C12orf6, RPS9, LIG1, NASP,

ARHGEF9，MANBA，SARM，SRPR，CDH9，MRPL16，FLJ20509，SNRPN，HLA-E，NTS，ZNF232，FLJ12903，PHKA2，ARHGEF9, MANBA, SARM, SRPR, CDH9, MRPL16, FLJ20509, SNRPN, HLA-E, NTS, ZNF232, FLJ12903, PHKA2,

MSH5，PURA，ATP9B，TRM28，FLJ12768，ME2，IDS，MPHOSPH9，DIA1，ADAM8，HADHSC，STX12，cOX15，RPA2，MSH5, PURA, ATP9B, TRM28, FLJ12768, ME2, IDS, MPHOSPH9, DIA1, ADAM8, HADHSC, STX12, cOX15, RPA2,

SHANK1，GGA1，LANCL1，UBE3A，SOX11，LAT，BCL7A，DKFZp434K1210，BRAP，SMARCC2，DKFZP434H132，SHANK1, GGA1, LANCL1, UBE3A, SOX11, LAT, BCL7A, DKFZp434K1210, BRAP, SMARCC2, DKFZP434H132,

NHP2L1，FLJ11294，FLJ12270，KIAA1649，SRP46，PSMB9，GGA1，MGC4368，TOP2B，PTK2B，FLJ13912，EZH1，THRA，NHP2L1, FLJ11294, FLJ12270, KIAA1649, SRP46, PSMB9, GGA1, MGC4368, TOP2B, PTK2B, FLJ13912, EZH1, THRA,

BAX，NAG，MERTK，HADHA，SRRM2，HNRPH3，GNG7，HSPC018，FLJ22573，HPCALA，MBC2，MAPK4，FLJ10716，BAX, NAG, MERTK, HADHA, SRRM2, HNRPH3, GNG7, HSPC018, FLJ22573, HPCALA, MBC2, MAPK4, FLJ10716,

ITGAL，NFRKB，MRP63，DKFZP434L187，GABARAP，CHD4，DKFZP564D172，FGL2，IOC57019，KIAA0478，NTSR1，ITGAL, NFRKB, MRP63, DKFZP434L187, GABARAP, CHD4, DKFZP564D172, FGL2, IOC57019, KIAA0478, NTSR1,

LP1N1，USP4，KIAAA0391，ASGR1，KIAA0174，TBXA2R，TRAP95，FLJ22649，NEK3，ZNF271，SILI，76P，CYLD，CD164，LP1N1, USP4, KIAAA0391, ASGR1, KIAA0174, TBXA2R, TRAP95, FLJ22649, NEK3, ZNF271, SILI, 76P, CYLD, CD164,

TINF2，ZNF220，DAB2，HRIHFB2206，SF3A3，TRO，FLJ13373，UBE4B，GC20，ADAM28，PHKB，BCAS3，MGC14258，TINF2, ZNF220, DAB2, HRIHFB2206, SF3A3, TRO, FLJ13373, UBE4B, GC20, ADAM28, PHKB, BCAS3, MGC14258,

RAD52，HLA-F，KIAA0721，MRC1，CHD1L，LMOD1，FLJ10315，CHRNA7，NAP1L1，PIB5PA，GADD45A，RPL35A，RAD52, HLA-F, KIAA0721, MRC1, CHD1L, LMOD1, FLJ10315, CHRNA7, NAP1L1, PIB5PA, GADD45A, RPL35A,

LPIN1，TFP1，FLJ14213，KIAA0746，KIAA0981，C22orf4，PP1044，ABCF2，FLJ10379，RASSF1，FLJ23392，RPS8，DAB2，LPIN1, TFP1, FLJ14213, KIAA0746, KIAA0981, C22orf4, PP1044, ABCF2, FLJ10379, RASSF1, FLJ23392, RPS8, DAB2,

FLJ14011，CDC2L2，GAD1，MGC17330，FLJ23342，HEI10，NPDC1，KIAA0710，BIRC1，KIAA0349，SF3B3，MST4，IRAK3，FLJ14011, CDC2L2, GAD1, MGC17330, FLJ23342, HEI10, NPDC1, KIAA0710, BIRC1, KIAA0349, SF3B3, MST4, IRAK3,

CD81，LOC57406，FLJ12610，SF1，SLC27A2，KIAA0804，KIAA1055，GTF2F1，SEPX1，SCAMP2，PPP3CB，U5-200KD，CD81, LOC57406, FLJ12610, SF1, SLC27A2, KIAA0804, KIAA1055, GTF2F1, SEPX1, SCAMP2, PPP3CB, U5-200KD,

HMGN2，F2，PCBP3，FLJ20721，ING4，HADHSC，KIAA0286，TREX1，ATP11B，RUFY2，SUPT3H，SFS11，P1AS1，HBOA，HMGN2, F2, PCBP3, FLJ20721, ING4, HADHSC, KIAA0286, TREX1, ATP11B, RUFY2, SUPT3H, SFS11, P1AS1, HBOA,

HAS1，HYMAI，NUP210，TGT，FLJ11896，CIDEB，TRHDE，FLJ90524，TOX，KIAA0261，GSTM2，GAS7，MBD1，HAS1, HYMAI, NUP210, TGT, FLJ11896, CIDEB, TRHDE, FLJ90524, TOX, KIAA0261, GSTM2, GAS7, MBD1,

KIAA1305，PPP2R2B，CDT1，FLJ11164，TMPRSS2，TYROBP，G6PT1，PRM1，GP5，DKFZP566H073，RPS14，CCNG1，KIAA1305, PPP2R2B, CDT1, FLJ11164, TMPRSS2, TYROBP, G6PT1, PRM1, GP5, DKFZP566H073, RPS14, CCNG1,

FANCG，CMAH，SORBS1，KIAA0800，C1QTNF3，UBCE71P5，FXR1，ZNF334，CNN2，RFC5，ACAA2，GNB1，FLJ22757，FANCG, CMAH, SORBS1, KIAA0800, C1QTNF3, UBCE71P5, FXR1, ZNF334, CNN2, RFC5, ACAA2, GNB1, FLJ22757,

CDKN1C，UROD，KIAA1028，HD，CTSG，CLNS1A，P2RX1，TACC1，ADH5，RPL13A，ZNF363，PRKCH，AF020591，CDKN1C, UROD, KIAA1028, HD, CTSG, CLNS1A, P2RX1, TACC1, ADH5, RPL13A, ZNF363, PRKCH, AF020591,

LOC51659，PER1，TFP1，TSN，BM11，K1AA0625，MLLT2，TAF1C，DHFR，SLC23A1，HAGE，NAP1L4，EGFL3，SCA2，LOC51659, PER1, TFP1, TSN, BM11, K1AA0625, MLLT2, TAF1C, DHFR, SLC23A1, HAGE, NAP1L4, EGFL3, SCA2,

FLJ20489，SNAP25，USF2，CRYL1，GG2-1，EDN3，TRPC1，AP1S2，ERCC1，KIAA0582，RPL15，LOC54103，FLJ22557，CG1-FLJ20489, SNAP25, USF2, CRYL1, GG2-1, EDN3, TRPC1, AP1S2, ERCC1, KIAA0582, RPL15, LOC54103, FLJ22557, CG1-

127，CSNK2A2，ZNF278，EDG5，IPW，RASGRP2，SAE1，KIAA0725，RTN2，CTNS，FLJ20274，FLJ10276，LTBP4，FLJ10539，127, CSNK2A2, ZNF278, EDG5, IPW, RASGRP2, SAE1, KIAA0725, RTN2, CTNS, FLJ20274, FLJ10276, LTBP4, FLJ10539,

HYAL3，MTL5，MGEA6，BN1P3L，PARVB，MGC15523，KCNK7，IGHM，PASK，KIDINS220，PCM1，KIAA0092，ASB9，HYAL3, MTL5, MGEA6, BN1P3L, PARVB, MGC15523, KCNK7, IGHM, PASK, KIDINS220, PCM1, KIAA0092, ASB9,

MAP3K4，CDlB，COL6A1，HCA127，ZNF262，GG2-1，CAPN3，SAP18，EIF3S5，ZNF337，EIF4Al，DBT，CROT，FLJ10474，MAP3K4, CDlB, COL6A1, HCA127, ZNF262, GG2-1, CAPN3, SAP18, EIF3S5, ZNF337, EIF4Al, DBT, CROT, FLJ10474,

FLJ10483，CBX8，DKFZP586M1523，CCRL1AP，FLJ14153，KIAA0397，COL2A1，CD164，TLE4，PRO2730，ATM，RFX5，FLJ10483, CBX8, DKFZP586M1523, CCRL1AP, FLJ14153, KIAA0397, COL2A1, CD164, TLE4, PRO2730, ATM, RFX5,

KIAA05l5，FLJ20542，HYPH，ERG-1，DBH，SCML2，GNAO1，WDR13，GCA，FLJ23323，FLJ11362，CGBP，MGAT1，KIAA05l5, FLJ20542, HYPH, ERG-1, DBH, SCML2, GNAO1, WDR13, GCA, FLJ23323, FLJ11362, CGBP, MGAT1,

HMGB2，NDUFA6，KIAA0515，KIF13A，OPA1，BRD1，ATP2B4，PSME1，KIAA0931，HPS4，KIAA1966，DKFZP564J0123，HMGB2, NDUFA6, KIAA0515, KIF13A, OPA1, BRD1, ATP2B4, PSME1, KIAA0931, HPS4, KIAA1966, DKFZP564J0123,

DBY，HUMNPIlY20，MAT2A，DFFB，FLJ20294，ADSL，CSTF2T，，ZNFNIA1，LOC51194，FLJ21269，DJ79P11.1，BCAT1，DBY, HUMNPIlY20, MAT2A, DFFB, FLJ20294, ADSL, CSTF2T,, ZNFNIA1, LOC51194, FLJ21269, DJ79P11.1, BCAT1,

MGC21854，DKFZP586D0824，EMCN，C21orf91，SDPR，PRO1635，ITGA4，FLJ20171，ROBO4，ZNF6，DRLM，TAGAP，MGC21854, DKFZP586D0824, EMCN, C21orf91, SDPR, PRO1635, ITGA4, FLJ20171, ROBO4, ZNF6, DRLM, TAGAP,

PRDM16，ST6GallI，GNA11，EHZF，MGC10966，ARHGAP9，HEMGN，GNG2，LOC83690，PTGS1，MGC41924，USP2，PRDM16, ST6GallI, GNA11, EHZF, MGC10966, ARHGAP9, HEMGN, GNG2, LOC83690, PTGS1, MGC41924, USP2,

FLJ33069，CT2，C4ST3，PRAM-1，FLJ32122，SLC11A3，BIC，TNFSSF13B，FLJ37080，FLJ35564，KIAA1913，CDH26，FLJ33069, CT2, C4ST3, PRAM-1, FLJ32122, SLC11A3, BIC, TNFSSF13B, FLJ37080, FLJ35564, KIAA1913, CDH26,

BCL11A，FLJ30046，MGC7036，DKFZP566N034，RARA，C1orf21，PAG，SH2D3C，FLJ00026，STIP-1，FLJ39957，KLHL6，BCL11A, FLJ30046, MGC7036, DKFZP566N034, RARA, C1orf21, PAG, SH2D3C, FLJ00026, STIP-1, FLJ39957, KLHL6,

VIK，FLJ34922，SHANK3，FLJ00026，PTPN22，HRB2，ZDHHC2，DKFZP566K1924，SYTL4，DACH，FLJ21986，EVIN2，VIK, FLJ34922, SHANK3, FLJ00026, PTPN22, HRB2, ZDHHC2, DKFZP566K1924, SYTL4, DACH, FLJ21986, EVIN2,

GAB3，CYYR1，MMP28，EHZF，FLJ00058，LOC93589，KLF12，CLLD8，KIAA1218，MGC16179，HS3ST3B1，ARHGAP9，GAB3, CYYR1, MMP28, EHZF, FLJ00058, LOC93589, KLF12, CLLD8, KIAA1218, MGC16179, HS3ST3B1, ARHGAP9,

LOC144402，LOC114928，FLJ39370，PRKACB，MGC13105，Ells1，CGI-145，EPB41L5，RAB39B，LOC145553，HRB2，LOC144402, LOC114928, FLJ39370, PRKACB, MGC13105, Ells1, CGI-145, EPB41L5, RAB39B, LOC145553, HRB2,

SDCCAG33，ARRB1，EEF1A1，MGC12992，BBX，DAP10，CMG2，GPR27，GBP5，FLJ20202，UCC1，RAD52B，KIAA1554，SDCCAG33, ARRB1, EEF1A1, MGC12992, BBX, DAP10, CMG2, GPR27, GBP5, FLJ20202, UCC1, RAD52B, KIAA1554,

AKNA，TBXAS1，al/3GTP，JAK3，B2M，MGC20496，CLLD8，ALEX3，FLJ21438，MJD，FLJ22570，APlS2，TFDP2，P5CR2，AKNA, TBXAS1, al/3GTP, JAK3, B2M, MGC20496, CLLD8, ALEX3, FLJ21438, MJD, FLJ22570, APlS2, TFDP2, P5CR2,

C1orf21，KIAA1554，EvIL，MGC8721，FACL5，CYSLTRl，CTSS，Rgr，NID67，FLJ32194，MGC45400，KIAA1789，DCP1B，C1orf21, KIAA1554, EvIL, MGC8721, FACL5, CYSLTRl, CTSS, Rgr, NID67, FLJ32194, MGC45400, KIAA1789, DCP1B,

MGC4251，CPXM，SMBP，PARVG，ESRRBL1，C6orO3，MGC20262，C6orf33，MGC27027，LOC51234，ZNF33A，RGS18，MGC4251, CPXM, SMBP, PARVG, ESRRBL1, C6orO3, MGC20262, C6orf33, MGC27027, LOC51234, ZNF33A, RGS18,

KIAA1607，TIGAI，HOXA7，NAALADASEL，ATP8B2，CLYBL，DKFZP727G051，KIAA1214，WHIP，IRF5，UBL5，KIAA1607, TIGAI, HOXA7, NAALADASEL, ATP8B2, CLYBL, DKFZP727G051, KIAA1214, WHIP, IRF5, UBL5,

KIAA1946，GLTSCR2，CMG2，OSM，KIAA0748，FLJ11113，FLJ12994，ERO1-L(BETA)，NUCB2，KIAA1337，DEF6，POLH，KIAA1946, GLTSCR2, CMG2, OSM, KIAA0748, FLJ11113, FLJ12994, ERO1-L(BETA), NUCB2, KIAA1337, DEF6, POLH,

FLJ11712，LOC91526，TTYH2，ACRBP，MAML3，FLJ00012，C6orf37，MYH11，C9orf24，HNRPD，CCNDBP1，FLJ11712, LOC91526, TTYH2, ACRBP, MAML3, FLJ00012, C6orf37, MYH11, C9orf24, HNRPD, CCNDBP1,

DKFZP434L0117，GPR114，ANKH，MGC13170，NOG，CXorf10，C1QTNF4，NAV1，RPIB9，DKFZp571K0837，SFXN1，DKFZP434L0117, GPR114, ANKH, MGC13170, NOG, CXorf10, C1QTNF4, NAV1, RPIB9, DKFZp571K0837, SFXN1,

KIAA1497，PHACS，PAPOLA，ELAC1，MDS006，FLJ14167，LOC136895，CcGGBP1，MGc45962，CGI-85，AUTS2，FXYD5，KIAA1497, PHACS, PAPOLA, ELAC1, MDS006, FLJ14167, LOC136895, CcGGBP1, MGc45962, CGI-85, AUTS2, FXYD5,

FLJ32009，FGD3，HSAJ1454，GRP58，KIAA1954，ELD/OSAl，PRex1，MGC11324，FLJ90013，NIN283，HCA127，FLJ32009, FGD3, HSAJ1454, GRP58, KIAA1954, ELD/OSAl, PRex1, MGC11324, FLJ90013, NIN283, HCA127,

DIKFZP564D1378，HMGB1，TRB@，MGC4796，ASE-1，YR-29，FLJ25476，CGI-67，STK33，SLC25A21，ZNFN1A1，DRLM，DIKFZP564D1378, HMGB1, TRB@, MGC4796, ASE-1, YR-29, FLJ25476, CGI-67, STK33, SLC25A21, ZNFN1A1, DRLM,

PP2135，STMN3，CAMK2G，MGC16169，DC6，GCNT1，PRO1635，STRIN，DLC1，DKFZp761D221，FLJ10656，ZNFN1A4，PP2135, STMN3, CAMK2G, MGC16169, DC6, GCNT1, PRO1635, STRIN, DLC1, DKFZp761D221, FLJ10656, ZNFN1A4,

SENP7，MGC34827，MGC15619，FLJ32942，RPL28，FLJ00005，FLJ23462，DKFZp762L0311，FLJ30726，MGC3200，ARRB1，SENP7, MGC34827, MGC15619, FLJ32942, RPL28, FLJ00005, FLJ23462, DKFZp762L0311, FLJ30726, MGC3200, ARRB1,

EIF3S7，HSA9761，FLJ11896，MGC10744，KIAA1309，WDR9，KIAA1587，MIR，FLJ12953，MGC12921，LOC130617，NAV1，EIF3S7, HSA9761, FLJ11896, MGC10744, KIAA1309, WDR9, KIAA1587, MIR, FLJ12953, MGC12921, LOC130617, NAV1,

HPSE，FLJ20085，KIAA1982，KCNK17，KIAA1495，LOC64744，AUTL1，LOC91689，SEPP1，PPP2CA，KHDRBS1，DREV1，HPSE, FLJ20085, KIAA1982, KCNK17, KIAA1495, LOC64744, AUTL1, LOC91689, SEPP1, PPP2CA, KHDRBS1, DREV1,

MGC35274，SNRPE，LOC91689，KIAA0853，FLJ13215，TACC1，MGC20262，MGC17515，MGC40157，DKFZP572C163，MGC35274, SNRPE, LOC91689, KIAA0853, FLJ13215, TACC1, MGC20262, MGC17515, MGC40157, DKFZP572C163,

PRPF8，HINT1，FUS1P1，MEF2D，C20orf24，TADA2L，NlN283，FS，HSPC063，ALS2，NHP2L1，LGALS12，MGC10986，PRPF8, HINT1, FUS1P1, MEF2D, C20orf24, TADA2L, NlN283, FS, HSPC063, ALS2, NHP2L1, LGALS12, MGC10986,

KlAA1871，DKFZP434A0131，KIAA1949，DTNBP1，GPHN，SUV39H2，BRD7，FL32001，HYPc，EEF2K，ESRRB，ZNF226，KlAA1871, DKFZP434A0131, KIAA1949, DTNBP1, GPHN, SUV39H2, BRD7, FL32001, HYPc, EEF2K, ESRRB, ZNF226,

IL18BP，CSRP2BP，HEMGN，FOXP1，SGKL，FLJ11220，TRIM4，FLJ21918，KIAA1545，MGC2474，CDCA7，HSPC002，IL18BP, CSRP2BP, HEMGN, FOXP1, SGKL, FLJ11220, TRIM4, FLJ21918, KIAA1545, MGC2474, CDCA7, HSPC002,

LOC115294，LOC119710，GTF3A，TAGAP，TCF7L2，FLJ22690，OAZIN，TRAP1，MGC42174，MGC9850，KIAA1632，LOC115294, LOC119710, GTF3A, TAGAP, TCF7L2, FLJ22690, OAZIN, TRAP1, MGC42174, MGC9850, KIAA1632,

HSU53209，BlVM，BAALC，WHSC1，C16orf5，KIAA1238，MRS2L，CGI-105，ZDHHC2，LOC143903，DKFZp762N0610，HSU53209, BlVM, BAALC, WHSC1, C16orf5, KIAA1238, MRS2L, CGI-105, ZDHHC2, LOC143903, DKFZp762N0610,

NSE1，OSBPL7，HAVCR2，ASAHL，KlAA1798，TLR4，MGC10946，PRexl，FLJ31340，TAHCCP1，C20orf141，FLJ20313，NSE1, OSBPL7, HAVCR2, ASAHL, KlAA1798, TLR4, MGC10946, PRexl, FLJ31340, TAHCCP1, C20orf141, FLJ20313,

TAF9L，FRSB，PRKRA，P66，KIAA0141，RARA，BANP，FLJ00007，DTNBP1，LRP5，KIAA1337，MGC29667，WHSC1，TAF9L, FRSB, PRKRA, P66, KIAA0141, RARA, BANP, FLJ00007, DTNBP1, LRP5, KIAA1337, MGC29667, WHSC1,

MMP28，EVIN2，Cab45，CED-6，PTER，ZNFN2A1，NDP52，CHES1，KIAA1635，NFAT5，FLJ32332，HTRA3，MAP4K1，MMP28, EVIN2, Cab45, CED-6, PTER, ZNFN2A1, NDP52, CHES1, KIAA1635, NFAT5, FLJ32332, HTRA3, MAP4K1,

KIAA1337，AP1S2，FLJ23306，HP1-BP74，KIAA1218，BTBD4，DKFZp761F0118，MGC16703，BAZ2B，MU，FLJ13614，KIAA1337, AP1S2, FLJ23306, HP1-BP74, KIAA1218, BTBD4, DKFZp761F0118, MGC16703, BAZ2B, MU, FLJ13614,

MYO15B，OAZIN，LOC92799，CANX，SUFU，KIAA1954，AGS3，LAPTM4A，HP1-BP74，FLJ23467，FLJ12892，MGC40042，MYO15B, OAZIN, LOC92799, CANX, SUFU, KIAA1954, AGS3, LAPTM4A, HP1-BP74, FLJ23467, FLJ12892, MGC40042,

KIAA1143，RPL11，LSR7，CENpJ，NY-REN-58，NRM，FLJ23563，WASF2，AMBP，NIP30，EIF2AK4，MGC15429，TTC7L1，KIAA1143, RPL11, LSR7, CENpJ, NY-REN-58, NRM, FLJ23563, WASF2, AMBP, NIP30, EIF2AK4, MGC15429, TTC7L1,

NICN1，FXC1，FLJ20793，SOC，RPL13，HYPC，CLONE24945，MGC24663，TEM7R，FLJ14768，DKFZp667M2411，STARD9，NICN1, FXC1, FLJ20793, SOC, RPL13, HYPC, CLONE24945, MGC24663, TEM7R, FLJ14768, DKFZp667M2411, STARD9,

FOXP1，ELP3，K1AA1337，CDA017，PPP6C，PAK1，FLJ10876，EPC1，ZNF397，C21orf63，KIAA1805，MIR，CYYR1，FOXP1, ELP3, K1AA1337, CDA017, PPP6C, PAK1, FLJ10876, EPC1, ZNF397, C21orf63, KIAA1805, MIR, CYYR1,

DKFFZp564B0769，EPST11，MDM4，MGC23947，MGC14421，SDCCAG33，DKFZp762O076，LOC93109，STN2，HSMPP8，DKFFZp564B0769, EPST11, MDM4, MGC23947, MGC14421, SDCCAG33, DKFZp762O076, LOC93109, STN2, HSMPP8,

FLJ20265，LOC85028，MGC15435，1-Sep，MGC41917，MS12，Jade-1，IL17D，MGC2752，MATR3，PRKRA，FLJ20265, LOC85028, MGC15435, 1-Sep, MGC41917, MS12, Jade-1, IL17D, MGC2752, MATR3, PRKRA,

DKFZp434C1714，MGC4415，DKFZP727C091，MY038，FLJ35453，FLJ30794，DJ462O23.2，FLJ90130，FLJ22283，EEF2，DKFZp434C1714, MGC4415, DKFZP727C091, MY038, FLJ35453, FLJ30794, DJ462O23.2, FLJ90130, FLJ22283, EEF2,

LOC155066，ATPAF1，FLJ23499，STAM2，LOC85028，FLJ21709，LOC51279，TRA@，JAM3，SIAT6，KIAA1453，EIF2S3，LOC155066, ATPAF1, FLJ23499, STAM2, LOC85028, FLJ21709, LOC51279, TRA@, JAM3, SIAT6, KIAA1453, EIF2S3,

LSR7，ROCK1，DKFZP56611024，FANCD2，MEF-2，MGC2664，MGC15548，ZNF75A，HSPC126，EIF3S5，RBM7，FLJ20280，LSR7, ROCK1, DKFZP56611024, FANCD2, MEF-2, MGC2664, MGC15548, ZNF75A, HSPC126, EIF3S5, RBM7, FLJ20280,

GSTA4，SEPP1，TIGD3，DKFZP434A1319，MCLC，MGC14136，DKFZP762N2316，LOC115330，D4ST-1，UCP4，PRMT6，GSTA4, SEPP1, TIGD3, DKFZP434A1319, MCLC, MGC14136, DKFZP762N2316, LOC115330, D4ST-1, UCP4, PRMT6,

LAK，NIN，FLJ10997，RAB4B，LMO4，RRN3，CENPH，FLJ23277，GBTS1，FLJ90013，LOC115509，PP2135，FLJ36175，LAK, NIN, FLJ10997, RAB4B, LMO4, RRN3, CENPH, FLJ23277, GBTS1, FLJ90013, LOC115509, PP2135, FLJ36175,

SPINO，PA1P2，DKFZp761G0122，ATF71P，WBP1，MGC29937，MGC9564，CASP2，TIGD7，C4S-2，MGC25181，LOC89887，SPINO, PA1P2, DKFZp761G0122, ATF71P, WBP1, MGC29937, MGC9564, CASP2, TIGD7, C4S-2, MGC25181, LOC89887,

KIAA1387，FLJ22283，GIT2，MIR，SSBP3，LOC159090，U5-200KD，FLJ10997，ZNF295，PGBD1，HEL308，POLH，AP3M1，KIAA1387, FLJ22283, GIT2, MIR, SSBP3, LOC159090, U5-200KD, FLJ10997, ZNF295, PGBD1, HEL308, POLH, AP3M1,

NOREI，SEMA6D，PPID，CUL5，LOC91663，FLJ13171，BAT4，RPLPl，KIAA1630，CT2，HSPC182，HMGB1，FLJ20280，NOREI, SEMA6D, PPID, CUL5, LOC91663, FLJ13171, BAT4, RPLPl, KIAA1630, CT2, HSPC182, HMGB1, FLJ20280,

FKBP5，EIF3S6，C15orf15，TRPC7，FLJ31153，TA-KRP，MGC17919，AP2A1，C20orf132，SECP43，PPIL2，FLJ14494，YARS，FKBP5, EIF3S6, C15orf15, TRPC7, FLJ31153, TA-KRP, MGC17919, AP2A1, C20orf132, SECP43, PPIL2, FLJ14494, YARS,

MGC10974，cLN6，C20orf81，U2AF1，KIAA1238，FLJ23861，LOC144455，DKFZp564D177，NIP30，TBC1Dl，ZNF265，和MGC10974, cLN6, C20orf81, U2AF1, KIAA1238, FLJ23861, LOC144455, DKFZp564D177, NIP30, TBC1Dl, ZNF265, and

PPP4R2.PPP4R2.

                            表8Table 8

                  优选的实体癌干细胞癌标记Preferred Solid Cancer Stem Cell Cancer Markers

Bmi-1、eed、easyh1、easyh2、rnf2、yy1、smarcA3、smarckA5、Bmi-1, eed, easyh1, easyh2, rnf2, yy1, smarcA3, smarckA5,

smarcD3、smarcE1、m11t3、frizzled2、frizzled6、frizzled7、smarcD3, smarcE1, m11t3, frizzled2, frizzled6, frizzled7,

mf2、Frizzled1、Frizzled2、Frizzled4、Frizzled10、Frizzled6、mf2, Frizzled1, Frizzled2, Frizzled4, Frizzled10, Frizzled6,

FZD1、FZD2、FZD3、FZD4、FZD6、FZD7、FZD8、FZD9、FZD10、WNT2、FZD1, FZD2, FZD3, FZD4, FZD6, FZD7, FZD8, FZD9, FZD10, WNT2,

WNT2B、WNT3、WNT5A、WNT10B、WNT16、AXIN1、BCL9、MYC、(TCF4)、WNT2B, WNT3, WNT5A, WNT10B, WNT16, AXIN1, BCL9, MYC, (TCF4),

SLC7A8、ILlRAP、TEM8、TMPRSS4、MUC16、GPRC5B、SLC6A14、SLC4A11、SLC7A8, ILlRAP, TEM8, TMPRSS4, MUC16, GPRC5B, SLC6A14, SLC4A11,

PPAP2C、CAV1、CAV2、PTPN3、EPHA1、SLC1A1、CX3CL1、ADORA2A、PPAP2C, CAV1, CAV2, PTPN3, EPHA1, SLC1A1, CX3CL1, ADORA2A,

MPZL1、FLJ10052、C4.4A、EDG3、RARRES1、TMEPAI、PTS、CEACAM6、MPZL1, FLJ10052, C4.4A, EDG3, RARRES1, TMEPAI, PTS, CEACAM6,

NID2、STEAP、ABCA3、CRIM1、IL1R1、OPN3、DAF、MUC1、MCP、CPD、NID2, STEAP, ABCA3, CRIM1, IL1R1, OPN3, DAF, MUC1, MCP, CPD,

NMA、ADAM9、GJA1、CD14、SLC19A2、ABCA1、PCDH7、ADCY9、SLC39A1、NMA, ADAM9, GJA1, CD14, SLC19A2, ABCA1, PCDH7, ADCY9, SLC39A1,

NPC1、ENPP1、N33、GPNMB、LY6E、CELSR1、LRP3、C20orf52、TMEPAI、NPC1, ENPP1, N33, GPNMB, LY6E, CELSR1, LRP3, C20orf52, TMEPAI,

FLVCR、PCDHA10、GPR54、TGFBR3、SEMA4B和PCDHB2。FLVCR, PCDHA10, GPR54, TGFBR3, SEMA4B, and PCDHB2.

使用例如下面实施例4中描述的方法可鉴定另外的实体瘤干细胞癌标记。Additional solid tumor stem cell cancer markers can be identified using, for example, the methods described in Example 4 below.

IV.实体癌干细胞癌标记的检测IV. Detection of cancer markers in solid cancer stem cells

在一些实施方案中，本发明提供了用于检测干细胞癌标记(例如，乳腺癌干细胞癌标记)表达的方法。在优选的实施方案中，直接测量表达(例如，在RNA或蛋白的水平)。在一些实施方案中，在组织样品(例如，生物活检组织)中检测表达。在其它实施方案中，在体液(例如包括但不限于，血浆、血清、全血、粘液和尿)中检测表达。本发明进一步提供了用于检测标记的套组(panel)和试剂盒。在优选的实施方案中，干细胞癌标记的存在用于提供对受试者的预后。提供的信息也用于指导治疗过程。例如，如果发现受试者具有标志实体瘤干细胞的标记(参见，例如，表4-8)，那么可在其更可能变得有效时，在更早的时刻(例如，转移前)开始进行另外的治疗(例如，激素或放射性治疗)。此外，如果发现受试者具有对激素治疗不起反应的肿瘤时，就可避免昂贵和不便的这类治疗。In some embodiments, the invention provides methods for detecting the expression of a stem cell cancer marker (eg, a breast cancer stem cell cancer marker). In preferred embodiments, expression is measured directly (eg, at the RNA or protein level). In some embodiments, expression is detected in a tissue sample (eg, biopsy tissue). In other embodiments, expression is detected in bodily fluids such as including, but not limited to, plasma, serum, whole blood, mucus, and urine. The present invention further provides panels and kits for detecting markers. In preferred embodiments, the presence of a stem cell cancer marker is used to provide a prognosis for the subject. The information provided is also used to guide the course of treatment. For example, if a subject is found to have markers for solid tumor stem cells (see, e.g., Tables 4-8), additional therapy can be initiated at an earlier time (e.g., before metastasis) when it is more likely to be effective. treatment (eg, hormone or radiation therapy). Furthermore, if a subject is found to have a tumor that does not respond to hormone therapy, costly and inconvenient treatments of this type can be avoided.

本发明不限于上述标记。可使用任何合适的与癌症或癌症发展相关的标记。本发明的范围之内也可涉及另外的标记。可使用任何合适的方法鉴定和表征适合用于本发明的方法的癌症标记，其包括但不限于，下面说明性实施例4中描述的标记。例如，在一些实施方案中，使用组织微阵列、免疫组织化学、Northern印迹分析、siRNA或反义RNA抑制、突变分析、具有临床结果的表达的观察和其它此处公开的方法进一步表征标记，所述标记是经本发明的基因表达微阵列方法鉴定在实体瘤干细胞中上调或下调的标记。The present invention is not limited to the above markers. Any suitable marker associated with cancer or cancer development may be used. Additional markers are also contemplated within the scope of the present invention. Cancer markers suitable for use in the methods of the invention may be identified and characterized using any suitable method, including, but not limited to, the markers described in Illustrative Example 4 below. For example, in some embodiments, markers are further characterized using tissue microarrays, immunohistochemistry, Northern blot analysis, siRNA or antisense RNA inhibition, mutational analysis, observation of expression with clinical consequences, and other methods disclosed herein, the The above-mentioned markers are markers that are up-regulated or down-regulated in solid tumor stem cells identified by the gene expression microarray method of the present invention.

在一些实施方案中，本发明提供了用于多个标记分析的套组。所述套组允许同时分析与致癌作用和/或转移相关的多个标记。依赖于受试者，可单独地或组合地分析套组以提供最可能的诊断和预后。通过使用合适的方法筛选其预测值以选择包含于套组中的标记，所述方法包括但不限于下列说明性实施例中描述的方法。In some embodiments, the present invention provides kits for the analysis of multiple markers. The set allows simultaneous analysis of multiple markers associated with carcinogenesis and/or metastasis. Depending on the subject, panels can be analyzed individually or in combination to provide the most likely diagnosis and prognosis. Markers for inclusion in the panel are selected by screening their predictive values using an appropriate method, including but not limited to those described in the following illustrative examples.

1.RNA的检测1. Detection of RNA

在一些优选的实施方案中，通过测量组织样品(例如，乳腺癌组织)中相应mRNA的表达来检测实体瘤干细胞癌标记(例如，包括但不限于，表4-8中描述的标记)。通过任何合适的方法，包括但不限于下面描述的方法，可测量mRNA的表达。In some preferred embodiments, solid tumor stem cell cancer markers (eg, including but not limited to, markers described in Tables 4-8) are detected by measuring the expression of the corresponding mRNA in a tissue sample (eg, breast cancer tissue). Expression of mRNA can be measured by any suitable method, including but not limited to those described below.

在一些实施方案中，通过Northern印迹分析检测RNA。Northern印迹分析包括RNA的分离和互补的标记探针的杂交。In some embodiments, RNA is detected by Northern blot analysis. Northern blot analysis involves isolation of RNA and hybridization of complementary labeled probes.

在其它实施方案中，通过与寡核苷酸探针杂交检测RNA(或相应的cDNA)。使用各种用于杂交和检测的技术进行的各种杂交测定是可获得的。例如，在一些实施方案中，使用TaqMan测定(PE Biosystems，Foster City，CA；参见例如，美国专利号5,962,233和5,538,848，各在此引用作为参考)。在PCR反应期间进行所述测定。所述TaqMan测定利用AMPLITAQ GOLD DNA聚合酶的5’-3’外切核酸酶活性。PCR反应包含由具有5’-报告染料(例如，荧光染料)和3’-淬灭染料的寡核苷酸构成的探针。在PCR期间，如果探针与其靶结合，AMPLITAQGOLD聚合酶的5’-3’溶核活性在所述报告和淬灭染料之间切割所述探针。报告染料与淬灭染料之间的分离导致荧光的增加。信号随着各轮PCR进行积累并可用荧光计进行监控。In other embodiments, RNA (or corresponding cDNA) is detected by hybridization to oligonucleotide probes. A variety of hybridization assays are available using a variety of techniques for hybridization and detection. For example, in some embodiments, a TaqMan assay (PE Biosystems, Foster City, CA; see, e.g., U.S. Patent Nos. 5,962,233 and 5,538,848, each incorporated herein by reference) is used. The assay is performed during the PCR reaction. The TaqMan assay utilizes the 5'-3' exonuclease activity of AMPLITAQ GOLD DNA polymerase. A PCR reaction comprises a probe consisting of an oligonucleotide with a 5'-reporter dye (eg, a fluorescent dye) and a 3'-quencher dye. During PCR, if the probe binds to its target, the 5'-3' nucleolytic activity of AMPLITAQGOLD polymerase cleaves the probe between the reporter and quencher dyes. Separation between the reporter dye and the quencher dye results in an increase in fluorescence. The signal accumulates with each round of PCR and can be monitored with a fluorometer.

在其它实施方案中，逆转录酶PCR(RT-PCR)用于检测RNA的表达。在RT-PCR中，通过使用逆转录酶，经酶促将RNA转变成互补的DNA或“cDNA”。然后将所述cDNA用作进行PCR反应的模板。可通过任何合适的方法检测PCR产物，其包括但不限于凝胶电泳和用DNA特异性染料进行染色或与标记的探针杂交。在一些实施方案中，使用描述于美国专利5,639,606、5,643,765和5,876,978(各专利在此引用作为参考)中的利用标准化的竞争模板混合物进行的定量逆转录酶PCR方法。In other embodiments, reverse transcriptase PCR (RT-PCR) is used to detect RNA expression. In RT-PCR, RNA is enzymatically converted to complementary DNA, or "cDNA," through the use of reverse transcriptase. The cDNA was then used as a template for PCR reactions. PCR products can be detected by any suitable method including, but not limited to, gel electrophoresis and staining with DNA-specific dyes or hybridization to labeled probes. In some embodiments, the quantitative reverse transcriptase PCR method using a standardized mixture of competing templates described in US Patent Nos. 5,639,606, 5,643,765, and 5,876,978 (each incorporated herein by reference) is used.

2.蛋白的检测2. Protein detection

在其它实施方案中，通过测量相应的蛋白或多肽的表达来检测干细胞癌标记的基因表达。可通过任何合适的方法检测蛋白表达。在一些实施方案中，通过免疫组织化学检测蛋白。在其它实施方案中，蛋白可通过其与针对所述蛋白产生的抗体结合来进行检测。抗体的产生如下所述。In other embodiments, gene expression of a stem cell cancer marker is detected by measuring the expression of the corresponding protein or polypeptide. Protein expression can be detected by any suitable method. In some embodiments, the protein is detected by immunohistochemistry. In other embodiments, a protein can be detected by its binding to antibodies raised against the protein. Antibody production is described below.

通过本领域已知的技术检测抗体结合，所述技术是例如，放射性免疫测定法、ELISA(酶联免疫吸附测定)、“三明冶”免疫测定法、免疫放射分析法、凝胶扩散沉淀反应法、免疫扩散测定法、原位免疫测定法(例如，使用胶体金、酶或放射性同位素标记)、Western印迹法、沉淀反应法、凝集测定法(例如凝胶凝集测定法、血细胞凝集测定法等)、互补固定测定法、免疫荧光测定法、蛋白A测定法和免疫电泳测定法等。Antibody binding is detected by techniques known in the art, e.g., radioimmunoassay, ELISA (enzyme-linked immunosorbent assay), "Sanmingye" immunoassay, immunoradiometric assay, gel diffusion precipitation reaction , immunodiffusion assays, in situ immunoassays (e.g., using colloidal gold, enzymes, or radioisotope labels), Western blotting, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays, etc.) , Complementary fixation assay, immunofluorescence assay, protein A assay and immunoelectrophoresis assay, etc.

在一个实施方案中，通过检测一抗上的标记来检测抗体结合。在另一个实施方案中，通过检测二抗或试剂与一抗的结合来检测一抗。在其它实施方案中，标记二抗。许多方法已知在本领域中用于在免疫测定中检测结合并且在本发明的范围之内。In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting the binding of the secondary antibody or reagent to the primary antibody. In other embodiments, the secondary antibody is labeled. A number of methods are known in the art for detecting binding in immunoassays and are within the scope of the present invention.

在一些实施方案中，使用了自动化检测测定法。用于免疫测定自动化的方法包括描述于美国专利5,885,530、4,981,785、6,159,750和5,358,691的方法，各专利在此引用作为参考。在一些实施方案中，结果的分析和提供也是自动的。例如，在一些实施方案中，使用了软件，所述软件基于对应于癌标记的系列蛋白的存在或不存在而产生预后。In some embodiments, automated detection assays are used. Methods for automating immunoassays include those described in US Patent Nos. 5,885,530, 4,981,785, 6,159,750, and 5,358,691, each of which is incorporated herein by reference. In some embodiments, the analysis and presentation of results is also automated. For example, in some embodiments, software is used that generates a prognosis based on the presence or absence of a series of proteins corresponding to cancer markers.

在其它实施方案中，免疫测定描述于美国专利5,599,677和5,672,480中，各专利在此引用作为参考。In other embodiments, immunoassays are described in US Patent Nos. 5,599,677 and 5,672,480, each of which is incorporated herein by reference.

3.数据分析3. Data Analysis

在一些实施方案中，使用基于计算机的分析程序将由检测测定产生的原始数据(例如，给定标记的存在、不存在或量)翻译成给临床医生使用的预测值数据。通过使用任何合适的手段临床医生可获得预测数据。因此，在一些优选的实施方案中，本发明提供了进一步有利方面，即那些不可能在遗传学或分子生物学受到训练的临床医生不需要理解原始数据。所述数据以其最有用的形式直接提供给临床医生。然后临床医生能够立即使用所述信息以最优化受试者的治疗。In some embodiments, computer-based analysis programs are used to translate raw data generated by detection assays (eg, the presence, absence or amount of a given marker) into predictive value data for use by clinicians. The predictive data may be obtained by a clinician using any suitable means. Thus, in some preferred embodiments, the present invention provides the further advantage that clinicians who may not be trained in genetics or molecular biology do not need to understand the raw data. The data is provided directly to the clinician in its most useful form. Clinicians can then immediately use this information to optimize the subject's treatment.

本发明涉及任何能够接收、处理和传递信息的方法，传递信息给进行所述测定的实验室、信息提供者、医疗人员和受试者，或从其获得信息。例如，在一些本发明的实施方案中，从受试者获得样品(例如，活检或血清或尿液样品)并提供给位于世界各地(例如，在与受试者居住或最终使用所述信息的国家不同的国家)的分析(profiling)部门(例如，例如医疗机构的临床实验室、基因组分析企业等)以产生原始数据。其中所述样品包含组织或其它生物学样品，受试者可以去医疗中心获取样品并将其提供给分析中心，或受试者可收集其自身的样品并直接将其送至分析中心。当所述样品包含前面确定的生物学信息时，所述信息可通过受试者(例如，可通过计算机扫描包含所述信息的信息卡并使用电子通讯系统将数据传递给分析机构的计算机)直接送至分析机构。当分析机构收到样品时，对所述样品进行处理并产生(例如，表达数据)分析结果，所述分析结果是针对受试者的想要的特异性的诊断或预后信息。The present invention relates to any method capable of receiving, processing and communicating information to or from laboratories performing said assays, information providers, medical personnel and subjects. For example, in some embodiments of the invention, a sample (e.g., a biopsy or a serum or urine sample) is obtained from a subject and provided to a provider located anywhere in the world (e.g., at a facility where the subject resides or ultimately uses the information). The analysis (profiling) departments in different countries (for example, such as clinical laboratories of medical institutions, genome analysis companies, etc.) to generate raw data. Where the sample comprises a tissue or other biological sample, the subject may go to a medical center to obtain the sample and provide it to the analysis center, or the subject may collect his own sample and send it directly to the analysis center. When the sample contains previously determined biological information, the information can be obtained directly from the subject (for example, by computer scanning an information card containing the information and using an electronic communication system to transmit the data to the computer of the analysis facility). sent to the analytical agency. When the analysis facility receives the sample, it processes the sample and produces (eg, expression data) an analysis result that is the desired specific diagnostic or prognostic information for the subject.

然后以适合治疗医生解释的格式制备分析数据。例如，除了提供原始表达数据(例如，检查描述于表4-8中的标记的数目)，制备的格式可代表针对受试者的诊断和风险估计以及对特定治疗选择的评价。可通过任何合适的方法将数据呈现给医生。例如，在一些实施方案中，分析机构产生可为医生(例如，在治疗地点)打印的或在计算机显示器上为医生显示的报告。The analytical data are then prepared in a format suitable for interpretation by the treating physician. For example, in addition to providing raw expression data (eg, examining the number of markers described in Tables 4-8), the format prepared can represent a diagnosis and risk estimate for a subject as well as an evaluation of specific treatment options. The data may be presented to the physician by any suitable method. For example, in some embodiments, the analysis mechanism generates a report that can be printed by the physician (eg, at the treatment site) or displayed for the physician on a computer monitor.

在一些实施方案中，首先在治疗地或在当地机构分析信息。然后将原始数据送到中心处理机构以进一步分析和/或将原始数据转化成供医生或患者使用的信息。中心处理机构提供了保密(所有数据用统一的安全保密方案保存在中心机构)、快速和一致的数据分析的有利方面。然后中心处理机构可在受试者治疗后控制数据的命运。例如，通过使用电子通讯系统，中心机构可将数据提供给医生、受试者或研究人员。In some embodiments, the information is first analyzed at the site of treatment or at a local facility. The raw data is then sent to a central processing facility for further analysis and/or transformation of the raw data into information for use by physicians or patients. The central processing facility provides the advantages of confidentiality (all data is kept at the central facility with a uniform security scheme), fast and consistent data analysis. The central processing facility can then control the fate of the data after the subject is treated. For example, through the use of electronic communication systems, central institutions may provide data to physicians, subjects or researchers.

在一些实施方案中，受试者通过使用电子通讯系统能够直接获得数据。基于所述结果受试者可选择进一步的干涉或建议。在一些实施方案中，所述数据用于研究使用。例如，所述数据可用于进一步最优化标记的包含或去除，所述标记用作疾病的特定状况或阶断的标志。In some embodiments, the subject has direct access to the data through the use of an electronic communication system. Based on the results the subject can choose further intervention or advice. In some embodiments, the data is for research use. For example, the data can be used to further optimize the inclusion or removal of markers that serve as markers for a particular condition or stage of disease.

4.试剂盒4. Kit

在其它实施方案中，本发明提供了用于检测和表征癌症(例如，检测一个或多个显示于表4-8中的标记，或调节由一个或多个显示于表4-8中的标记表达的肽的活性)的试剂盒。在一些实施方案中，除了检测试剂和缓冲剂外，试剂盒还包含特异性针对癌标记的抗体。在其它实施方案中，试剂盒包含特异性用于mRNA或cDNA(例如，寡核苷酸探针或引物)检测的试剂。在优选的实施方案中，所述试剂盒包含进行检测测定所必需的所有组分，包括所有对照、进行测定的说明书和任何用于结果分析和提供的必需软件。In other embodiments, the invention provides methods for detecting and characterizing cancer (eg, detecting one or more of the markers shown in Tables 4-8, or modulating one or more of the markers shown in Tables 4-8 activity of the expressed peptide). In some embodiments, the kit comprises, in addition to detection reagents and buffers, an antibody specific for a cancer marker. In other embodiments, the kits comprise reagents specific for the detection of mRNA or cDNA (eg, oligonucleotide probes or primers). In preferred embodiments, the kit contains all components necessary to perform the detection assay, including all controls, instructions for performing the assay and any necessary software for analysis and presentation of the results.

5.体内成像5. In Vivo Imaging

在一些实施方案中，体内成像技术用于观察动物(例如，人或非人哺乳动物)中癌标记的表达。例如，在一些实施方案中，使用特异性针对癌标记的标记抗体标记癌标记mRNA或蛋白。可通过使用体内成像方法在个体中检测特异性结合和标记的抗体，所述方法包括但不限于放射性核素成像、正电子发射断层显像、计算机化轴断层显像、X射线或磁共振成像方法、荧光检测和化学发光检测。用于产生针对本发明的癌标记的抗体的方法在下面进行描述。In some embodiments, in vivo imaging techniques are used to observe the expression of cancer markers in animals (eg, humans or non-human mammals). For example, in some embodiments, a cancer marker mRNA or protein is labeled with a labeled antibody specific for the cancer marker. Specifically bound and labeled antibodies can be detected in an individual by using in vivo imaging methods including, but not limited to, radionuclide imaging, positron emission tomography, computerized axial tomography, X-ray or magnetic resonance imaging Methods, fluorescence detection and chemiluminescence detection. Methods for generating antibodies against the cancer markers of the present invention are described below.

本发明的体内成像方法用于诊断表达本发明的实体瘤干细胞癌标记的癌症(例如，在乳腺癌中)。体内成像用于观察标志癌症的标记的存在。这样的技术允许不使用令人不愉快的活检即可进行诊断。本发明的体内成像方法也用于提供对癌症患者的预后。例如，可检测表示癌干细胞的标记的存在。本发明的体内成像方法可进一步用于在身体的其它部分检测转移的癌症。The in vivo imaging methods of the invention are useful for diagnosing cancers expressing the solid tumor stem cell cancer markers of the invention (eg, in breast cancer). In vivo imaging is used to see the presence of markers that are hallmarks of cancer. Such techniques allow diagnosis without the use of unpleasant biopsies. The in vivo imaging methods of the present invention are also useful for providing prognosis in cancer patients. For example, the presence of markers indicative of cancer stem cells can be detected. The in vivo imaging methods of the present invention can further be used to detect metastatic cancer in other parts of the body.

在一些实施方案中，荧光标记特异性针对本发明癌标记的试剂(例如，抗体)。将标记的抗体导入受试者(例如，经口或肠胃外)。使用任何合适的方法(例如，使用描述于美国专利6,198,107中的设备，此处引用作为参考)检测荧光标记的抗体。In some embodiments, the fluorescent label is specific to a cancer-marking reagent (eg, an antibody) of the invention. The labeled antibody is introduced into the subject (eg, orally or parenterally). Fluorescently labeled antibodies are detected using any suitable method (eg, using the apparatus described in US Pat. No. 6,198,107, incorporated herein by reference).

在其它实施方案中，放射性标记抗体。抗体在体内诊断中的用途在本领域是熟知的。Sumerdon等人，(Nucl.Med.Biol 17：247-254[1990])已描述了用于使用铟-111作为标记的肿瘤放射免疫闪烁成像的最优化的抗体-螯合剂。Griffin等人，(J Clin Onc 9：631-640[1991])已描述了该试剂在被疑患有复发性结肠直肠癌的患者中用于检测肿瘤的用途。具有顺磁性离子作为标记的相似试剂在磁共振成像中的用途在本领域是已知的(Lauffer，MagneticResonance in Medicine 22：339-342[1991])。所使用的标记依赖于成像形式的选择。放射性标记例如铟-111、锝-99m或碘-131可用于平面扫描或单光子发射计算机化断层显像(SPECT)。正电子发射标记例如氟-19也可用于正电子发射断层显像(PET)。对MRI，可使用顺磁性离子例如钆(III)或锰(II)。In other embodiments, the antibody is radiolabeled. The use of antibodies for in vivo diagnostics is well known in the art. Sumerdon et al., (Nucl. Med. Biol 17:247-254 [1990]) have described optimized antibody-chelators for radioimmunoscintigraphy of tumors using indium-111 as a label. Griffin et al., (J Clin Onc 9:631-640 [1991]) have described the use of this reagent for the detection of tumors in patients suspected of having recurrent colorectal cancer. The use of similar reagents with paramagnetic ions as labels in magnetic resonance imaging is known in the art (Lauffer, Magnetic Resonance in Medicine 22:339-342 [1991]). The marker used depends on the choice of imaging modality. Radioactive labels such as indium-111, technetium-99m or iodine-131 can be used for planar scanning or single photon emission computed tomography (SPECT). Positron emission labels such as fluorine-19 can also be used in positron emission tomography (PET). For MRI, paramagnetic ions such as gadolinium (III) or manganese (II) can be used.

可获得用于缀合抗体的具有从1小时至3.5天之间变化的半衰期的放射性金属，例如钪-47(3.5天)、镓-67(2.8天)、镓-68(68分钟)、锝-99m(6小时)和铟-111(3.2天)，其中镓-67、锝-99m和铟-111优选地用于γ照相机成像，镓-68优选地用于正电子发射断层显像。Radioactive metals with half-lives varying from 1 hour to 3.5 days are available for conjugating antibodies, such as scandium-47 (3.5 days), gallium-67 (2.8 days), gallium-68 (68 minutes), technetium -99m (6 hours) and indium-111 (3.2 days), where gallium-67, technetium-99m and indium-111 are preferred for gamma camera imaging and gallium-68 is preferred for positron emission tomography.

用这些放射性金属标记抗体的有用方法是通过双功能螯合剂例如二乙基三胺五乙酸(DTPA)进行的，例如由Khaw等人(Science 209：295[1980])所描述的用铟-111和锝-99m标记的方法，和由Scheinberg等人(Science 215：1511[1982])描述的方法。也可使用其它螯合剂，但1-(对羧基甲氧基苄基)EDTA和DTPA的羧基碳酸酐是有利的，因为其应用允许缀合而基本上不影响抗体的免疫反应性。A useful method for labeling antibodies with these radioactive metals is by bifunctional chelating agents such as diethyltriaminepentaacetic acid (DTPA), such as described by Khaw et al. (Science 209:295 [1980]) with indium-111 and technetium-99m labeling methods, and the method described by Scheinberg et al. (Science 215:1511 [1982]). Other chelating agents can also be used, but the carboxycarbonic anhydride of 1-(p-carboxymethoxybenzyl)EDTA and DTPA is advantageous because its use allows conjugation without substantially affecting the immunoreactivity of the antibody.

另一个用于偶联DPTA和蛋白的方法是通过使用DTPA的环酐进行的，如由Hnatowich等人(Int.J.Appl.Radiat.Isot.33：327[1982])描述的用铟-111标记白蛋白的方法，但其可经改变用来标记抗体。合适的用锝-99m标记抗体的方法(不使用DPTA进行螯合)是Crockford等人(美国专利4,323,546，此处引用作为参考)的pretinning方法。Another method for coupling DPTA and proteins is by using the cyclic anhydride of DTPA, as described by Hnatowich et al. (Int. J. Appl. Radiat. Isot. 33:327 [1982]) with indium-111 method for labeling albumin, but it can be adapted for labeling antibodies. A suitable method for labeling antibodies with technetium-99m (without using DPTA for chelation) is the pretinning method of Crockford et al. (US Patent 4,323,546, incorporated herein by reference).

用锝-99m标记免疫球蛋白的优选方法是Wong等人(Int.J.Appl.Radiat.Isot.，29：251[1978])描述的用于血浆蛋白的方法和近来由Wong等人(J.Nucl.Med.，23：229[1981])用于标记抗体的方法。The preferred method for labeling immunoglobulins with technetium-99m is that described by Wong et al. (Int. J. Appl. Radiat. Isot., 29:251 [1978]) for plasma proteins and more recently by Wong et al. . Nucl. Med., 23:229 [1981]) for the method of labeling antibodies.

在被缀合至特异性抗体的放射性金属的情况下，尽可能地向抗体引入高比例的放射性标记而不破坏其免疫特异性同样是想要的。在本发明的特异性干细胞癌标记存在的情况下可通过放射性标记获得进一步的改进，以确保抗体上的抗原结合位点得到保护。In the case of radioactive metals conjugated to specific antibodies, it is also desirable to introduce as high a proportion of radiolabel as possible into the antibody without destroying its immunospecificity. Further improvement can be achieved by radiolabelling in the presence of the specific stem cell cancer markers of the invention to ensure protection of the antigen binding site on the antibody.

在其它实施方案中，体内生物光子成像(Xenogen，Almeda，CA)被用来进行体内成像。该实时体内成像使用荧光素酶。将荧光素酶基因整合入细胞、微生物和动物中(例如，与本发明的癌标记形成的融合蛋白)。当被激活时，其导致发光的反应。使用CCD照相机和软件捕获图象并对其进行分析。In other embodiments, in vivo biophotonic imaging (Xenogen, Almeda, CA) is used for in vivo imaging. This real-time in vivo imaging uses luciferase. The luciferase gene is integrated into cells, microorganisms, and animals (eg, as a fusion protein with a cancer marker of the invention). When activated, it results in a luminescent response. Images are captured and analyzed using a CCD camera and software.

V.抗体和抗体片段V. Antibodies and Antibody Fragments

本发明提供了分离的抗体和抗体片段(例如，Fabs)。在优选的实施方案中，本发明提供了单克隆抗体或抗体片段，所述抗体或抗体片段特异性地结合分离的包含至少5个或至少15个此处描述(例如，显示于表4-8中的)的干细胞癌标记的氨基酸残基的多肽。这些抗体或抗体片段在此处描述的诊断、药物筛选和治疗方法中找到了用途(例如，检测或调节干细胞癌标记肽的活性)。The invention provides isolated antibodies and antibody fragments (eg, Fabs). In preferred embodiments, the invention provides monoclonal antibodies or antibody fragments that specifically bind to an isolated antibody comprising at least 5 or at least 15 of the compounds described herein (eg, shown in Tables 4-8). In the polypeptide of the amino acid residues of the stem cell cancer marker. These antibodies or antibody fragments find use in the diagnostic, drug screening, and therapeutic methods described herein (eg, to detect or modulate the activity of stem cell cancer marker peptides).

针对本发明的蛋白的抗体或抗体片段可以是任何单克隆或多克隆抗体，只要其能识别所述蛋白。通过使用本发明的蛋白作为抗原，根据常规的抗体或抗血清制备方法可产生抗体。The antibody or antibody fragment against the protein of the present invention may be any monoclonal or polyclonal antibody as long as it recognizes the protein. By using the protein of the present invention as an antigen, antibodies can be produced according to conventional antibody or antiserum preparation methods.

本发明涉及单克隆抗体和多克隆抗体的用途。任何合适的方法可用于产生用于本发明的方法和组合物中的抗体，其包括但不限于此处描述的方法。例如，为制备单克隆抗体，将单独的蛋白，或与合适的载体或稀释剂一起在允许产生抗体的条件下给动物(例如哺乳动物)施用。为增强抗体生产能力，可施用完全的或不完全的弗氏佐剂。通常，每2周至6周施用蛋白，总共大约2次至10次。适合用于这类方法的动物包括但不限于灵长类动物、兔、狗、豚鼠、小鼠、大鼠、绵羊、山羊等。The present invention relates to the use of monoclonal antibodies and polyclonal antibodies. Any suitable method can be used to generate antibodies for use in the methods and compositions of the invention, including but not limited to the methods described herein. For example, to prepare monoclonal antibodies, the protein alone, or together with a suitable carrier or diluent, is administered to an animal (eg, a mammal) under conditions that permit antibody production. To enhance antibody production ability, complete or incomplete Freund's adjuvant can be administered. Typically, protein is administered every 2 to 6 weeks for a total of about 2 to 10 administrations. Animals suitable for use in such methods include, but are not limited to, primates, rabbits, dogs, guinea pigs, mice, rats, sheep, goats, and the like.

为制备单克隆抗体生成性细胞，选择抗体滴度已经确定的单个动物(例如，小鼠)，在最终的免疫后2天至5天，收获其脾脏或淋巴结并将其中包含的抗体生成性细胞与骨髓瘤细胞融合以制备想要的单克隆抗体产生者杂交瘤。可通过例如将标记的蛋白(如下文中描述的)和抗血清反应，然后测量结合所述抗体的标记试剂的活性来测量抗血清中的抗体滴度。可根据已知的方法例如由Koehler和Milstein(Nature 256：495[1975])描述的方法进行细胞融合。作为融合促进剂，例如，使用聚乙二醇(PEG)或仙台病毒(HVJ)，优选地使用PEG。To prepare monoclonal antibody-producing cells, individual animals (eg, mice) whose antibody titers have been determined are selected and their spleens or lymph nodes are harvested 2 to 5 days after the final immunization and the antibody-producing cells contained therein are harvested Fusion with myeloma cells to produce desired monoclonal antibody producer hybridomas. Antibody titers in antisera can be measured, for example, by reacting a labeled protein (as described below) with antiserum, and then measuring the activity of a labeling reagent that binds the antibodies. Cell fusion can be performed according to known methods such as those described by Koehler and Milstein (Nature 256:495 [1975]). As a fusion promoter, for example, polyethylene glycol (PEG) or Sendai virus (HVJ) is used, preferably PEG is used.

骨髓瘤细胞的示例包括NS-1、P3U1、SP2/0、AP-1等。抗体产生者细胞(脾细胞)的数目和要使用的骨髓瘤细胞的数目的比例优选地是大约1∶1至大约20∶1。优选地以大约10％至大约80％的浓度加入PEG(优选地PEG 1000-PEG 6000)。通过将两种细胞的混合物在大约20℃下至大约40℃下，优选地在大约30℃至大约37℃下温育大约1分钟至10分钟可有效地进行细胞融合。Examples of myeloma cells include NS-1, P3U1, SP2/0, AP-1, and the like. The ratio of the number of antibody producer cells (spleen cells) to the number of myeloma cells to be used is preferably about 1:1 to about 20:1. PEG (preferably PEG 1000-PEG 6000) is preferably added at a concentration of about 10% to about 80%. Cell fusion can be effectively performed by incubating a mixture of the two cells at about 20°C to about 40°C, preferably at about 30°C to about 37°C for about 1 minute to 10 minutes.

可使用各种方法筛选产生抗体(例如抗本发明的肿瘤抗原或自身抗体)的杂交瘤。例如，向抗体被直接或与载体一起被吸附的固相(例如，微量培养板)中加入杂交瘤的上清液，然后加入抗免疫球蛋白抗体(如果在细胞融合中使用小鼠细胞，那么使用抗小鼠免疫球蛋白抗体)或标记有放射性物质或酶的蛋白A以检测抗结合至所述固相的蛋白的单克隆抗体。可选择地，将杂交瘤的上清液加到抗免疫球蛋白抗体或蛋白A被吸附的固相中，然后加入标记有放射性物质或酶的蛋白以检测抗结合至所述固相的蛋白的单克隆抗体。Hybridomas that produce antibodies (eg, against tumor antigens or autoantibodies of the invention) can be screened using a variety of methods. For example, to a solid phase (e.g., a microplate) to which antibodies are adsorbed directly or with a carrier, hybridoma supernatants are added, followed by anti-immunoglobulin antibodies (if mouse cells are used in cell fusion, then Anti-mouse immunoglobulin antibodies) or protein A labeled with radioactive substances or enzymes were used to detect monoclonal antibodies against proteins bound to the solid phase. Alternatively, hybridoma supernatants are added to a solid phase to which anti-immunoglobulin antibodies or protein A are adsorbed, and then proteins labeled with radioactive substances or enzymes are added to detect activity against proteins bound to the solid phase. Monoclonal antibodies.

可根据任何已知的方法或其修饰形式进行单克隆抗体的选择。通常，使用加入HAT(次黄嘌呤、氨基蝶呤、胸苷)的动物细胞培养基。可使用任何选择和生长培养基，只要杂交瘤能够生长。例如，可使用含有1％至20％，优选地10％至20％胎牛血清的RPMI 1640培养基、含有1％至10％胎牛血清的GIT培养基、用于培养杂交瘤的无血清培养基(SFM-101，Nissui Seiyaku)等。通常，在20℃至40℃，优选37℃下，在大约5％的CO₂气体下，培养大约5天至3周，优选地培养1周至2周。可根据上述关于抗血清中抗蛋白的抗体滴度的相同方法测量杂交瘤培养物的上清液的抗体滴度。Selection of monoclonal antibodies can be performed according to any known method or a modification thereof. Usually, animal cell culture medium to which HAT (hypoxanthine, aminopterin, thymidine) is added is used. Any selection and growth media can be used provided that the hybridomas are capable of growing. For example, RPMI 1640 medium containing 1% to 20%, preferably 10% to 20% fetal bovine serum, GIT medium containing 1% to 10% fetal bovine serum, serum-free culture medium for culturing hybridomas can be used base (SFM-101, Nissui Seiyaku) et al. Usually, at 20° C. to 40° C., preferably 37° C., under about 5% CO₂ gas, culture for about 5 days to 3 weeks, preferably 1 week to 2 weeks. The antibody titer of the supernatant of the hybridoma culture can be measured according to the same method as described above for the antibody titer against the protein in the antiserum.

可根据与常规多克隆抗体的分离和纯化方法例如免疫球蛋白的分离和纯化方法相同的方法进行单克隆抗体(例如，抗本发明的癌标记)的分离和纯化，例如，盐析、乙醇沉淀、等电点沉淀、电泳、使用离子交换剂(例如，DEAE)的吸附和解吸附作用、超速离心、凝胶过滤或其中只有抗体被活性吸附剂例如抗原结合固相、蛋白A或蛋白G收集并解离结合以获得所述抗体的特异性纯化方法。Isolation and purification of monoclonal antibodies (for example, anti-cancer markers of the present invention) can be performed according to the same method as the isolation and purification methods of conventional polyclonal antibodies such as immunoglobulins, for example, salting out, ethanol precipitation , isoelectric precipitation, electrophoresis, adsorption and desorption using ion exchangers (e.g., DEAE), ultracentrifugation, gel filtration or where only antibodies are collected by active adsorbents such as antigen-binding solid phases, protein A or protein G and The binding is dissociated to obtain a specific purification method for the antibody.

可通过任何已知的方法或这些方法的经修饰后的形式制备多克隆抗体，包括从患者获取抗体。例如，制备免疫原(抗蛋白质的抗原)和载体蛋白的复合物，和按照与上述关于制备单克隆抗体的方法相同的方法用所述复合物免疫动物。从经免疫的动物中回收包含抗体的材料并分离和纯化抗体。Polyclonal antibodies can be prepared by any known method or modified versions of these methods, including obtaining antibodies from a patient. For example, a complex of an immunogen (antigen against a protein) and a carrier protein is prepared, and an animal is immunized with the complex in the same manner as described above for the preparation of a monoclonal antibody. Antibody-containing material is recovered from the immunized animal and the antibodies are isolated and purified.

对于用于动物免疫的免疫原和载体蛋白，可使用任何载体蛋白和任何混合比例的该载体和半抗原，只要有效地产生抗所述半抗原的抗体，所述半抗原交联在载体上并用于免疫。例如，牛血清白蛋白、牛周期球蛋白(cycloglobulin)、匙孔血蓝蛋白等可以每1份半抗原含大约0.1份至大约20份，优选地大约1份至大约5份的重量比与半抗原偶联。For the immunogen and carrier protein used for animal immunization, any carrier protein and any mixing ratio of the carrier and hapten can be used, as long as the antibody against the hapten cross-linked on the carrier and used for immunity. For example, bovine serum albumin, bovine cycle globulin (cycloglobulin), keyhole limpet hemocyanin, etc. may contain about 0.1 part to about 20 parts per hapten, preferably about 1 part to about 5 parts by weight to half Antigen conjugation.

此外，可使用各种缩合剂偶联半抗原和载体。例如，戊二醛、碳二亚胺、马来酰亚胺活化的酯、包含硫醇基或二硫吡啶基的活化的酯试剂等用于本发明中。将所述缩合产物单独地或与合适的载体或稀释剂一起施用到允许抗体产生的动物部位。为增强抗体产生能力，可施用完全或不完全的弗氏佐剂。通常，每2周至6周施用所述蛋白1次，总共大约3次至大约10次。In addition, various condensing agents can be used to couple haptens and carriers. For example, glutaraldehyde, carbodiimides, maleimide activated esters, activated ester reagents containing thiol or dithiopyridyl groups, and the like are useful in the present invention. The condensation product is administered alone or with a suitable carrier or diluent to the site of the animal where antibody production is permitted. To enhance antibody production ability, complete or incomplete Freund's adjuvant can be administered. Typically, the protein is administered once every 2 to 6 weeks for a total of about 3 to about 10 administrations.

从用上述方法免疫的动物的血液、腹水等中回收多克隆抗体。可根据与上述关于杂交瘤培养物上清液的方法相同的方法测量抗血清中的抗体滴度。可按照与上述关于分离和纯化单克隆抗体的方法相同的方法分离和纯化所述抗体。Polyclonal antibodies are recovered from the blood, ascites, etc. of animals immunized by the above method. The antibody titer in the antiserum can be measured according to the same method as described above for the hybridoma culture supernatant. The antibody can be isolated and purified in the same manner as described above for the isolation and purification of the monoclonal antibody.

此处用作免疫原的蛋白不限于任何特定类型的免疫原。例如，本发明的干细胞癌标记(进一步包括具有部分改变的核苷酸序列的基因)可用作免疫原。此外，可使用蛋白的片段。可通过任何方法获得片段，其包括但不限于表达所述基因的片段、酶促加工蛋白、化学合成等。也可将所述抗体和抗体片段缀合至治疗剂(例如，杀死癌细胞的化合物)。在这点上，使用针对所述干细胞癌标记之一的抗体以特异性地递送治疗剂至实体瘤癌细胞(例如以抑制该细胞增殖或杀死该细胞)。The proteins used as immunogens herein are not limited to any particular type of immunogen. For example, the stem cell cancer markers of the present invention (further including genes with partially altered nucleotide sequences) can be used as immunogens. In addition, fragments of proteins may be used. Fragments can be obtained by any method including, but not limited to, expressing fragments of the gene, enzymatic processing of proteins, chemical synthesis, and the like. The antibodies and antibody fragments can also be conjugated to therapeutic agents (eg, compounds that kill cancer cells). In this regard, antibodies directed against one of the stem cell cancer markers are used to specifically deliver a therapeutic agent to solid tumor cancer cells (eg, to inhibit proliferation of the cells or to kill the cells).

VI.药物筛选VI. Drug Screening

在一些实施方案中，本发明提供了药物筛选测定法(例如，以筛选抗癌药物)。本发明的筛选方法利用使用本发明方法鉴定的干细胞癌标记(例如，包括但不限于，显示于表4-8中的干细胞癌标记)。例如，在一些实施方案中，本发明提供了筛选改变(例如，增加或减少)干细胞癌标记基因表达的化合物的方法。在一些实施方案中，候选化合物是针对癌标记的反义试剂或siRNA试剂(例如，寡核苷酸)。在其它实施方案中，候选化合物是特异性结合本发明干细胞癌标记的抗体。在某些实施方案中，使用此处描述的方法筛选小分子化合物文库。In some embodiments, the invention provides drug screening assays (eg, to screen for anticancer drugs). The screening methods of the invention utilize stem cell cancer markers identified using the methods of the invention (eg, including, but not limited to, the stem cell cancer markers shown in Tables 4-8). For example, in some embodiments, the invention provides methods of screening for compounds that alter (eg, increase or decrease) expression of stem cell cancer marker genes. In some embodiments, candidate compounds are antisense or siRNA agents (eg, oligonucleotides) directed against cancer markers. In other embodiments, the candidate compound is an antibody that specifically binds a stem cell cancer marker of the invention. In certain embodiments, small molecule compound libraries are screened using the methods described herein.

在一个筛选方法中，通过将化合物与表达干细胞癌标记的细胞接触，然后测定候选化合物对表达的影响来就候选化合物改变干细胞癌标记表达的能力对候选化合物进行评估。在一些实施方案中，通过检测细胞表达的癌标记mRNA的水平来测定候选化合物对癌标记基因表达的影响。可通过任何合适的方法检测mRNA表达。在其它实施方案中，通过测量由癌标记编码的多肽的水平来检测候选化合物对癌标记基因的影响。可使用任何合适的方法测量表达的多肽的水平，包括但不限于此处公开的方法。在一些实施方案中，检测细胞生物学中的其它变化(例如，凋亡)。In one screening method, candidate compounds are evaluated for their ability to alter expression of a stem cell cancer marker by contacting the compound with cells expressing the stem cell cancer marker and then determining the effect of the candidate compound on expression. In some embodiments, the effect of a candidate compound on the expression of a cancer marker gene is determined by detecting the level of cancer marker mRNA expressed by the cells. mRNA expression can be detected by any suitable method. In other embodiments, the effect of a candidate compound on a cancer marker gene is detected by measuring the level of a polypeptide encoded by the cancer marker. The level of expressed polypeptide can be measured using any suitable method, including but not limited to the methods disclosed herein. In some embodiments, other changes in cell biology (eg, apoptosis) are detected.

特别地，本发明提供了用于鉴定调节剂的筛选方法，所述调节剂即结合或改变与本发明的癌标记相关的信号传导或功能的候选或受试化合物或试剂(例如，蛋白、肽、肽模拟物(peptidomimetic)、类肽(peptoids)、小分子或其它药物)，所述候选或受试化合物或试剂具有对例如干细胞癌标记表达或癌标记活性的抑制(或刺激)作用，或具有对例如癌标记底物的表达或活性的刺激或抑制作用。在治疗方案中，经如此鉴定的化合物可直接或间接地用于调节靶基因产物(例如，干细胞癌标记基因)的活性，以详细阐述靶基因产物的生物学功能或鉴定破坏正常靶基因相互作用的化合物。抑制癌标记的活性或表达的化合物用于治疗增殖紊乱，例如癌症，特别是转移性癌症，或消除或控制肿瘤干细胞以预防或减少癌症的风险。In particular, the invention provides screening methods for identifying modulators, i.e., candidate or test compounds or agents (e.g., proteins, peptides, , peptidomimetic, peptoids, small molecules or other drugs), the candidate or test compound or agent has an inhibitory (or stimulating) effect on, for example, stem cell cancer marker expression or cancer marker activity, or Stimulatory or inhibitory effects on, for example, the expression or activity of cancer marker substrates. In therapeutic regimens, the compounds thus identified can be used directly or indirectly to modulate the activity of target gene products (e.g., stem cell cancer marker genes), to elucidate the biological function of the target gene product or to identify disruption of normal target gene interactions compound of. Compounds that inhibit the activity or expression of cancer markers are useful in the treatment of proliferative disorders, such as cancer, especially metastatic cancer, or in the elimination or control of tumor stem cells to prevent or reduce the risk of cancer.

在一个实施方案中，本发明提供了用于筛选候选或受试化合物的测定方法，所述候选或受试化合物是癌标记蛋白或多肽或其生物学活性部分的底物。在另一个实施方案中，本发明提供了用于筛选结合癌标记蛋白或多肽或其生物学活性部分或者调节其活性的候选或受试化合物的测定法。In one embodiment, the invention provides assays for screening candidate or test compounds that are substrates of cancer marker proteins or polypeptides or biologically active portions thereof. In another embodiment, the present invention provides assays for screening candidate or test compounds that bind to, or modulate the activity of, a cancer marker protein or polypeptide, or a biologically active portion thereof.

本发明的受试化合物可通过使用在本领域已知的组合文库方法中的许多途径中的任一种而获得，其包括生物学文库；类肽文库(具有肽功能性但具有新的、非肽主链的分子的文库，所述分子对酶促降解具有抗性但同时保持生物活性；参见，例如，Zuckennann等人，J.Med.Chem.37：2678-85[1994])：空间上可到达的(addressable)平行固相或液相文库；要求去卷积的合成文库方法；‘一个微珠一个化合物，的文库方法；和使用亲和层析选择的合成文库方法。生物学文库和类肽文库方法优选地用于肽文库，而其它四种方法可用于化合物的肽、非肽寡聚体或小分子文库(Lam(1997)Anticancer Drug Des.12：145)。Test compounds of the invention can be obtained by any of a number of approaches using combinatorial library methods known in the art, including biological libraries; peptoid libraries (with peptide functionality but with novel, non- Libraries of molecules of peptide backbones that are resistant to enzymatic degradation while retaining biological activity; see, e.g., Zuckennann et al., J. Med. Chem. 37:2678-85 [1994]): spatially Addressable parallel solid or liquid phase libraries; synthetic library methods requiring deconvolution; 'one compound, one bead' library methods; and synthetic library methods using affinity chromatography selection. The biological library and peptoid library methods are preferably used for peptide libraries, while the other four methods can be used for peptide, non-peptide oligomer or small molecule libraries of compounds (Lam (1997) Anticancer Drug Des. 12:145).

在本领域中，用于分子文库合成的方法的示例，例如可在下列文献中找到：DeWit等人，Proc.Natl.Acad.Sci.U.S.A.90：6909[1993]；Erb等人，Proc.Nad.Acad.Sci.USA 91：11422[1994]；Zuckermann等人，J.Med.Chem.37：2678[1994]；Cho等人，Science 261：1303[1993]；Carrell等人，Angew.Chem.Int.Ed.Engl.33.2059[1994]；Carell等人，Angew.Chem.Int.Ed.Engl.33：2061[1994]；和Gallop等人，J.Med.Chem.37：1233[1994].Examples of methods used in the art for molecular library synthesis can be found, for example, in: DeWit et al., Proc. Natl. Acad. Sci. U.S.A. 90:6909 [1993]; USA 91:11422 [1994]; Zuckermann et al., J.Med.Chem.37:2678 [1994]; Cho et al., Science 261:1303 [1993]; Carrell et al., Angew.Chem. Int. Ed. Engl. 33.2059 [1994]; Carell et al., Angew. Chem. Int. Ed. Engl. 33: 2061 [1994]; and Gallop et al., J. Med. Chem. 37: 1233 [1994].

化合物文库可存在于溶液中(例如，Houghten，Biotechniques 13：412-421[1992])，或存在于微珠上(Lam，Nature 354：82-84[1991])，芯片上(Fodor，Nature 364：555-556[1993])、细菌或孢子上(U.S.Patent No.5,223,409；此处引用作为参考)、质粒上(Cull等人，Proc.Nad.Acad.Sci.USA 89：18651869[1992])或噬菌体上(Scott和Smith，Science 249：386-390[1990]；DevlinScience 249：404-406[1990]；Cwirla等人，Proc.Natl.Acad.Sci.87：6378-6382[1990]；Felici，J.Mol.Biol.222：301[1991])。Compound libraries can exist in solution (e.g., Houghten, Biotechniques 13:412-421 [1992]), or on beads (Lam, Nature 354:82-84 [1991]), on a chip (Fodor, Nature 364 : 555-556 [1993]), on bacteria or spores (U.S. Patent No. 5,223,409; incorporated herein by reference), on plasmids (Cull et al., Proc. Nad. Acad. Sci. USA 89: 18651869 [1992]) or on phage (Scott and Smith, Science 249:386-390 [1990]; DevlinScience 249:404-406 [1990]; Cwirla et al., Proc. Natl. Acad. Sci. 87: 6378-6382 [1990]; Felici , J. Mol. Biol. 222:301 [1991]).

在一个实施方案中，测定是基于细胞的测定，其中将表达干细胞癌标记蛋白或其生物学活性部分的细胞与受试化合物接触，并确定所述受试化合物调节癌标记活性的能力。通过监控例如酶活性的变化来确定受试化合物调节干细胞癌标记活性的能力。所述细胞可以是例如哺乳动物来源的。In one embodiment, the assay is a cell-based assay in which cells expressing a stem cell cancer marker protein or a biologically active portion thereof are contacted with a test compound and the ability of the test compound to modulate cancer marker activity is determined. The ability of a test compound to modulate the activity of a stem cell cancer marker is determined by monitoring, for example, changes in enzyme activity. The cells may be, for example, of mammalian origin.

也可评估受试化合物调节癌标记与化合物例如干细胞癌标记底物的结合的能力。这可以通过例如用放射性同位素或酶标记偶联至所述化合物例如底物上来进行，这样可通过检测复合物中经标记的化合物例如底物来确定所述化合物例如底物与癌标记的结合。Test compounds can also be assessed for their ability to modulate the binding of a cancer marker to a substrate of the compound, such as a stem cell cancer marker. This can be done eg by coupling to the compound eg substrate with a radioactive isotope or enzymatic label such that binding of the compound eg substrate to the cancer marker can be determined by detecting the labeled compound eg substrate in the complex.

可选择地，用放射性同位素或酶标记偶联干细胞癌标记以监控受试化合物调节癌标记在复合物中结合癌标记底物的能力。例如，可用¹²⁵I、³⁵S、¹⁴C或³H直接或间接地标记化合物(例如，底物)，并通过直接的放射性发射计数或通过闪烁计数检测放射性同位素。可选择地，可用例如辣根过氧化物酶、碱性磷酸酶或荧光素酶对化合物进行酶标记，并通过确定合适的底物到产物的转化来检测酶标记。Alternatively, the stem cell cancer marker is coupled with a radioisotope or enzyme label to monitor the ability of the test compound to modulate the binding of the cancer marker in complex to the cancer marker substrate. For example, compounds (eg, substrates) can be directly or indirectly labeled^with125I ,^35S ,^14C ,^or3H , and the radioisotope detected by direct radioemission counting or by scintillation counting. Alternatively, compounds can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determining conversion of the appropriate substrate to product.

可在标记或不标记任何一种相互作用物的情况下评估化合物(例如，干细胞癌标记底物)与干细胞癌标记相互作用的能力。例如，在不标记化合物或癌标记的情况下可使用microphysiometer检测化合物与癌标记的相互作用(McConnell等人Science 257：1906-1912[1992])。如此处所用的，“microphysiometer”(例如，细胞传感器(cytosensor))是使用可感受光的(light-addressable)电位计量传感器(LAPS)测量细胞酸化其环境的速率的分析仪器。这种酸化速率的改变可用作化合物和癌标记之间相互作用的指标。The ability of a compound (eg, a stem cell cancer marker substrate) to interact with a stem cell cancer marker can be assessed with or without labeling of either interactor. For example, a microphysiometer can be used to detect the interaction of a compound with a cancer marker without labeling the compound or the cancer marker (McConnell et al. Science 257:1906-1912 [1992]). As used herein, a "microphysiometer" (eg, cytosensor) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-addressable potentiometric sensor (LAPS). This change in acidification rate can be used as an indicator of the interaction between the compound and the cancer marker.

在另一个实施方案中，提供了无细胞的测定法，其中将癌标记蛋白或其生物学活性部分与受试化合物接触，并评估所述受试化合物与干细胞癌标记蛋白或其生物学活性部分的结合能力。用于本发明的测定法的优选的癌标记蛋白的生物学活性部分包括参与与底物或其它蛋白相互作用的片段，例如具有高表面概率分值的片段。In another embodiment, there is provided a cell-free assay wherein a cancer marker protein or biologically active portion thereof is contacted with a test compound and the association of the test compound with stem cell cancer marker protein or biologically active portion thereof is assessed binding ability. Preferred biologically active portions of cancer marker proteins for use in the assays of the invention include fragments that are involved in interactions with substrates or other proteins, eg, fragments with high surface probability scores.

无细胞测定法包括在足以允许两种组分相互作用和结合的条件下和时间内制备靶基因蛋白和受试化合物的反应混合物，从而形成可被除去和/或检测的复合物。Cell-free assays involve preparing a reaction mixture of a target gene protein and a test compound under conditions and for a time sufficient to allow the two components to interact and bind, thereby forming a complex that can be removed and/or detected.

也可使用例如荧光能量转移(FRET)法(参见，例如，Lakowicz等人，美国专利号5,631,169；Stavrianopoulos等人，美国专利号4,968,103；各专利在此引用作为参考)检测两个分子间的相互作用。选择荧光团标记以使第一供体分子的发射的荧光能量被第二“受体”分子上的荧光标记吸收，从而其能够因吸收的能量产生荧光。Interactions between two molecules can also be detected using, for example, fluorescence energy transfer (FRET) methods (see, e.g., Lakowicz et al., U.S. Patent No. 5,631,169; Stavrianopoulos et al., U.S. Patent No. 4,968,103; each patent is incorporated herein by reference). . The fluorophore label is chosen so that the emitted fluorescent energy of the first donor molecule is absorbed by the fluorescent label on the second "acceptor" molecule so that it can fluoresce due to the absorbed energy.

可选择地，所述‘供体’蛋白分子可简单地利用色氨酸残基的天然荧光能量。可选择发射不同波长的光的标记，这样所述“受体”分子标记可与“供体”的标记区分开。因为标记之间的能量转移的效率与分子间的距离有关，所以可估计分子之间的空间关系。在两个分子之间发生结合的状况下，在15测定中“受体”分子标记的荧光发射应当是最大的。通过本领域熟知的标准荧光测定检测方法(例如，使用荧光计)可方便地测量FRET结合事件。Alternatively, the 'donor' protein molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels may be selected to emit light of different wavelengths so that the "acceptor" molecular label is distinguishable from that of the "donor". Since the efficiency of energy transfer between labels is related to the distance between molecules, the spatial relationship between molecules can be estimated. In the case of binding between the two molecules, the fluorescent emission of the "acceptor" molecule label should be maximal in the 15 assay. FRET binding events are conveniently measured by standard fluorometric detection methods well known in the art (eg, using a fluorometer).

在另一个实施方案中，可通过使用实时生物分子相互作用分析法(BIA)(参见，例如，Sjolander和Urbaniczky，Anal.Chem.63：2338-2345[1991]和Szabo等人Curr.Opin.Struct.Biol.5：699-705[1995])确定干细胞癌标记蛋白与靶分子结合的能力。在不标记任何一种相互作用物质(例如，BIAcore)的情况下，“表面等离子体(plasmon)共振”或“BIA”实时检测生物特异性相互作用。结合表面的质量改变(结合事件的标志)导致表面附近光折射率的改变(表面等离子体共振(SPR)的光学现象)，产生可用作生物分子间实时反应的标志的可检测信号。In another embodiment, the biomolecular interaction assay (BIA) (see, e.g., Sjolander and Urbaniczky, Anal. Chem. 63:2338-2345 [1991] and Szabo et al. Curr. Opin. Struct. Biol. 5:699-705 [1995]) to determine the ability of stem cell cancer marker proteins to bind target molecules. "Surface plasmon resonance" or "BIA" detects biospecific interactions in real time without labeling either of the interacting species (eg, BIAcore). A change in the mass of the bound surface (a signature of a binding event) results in a change in the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance (SPR)), producing a detectable signal that can be used as a signature of real-time reactions between biomolecules.

在一个实施方案中，靶基因产物或受试物质被锚定在固相上。在反应结束时可检测锚定在固相上的靶基因产物/受试化合物复合物。优选地，靶基因产物可被锚定在固体表面，而受试化合物(未被锚定)可直接或间接地用此处讨论的可检测的标记进行标记。In one embodiment, the target gene product or test substance is anchored to a solid phase. The target gene product/test compound complex anchored to the solid phase can be detected at the end of the reaction. Preferably, the target gene product can be anchored to a solid surface, while the test compound (unanchored) can be directly or indirectly labeled with a detectable label as discussed herein.

理想的是，固定干细胞癌标记、抗癌标记抗体或其靶分子以有利于从一种或两种蛋白的非复合物形式中分离复合物形式和提供自动化的测定。受试化合物与干细胞癌标记蛋白的结合，或在候选化合物存在或不存在的情况下的癌标记蛋白与靶分子的相互作用，可在任何适合盛装所述反应物的容器中完成。这种容器的示例包括微量滴定板、试管和微量离心管。在一个实施方案中，可提供加入了结构域的融合蛋白，所述结构域允许一种或两种蛋白结合至基质上。例如，谷胱甘肽-S-转移酶-癌标记融合蛋白或谷胱甘肽-S-转移酶/靶融合蛋白可被吸附到谷胱甘肽Sepharose微珠(Sigma Chemical，St.Louis，MO)或谷胱甘肽衍生的微量滴定板上，然后将其与受试化合物，或受试化合物和非吸附的靶蛋白或癌标记蛋白结合，在有助于复合物形成的条件下(例如，在生理条件的盐和pH下)温育所述混合物。温育后，清洗微珠或微量滴定板小孔以除去任何未结合组分，在微珠的情况下基质是固定的，直接或间接地确定复合物，例如，如上面所描述的。Ideally, immobilization of stem cell cancer markers, anti-cancer marker antibodies, or target molecules thereof facilitates the separation of the complexed form from the uncomplexed form of one or both proteins and provides automated assays. Binding of the test compound to the stem cell cancer marker protein, or the interaction of the cancer marker protein with the target molecule in the presence or absence of the candidate compound, can be accomplished in any vessel suitable for holding the reactants. Examples of such containers include microtiter plates, test tubes, and microcentrifuge tubes. In one embodiment, fusion proteins may be provided that incorporate domains that allow binding of one or both proteins to the matrix. For example, glutathione-S-transferase-cancer marker fusion proteins or glutathione-S-transferase/target fusion proteins can be adsorbed to glutathione Sepharose beads (Sigma Chemical, St. Louis, MO ) or glutathione-derivatized microtiter plates, which are then combined with the test compound, or the test compound and a non-adsorbed target protein or cancer marker protein, under conditions that favor complex formation (e.g., The mixture is incubated under physiological conditions (salt and pH). Following incubation, the beads or wells of the microtiter plate are washed to remove any unbound components, in the case of beads where the matrix is immobilized, to determine the complexes, either directly or indirectly, eg, as described above.

可选择地，可使用标准技术从基质上解离复合物和确定癌标记结合或活性的水平。其它用于将癌标记蛋白或靶分子固定在基质上的技术包括使用生物素和链霉抗生物素的缀合。可通过使用本领域已知的技术(例如，生物素化试剂盒，Pierce Chemicals，Rockford，EL)从生物素-NHS(N-羟基-琥珀酰亚胺)制备生物素化的癌标记蛋白或靶分子，和将其固定在包被链霉抗生物素的96孔板(Pierce Chemical)的小孔中。Alternatively, the complex can be dissociated from the matrix and the level of cancer marker binding or activity determined using standard techniques. Other techniques for immobilizing cancer marker proteins or target molecules on matrices include the use of biotin and streptavidin conjugation. Biotinylated cancer marker proteins or targets can be prepared from biotin-NHS (N-hydroxy-succinimide) by using techniques known in the art (e.g., Biotinylation Kit, Pierce Chemicals, Rockford, EL). molecules, and immobilized in the wells of a streptavidin-coated 96-well plate (Pierce Chemical).

为了进行所述测定，向含有锚定的组分的、包被的表面加入非固定的组分。在反应完全后，在任何形成的复合物在固体表面上保持固定的条件下除去(例如，通过清洗)未反应的组分。可用许多方法完成对锚定在固体表面上的复合物的检测。当先前未固定的组分被预先标记时，检测到固定在表面上的标记则表示形成了复合物。当先前未固定的组分未预先标记时，可使用间接标记来检测锚定在表面上的复合物；例如，使用特异性针对固定的组分的标记的抗体(然后，可直接地标记或用例如经标记的抗IgG抗体间接地标记该抗体)。To perform the assay, the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (eg, by washing) under conditions such that any complexes formed remain immobilized on the solid surface. Detection of complexes anchored on solid surfaces can be accomplished in a number of ways. When previously unimmobilized components are prelabeled, detection of immobilized label on the surface indicates complex formation. When the previously unimmobilized components are not pre-labeled, indirect labeling can be used to detect complexes anchored on the surface; for example, using labeled antibodies specific for the immobilized components (which can then be labeled directly or with For example, a labeled anti-IgG antibody indirectly labels the antibody).

可利用与干细胞癌标记蛋白或靶分子反应但不干扰所述干细胞癌标记蛋白与其靶分子结合的抗体进行该测定。可将这些抗体衍生至板的小孔中，从而未结合的靶或癌标记蛋白通过抗体缀合被捕获在小孔中。除了上述用于GST固定的复合物的方法外，用于检测这些复合物的方法还包括使用与癌标记蛋白或靶分子反应的抗体的复合物的免疫检测法，以及基于检测与癌标记蛋白或靶分子相关的酶活性的酶联测定法。This assay can be performed using antibodies reactive with the stem cell cancer marker protein or target molecule without interfering with the binding of the stem cell cancer marker protein to its target molecule. These antibodies can be derivatized into the wells of the plate so that unbound target or cancer marker proteins are captured in the wells by antibody conjugation. In addition to the methods described above for GST-immobilized complexes, methods for detecting these complexes include immunoassays using complexes reactive with cancer marker proteins or target molecules, and methods based on detection of complexes with cancer marker proteins or Enzyme-linked assays for enzymatic activity associated with target molecules.

可选择地，可在液相中进行无细胞测定法。在该测定中，通过许多标准技术中的任一种从未反应的组分中分离出反应产物，所述技术包括但不限于：差速离心(参见，例如，Rivas和Minton，Trends BiochemSci 18：284-7[1993])；层析法(凝胶过滤层析，离子交换层析)；电泳(参见，例如，Ausubel等人，eds.Current Protocols inMolecular Biology 1999，J.Wiley：New York.)；和免疫沉淀(参见，例如，Ausubel等人，eds.Current Protocols in MolecularBiology 1999，J.Wiley：New York)。这些树脂和层析技术对本领域技术人员来说是熟知的(参见，例如，Heegaard J.Mol.Recognit11：141-8[1998]；Hageand Tweed J.Chromatogr.Biomed.Sci.Appl699：499-525[1997])。此外，如此处所描述的，也可方便地利用荧光能量转移法以在未进一步从溶液中纯化复合物的情况下检测结合。Alternatively, cell-free assays can be performed in liquid phase. In this assay, the reaction product is separated from unreacted components by any of a number of standard techniques including, but not limited to, differential centrifugation (see, e.g., Rivas and Minton, Trends Biochem Sci 18: 284-7 [1993]); chromatography (gel filtration chromatography, ion exchange chromatography); electrophoresis (see, e.g., Ausubel et al., eds. Current Protocols in Molecular Biology 1999, J. Wiley: New York.) and immunoprecipitation (see, for example, Ausubel et al., eds. Current Protocols in Molecular Biology 1999, J. Wiley: New York). These resins and chromatographic techniques are well known to those skilled in the art (see, e.g., Heegaard J. Mol. Recognit 11: 141-8 [1998]; Hage and Tweed J. Chromatogr. Biomed. Sci. Appl 699: 499-525 [ 1997]). In addition, fluorescence energy transfer methods may also be conveniently utilized, as described herein, to detect binding without further purification of the complex from solution.

测定可包括将干细胞癌标记蛋白或其生物学活性部分与已知的结合所述癌标记的化合物接触以形成测定混合物，将所述测定混合与受试化合物接触，并确定所述受试化合物与癌标记蛋白相互作用的能力，其中确定所述受试化合物与癌标记蛋白相互作用的能力包括和已知的化合物相比，确定受试化合物优先结合癌标记或其生物学活性部分或者调节靶分子的活性的能力。Assays may comprise contacting a stem cell cancer marker protein, or biologically active portion thereof, with a compound known to bind said cancer marker to form an assay mixture, contacting said assay mixture with a test compound, and determining the association of said test compound with The ability of the cancer marker protein to interact, wherein determining the ability of the test compound to interact with the cancer marker protein comprises determining that the test compound preferentially binds the cancer marker or a biologically active portion thereof or modulates a target molecule compared to known compounds active ability.

为确定干细胞癌标记在体内可与一个或多个细胞或细胞外大分子例如蛋白相互作用达到的程度，这种相互作用的抑制剂是非常有用的。可使用均相测定以鉴定抑制剂。To determine the extent to which a stem cell cancer marker can interact with one or more cellular or extracellular macromolecules such as proteins in vivo, inhibitors of such interactions are very useful. Homogeneous assays can be used to identify inhibitors.

例如，制备靶基因产物和相互作用的细胞或细胞外结合配偶体产物的预制复合物以使靶基因产物或其结合配偶体被标记，但由于复合物的形成导致所述标记产生的信号淬灭(参见，美国专利号4,109,496，此处引用作为参考，所述专利使用该方法进行免疫测定)。受试物质的加入将导致高于背景的信号产生，所述受试化合物与来自预制的复合物的其中一种物质竞争并取代之。以这种方式，可鉴定破坏靶基因产物-结合配偶体相互作用的受试物质。可选择地，癌标记蛋白在双杂交测定或三杂交测定(参见例如，美国专利号5,283,317；zervos等人，Cell 72：223-232[1993]；Madura等人，J.Biol.Chem.268.12046-12054[1993]；Bartel等人，Biotechniques 14：920-924[1993]；Iwabuchi等人，Oncogene 8：1693-1696[1993]；和Brent WO94/10300；各在此引用作为参考)中可用作“诱饵蛋白”，以鉴定其它结合或与癌标记相互作用的(“癌标记结合蛋白”或“癌标记-bp”)和参与癌标记活性的蛋白。这种癌标记-bp可以是由癌标记蛋白或靶产生的信号的激活剂或抑制剂，其例如作为癌标记介导的信号传导途径的下游元件。For example, preparing a prefabricated complex of a target gene product and an interacting cellular or extracellular binding partner product such that the target gene product or its binding partner is labeled, but the signal from the label is quenched due to complex formation (See, US Patent No. 4,109,496, incorporated herein by reference, which uses this method for immunoassays). The addition of a test substance that competes with and displaces one of the substances from the preformed complex will result in a signal above background. In this way, test substances that disrupt the target gene product-binding partner interaction can be identified. Alternatively, cancer marker proteins are tested in two-hybrid assays or three-hybrid assays (see, e.g., U.S. Pat. No. 5,283,317; zervos et al., Cell 72:223-232 [1993]; Madura et al., J. 12054 [1993]; Bartel et al., Biotechniques 14:920-924 [1993]; Iwabuchi et al., Oncogene 8:1693-1696 [1993]; and Brent WO94/10300; each incorporated herein by reference) may be used as "Bait proteins" to identify other proteins that bind or interact with cancer markers ("cancer marker binding proteins" or "cancer marker-bp") and participate in cancer marker activity. Such cancer marker-bp may be an activator or inhibitor of a signal produced by a cancer marker protein or target, eg as a downstream element of a cancer marker mediated signaling pathway.

也可以鉴定癌标记表达的调节剂。例如，将细胞或无细胞的混合物与候选化合物接触，并相对于在所述候选化合物不存在的情况下的干细胞癌标记mRNA或蛋白的表达水平，评估癌标记mRNA或蛋白的表达。当癌标记mRNA或蛋白在所述候选化合物存在时的表达高于其不存在时，所述候选化合物被鉴定为癌标记mRNA或蛋白表达的刺激剂。可选择地，当癌标记mRNA或蛋白在所述候选化合物存在时的表达低于(即，统计学上显著地低于)其不存在时，所述候选化合物被鉴定为癌标记mRNA或蛋白表达的抑制剂。通过此处描述的用于检测癌标记mRNA或蛋白的方法可确定癌标记mRNA或蛋白表达的水平。Modulators of expression of cancer markers can also be identified. For example, a mixture of cells or cell-free is contacted with a candidate compound, and the expression of a cancer marker mRNA or protein is assessed relative to the expression level of a stem cell cancer marker mRNA or protein in the absence of the candidate compound. The candidate compound is identified as a stimulator of cancer marker mRNA or protein expression when the expression of the cancer marker mRNA or protein is higher in the presence of the candidate compound than in its absence. Alternatively, the candidate compound is identified as having cancer marker mRNA or protein expression when the expression of the cancer marker mRNA or protein is lower (i.e., statistically significantly lower) in the presence of the candidate compound than in its absence inhibitors. The level of cancer marker mRNA or protein expression can be determined by the methods described herein for detecting cancer marker mRNA or protein.

可使用基于细胞的或无细胞的测定法鉴定调节剂，并可在体内例如在动物中确定所述试剂调节癌标记蛋白的活性的能力，所述动物例如是疾病的动物模型，例如，患有前列腺癌或转移的前列腺癌的动物；或含有前列腺癌异种移植物的动物，所述前列腺癌异种移植物来自动物(例如，人)或由前列腺癌转移(例如转移至淋巴结、骨或肝)造成的癌的细胞或前列腺癌细胞系的细胞。Modulators can be identified using cell-based or cell-free assays, and the ability of the agent to modulate the activity of a cancer marker protein can be determined in vivo, e.g., in an animal, e.g., an animal model of disease, e.g., with Animals with prostate cancer or metastatic prostate cancer; or animals containing prostate cancer xenografts from animals (e.g., humans) or resulting from prostate cancer metastasis (e.g., to lymph nodes, bone, or liver) cancer cells or cells of a prostate cancer cell line.

本发明进一步涉及由上述筛选测定法鉴定的新试剂(参见例如，下面对癌症治疗法的描述)。因此，进一步在合适的动物模型(例如此处描述的模型)中使用由此处描述的方法鉴定的试剂(例如，癌标记调节试剂、反义癌标记核酸分子、siRNA分子、癌标记特异性抗体或癌标记结合配偶体)以确定使用该试剂治疗的有效性、毒性、副作用或作用机制。此外，由上述筛选测定法鉴定的新试剂可用于例如此处描述的治疗(例如，治疗患有癌症的人患者)。The invention further relates to novel agents identified by the screening assays described above (see eg, description of cancer therapy below). Accordingly, reagents identified by the methods described herein (e.g., cancer marker modulating reagents, antisense cancer marker nucleic acid molecules, siRNA molecules, cancer marker-specific antibodies or cancer marker binding partners) to determine the efficacy, toxicity, side effects or mechanism of action of treatment with the agent. In addition, novel agents identified by the screening assays described above can be used in treatments such as those described herein (eg, to treat human patients with cancer).

VII.癌症治疗法VII. Cancer Therapy

在一些实施方案中，本发明提供了治疗癌症(例如乳腺癌)的方法。在一些实施方案中，治疗法靶向癌标记(例如，包括但不限于显示于表4-8中的那些)。In some embodiments, the present invention provides methods of treating cancer (eg, breast cancer). In some embodiments, the therapy targets cancer markers (eg, including but not limited to those shown in Tables 4-8).

A.反义治疗法A. Antisense Therapy

候选治疗剂也用于药物筛选和研究应用中。在一些实施方案中，本发明靶向干细胞癌标记的表达。例如，在一些实施方案中，本发明使用包含寡聚反义化合物特别是寡核苷酸(例如，在上述药物筛选方法中鉴定的那些)的组合物，用于调节编码本发明的干细胞癌标记的核酸分子的功能，从而最终调节表达的癌标记的量。通过提供特异性地与一种或多种编码本发明的癌标记的核酸杂交的反义化合物来实现该方案。寡聚化合物与其靶核酸的特异性杂交干扰了所述核酸的正常功能。这种通过特异性地与靶核酸杂交的化合物对靶核酸的功能的调节通常称作“反义”。被干扰的DNA的功能包括复制和转录。被干扰的RNA的功能包括所有重大的功能，例如，将RNA转移到蛋白翻译的位点，从RNA翻译蛋白，拼接RNA以产生一种或多种mRNA，和可由RNA进行或促进的催化活性。这种干涉靶核酸功能的总效应是调节本发明的癌标记的表达。在本发明的上下文中，“调节”表示增加(刺激)或减少(抑制)基因的表达。例如，可抑制表达以有效地预防肿瘤增殖。Candidate therapeutic agents are also used in drug screening and research applications. In some embodiments, the invention targets the expression of stem cell cancer markers. For example, in some embodiments, the invention uses compositions comprising oligomeric antisense compounds, particularly oligonucleotides (eg, those identified in the drug screening methods described above), for the modulation of stem cell cancer markers encoding the invention. function of nucleic acid molecules, thereby ultimately regulating the amount of expressed cancer markers. This is accomplished by providing antisense compounds that specifically hybridize to one or more nucleic acids encoding the cancer markers of the invention. Specific hybridization of the oligomeric compound to its target nucleic acid interferes with the normal function of the nucleic acid. Such modulation of the function of a target nucleic acid by a compound that specifically hybridizes to the target nucleic acid is commonly referred to as "antisense." The functions of disturbed DNA include replication and transcription. The function of the RNA that is interfered includes all the vital functions such as transfer of RNA to the site of protein translation, translation of protein from RNA, splicing of RNA to produce one or more mRNAs, and catalytic activities that may be performed or facilitated by RNA. The overall effect of this interference with the function of the target nucleic acid is to modulate the expression of the cancer markers of the invention. In the context of the present invention, "modulate" means to increase (stimulate) or decrease (repress) the expression of a gene. For example, expression can be inhibited to effectively prevent tumor proliferation.

优选地，将特异的核酸作为靶以进行反义。将反义化合物“靶向”特定核酸，在本发明的上下文中是个多步骤过程。该过程通常从鉴定其功能要被调节的核酸序列开始。其可以是例如细胞基因(或从所述基因转录的mRNA)或来自感染剂的核酸分子，所述基因的表达与特定的病症或疾病状态相关。在本发明中，所述靶是编码本发明的干细胞癌标记的核酸分子。所述靶向过程也包括确定该基因内反义相互作用发生的位点以获得想要的效果，例如检测或调节所述蛋白的表达。在本发明的上下文中，优选的基因内位点是包含所述基因的开放阅读框架(ORF)的翻译起始或终止密码子的区域。因为翻译起始密码子通常是5，-AUG(在转录的mRNA分子中；5’-ATG在相应的DNA分子中)，所以翻译起始密码子也称为“AUG密码子”、“起始密码子”或“AUG起始密码子”。少数基因具有含有RNA序列5’-GUG、5’-UUC或5’CUG的翻译起始密码子，并且5’-AUA、5’-ACG和5’-CUG已显示在体内发挥功能。因此，术语“翻译起始密码子”和“起始密码子”可包括许多密码子序列，尽管在每种情况下起始氨基酸通常是甲硫氨酸(在真核生物中)或甲酰甲硫氨酸(在原核生物中)。真核生物和原核生物基因可具有两种或更多种可替换的起始密码子，其中任何一种可优先地在特定的细胞类型或组织中或在特定的条件下用于翻译起始。在本发明的上下文中，“起始密码子”和“翻译起始密码子”是指在体内用于启动mRNA分子的翻译的密码子，所述mRNA分子转录自编码本发明的肿瘤抗原的基因，而不论所述密码子的序列如何。Preferably, specific nucleic acids are targeted for antisense. "Targeting" an antisense compound to a particular nucleic acid is, in the context of the present invention, a multi-step process. The process generally begins with the identification of a nucleic acid sequence whose function is to be modulated. It can be, for example, a cellular gene (or mRNA transcribed from said gene) or a nucleic acid molecule from an infectious agent whose expression is associated with a particular disorder or disease state. In the present invention, the target is a nucleic acid molecule encoding the stem cell cancer marker of the present invention. The targeting process also includes determining the sites within the gene where antisense interactions occur to achieve a desired effect, such as detecting or modulating the expression of the protein. In the context of the present invention, preferred intragenic sites are regions comprising translation initiation or termination codons of the open reading frame (ORF) of said gene. Because the translation initiation codon is usually 5'-AUG (in the transcribed mRNA molecule; 5'-ATG in the corresponding DNA molecule), the translation initiation codon is also called "AUG codon", "initiation codon" or "AUG start codon". A few genes have translation initiation codons containing the RNA sequence 5'-GUG, 5'-UUC or 5'CUG, and 5'-AUA, 5'-ACG and 5'-CUG have been shown to function in vivo. Thus, the terms "translation initiation codon" and "initiation codon" may include a number of codon sequences, although in each case the initiating amino acid is usually methionine (in eukaryotes) or formylform Thionine (in prokaryotes). Eukaryotic and prokaryotic genes can have two or more alternative initiation codons, any of which can be preferentially used for translation initiation in particular cell types or tissues or under particular conditions. In the context of the present invention, "initiation codon" and "translation initiation codon" refer to codons used in vivo to initiate translation of mRNA molecules transcribed from genes encoding tumor antigens of the present invention , regardless of the sequence of the codon.

基因的翻译终止密码子(或“终止密码子”)可具有三种序列(即，5′-UAA、5′-UAG和5′-UGA；对应的DNA序列分别是5′-TAA、5′-TAG和5′-TGA)中的一种。术语“起始密码子区域”和“翻译起始密码子区域”是指从翻译起始密码子开始在任一方向上(即，5’或3’)包含大约25至大约50个连续核苷酸的mRNA或基因的部分。类似地，术语“终止密码子区域”和“翻译终止密码子区域”是指从翻译终止密码子开始在任一方向上(即，5’或3’)包含大约25至大约50个连续核苷酸的mRNA或基因的部分。The translation termination codon (or "stop codon") of a gene can have three sequences (i.e., 5'-UAA, 5'-UAG, and 5'-UGA; the corresponding DNA sequences are 5'-TAA, 5' -TAG and 5'-TGA). The terms "initiation codon region" and "translation initiation codon region" refer to a region comprising about 25 to about 50 contiguous nucleotides in either direction (i.e., 5' or 3') from the translation initiation codon. mRNA or part of a gene. Similarly, the terms "stop codon region" and "translation stop codon region" refer to a region comprising about 25 to about 50 contiguous nucleotides in either direction (i.e., 5' or 3') from the translation stop codon. mRNA or part of a gene.

表示翻译起始密码子和翻译终止子之间的区域的开放阅读框架(ORF)或“编码区”也是可被有效靶向的区域。其它靶区域包括5’非翻译区(5’UTR)和3’非翻译区(3’UTR)，5’非翻译区是指从翻译起始密码子开始在5’方向上的mRNA的部分，因此包括mRNA的5’加帽位点和翻译起始密码子之间的核苷酸或基因上对应的核苷酸，3’非翻译区是指从翻译终止密码子开始在3’方向上的mRNA的部分，因此包括mRNA的翻译终止密码子和3’末端之间的核苷酸或基因上对应的核苷酸。mRNA的5’帽子包含通过5’-5’三磷酸键合而连接至mRNA的最5’的残基上的N7-甲基化的鸟苷残基。mRNA的5’帽子区域被认为包括5’帽子结构自身和与帽相邻的前50个核苷酸。帽子区域也可以是优选的靶区域。The open reading frame (ORF), or "coding region," which represents the region between the translation initiation codon and the translation terminator, is also a region that can be effectively targeted. Other target regions include the 5' untranslated region (5'UTR) and the 3' untranslated region (3'UTR), the 5' untranslated region refers to the portion of the mRNA starting from the translation initiation codon in the 5' direction, Thus including the nucleotides between the 5' capping site of the mRNA and the translation start codon or the corresponding nucleotides on the gene, the 3' untranslated region refers to the 3' direction from the translation stop codon The portion of the mRNA, thus including the nucleotides between the translation stop codon and the 3' end of the mRNA or the corresponding nucleotides on the gene. The 5' cap of the mRNA contains an N7-methylated guanosine residue attached to the 5'most residue of the mRNA by a 5'-5' triphosphate linkage. The 5' cap region of an mRNA is considered to include the 5' cap structure itself and the first 50 nucleotides adjacent to the cap. The cap region may also be a preferred target region.

尽管一些真核生物mRNA转录物被直接翻译，但许多包含一个或多个在转录物翻译前被从转录物中切除的区域，称作“内含子”。剩下的(因此被翻译的)区域称作“外显子”，其被拼接在一起形成连续的mRNA序列。mRNA拼接位点(即，内含子-外显子连接处)也可是优选的靶区域，并且特别可用于疾病牵涉异常的拼接或疾病牵涉特定mRNA拼接产物的过量产生的状况。由于重排或缺失造成的异常融合连接也是优选的靶。还发现内含子也可以是有效的从而是优选的、被靶向例如DNA或前mRNA的反义化合物的靶区域。Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, termed "introns", that are excised from the transcript before it is translated. The remaining (and thus translated) regions are called "exons", which are spliced together to form a continuous mRNA sequence. mRNA splice sites (ie, intron-exon junctions) may also be preferred target regions and are particularly useful in conditions where aberrant splicing is implicated in disease or the overproduction of specific mRNA splice products is involved in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred targets. It has also been found that introns may also be effective and thus preferred target regions for antisense compounds targeted to eg DNA or pre-mRNA.

在一些实施方案中，使用商业可购得的软件程序(例如，Biognostik，Gottingen，Germany；SysArris Software，Bangalore，India；Antisense Research Group，University of Liverpool，Liverpool，England；GeneTrove，Carlsbad，CA)鉴定反义抑制的靶位点。在其它实施方案中，使用描述于美国专利WO 0198537A2(此处引用作为参考)的可及位点(accessible site)方法鉴定用于反义抑制的靶位点。In some embodiments, antisense antibodies are identified using commercially available software programs (e.g., Biognostik, Gottingen, Germany; SysArris Software, Bangalore, India; Antisense Research Group, University of Liverpool, Liverpool, England; GeneTrove, Carlsbad, CA). Target sites for sense inhibition. In other embodiments, target sites for antisense inhibition are identified using the accessible site method described in US Patent WO 0198537A2 (incorporated herein by reference).

一旦鉴定了一个或多个靶位点，就选择与靶充分互补(即，十分良好地杂交和具有足够的特异性)的寡核苷酸以产生想要的作用。例如，在本发明优选的实施方案中，将反义寡核苷酸靶向至或接近起始密码子。Once one or more target sites have been identified, oligonucleotides are selected that are sufficiently complementary to the target (ie, hybridize sufficiently well and have sufficient specificity) to produce the desired effect. For example, in preferred embodiments of the invention, antisense oligonucleotides are targeted to or near the initiation codon.

在本发明的上下文中，“杂交”，对于反义组合物和方法，表示互补的核苷或核苷酸碱基之间的氢键，其可以是Watson-Crick、Hoogsteen或反向Hoogsteen氢键合。例如，腺嘌呤和胸腺嘧啶是通过形成氢键而配对的互补核碱基。要理解反义化合物的序列不必100％地与其靶核酸序列互补才可特异性杂交。当反义化合物与靶DNA或RNA分子的结合干扰所述靶DNA或RNA的正常功能从而导致功效丧失，并且存在足够的互补程度以避免在想要特异性结合的条件下(即，在体内测定或治疗处理的情况下是在生理学条件下而在体外测定的情况下，是处于进行测定的条件下)所述反义化合物与非靶序列形成非特异性结合时，反义化合物就是可特异性杂交的。In the context of the present invention, "hybridization", for antisense compositions and methods, means a hydrogen bond between complementary nucleoside or nucleotide bases, which may be a Watson-Crick, Hoogsteen or reverse Hoogsteen hydrogen bond combine. For example, adenine and thymine are complementary nucleobases that pair by forming hydrogen bonds. It is to be understood that the sequence of an antisense compound need not be 100% complementary to its target nucleic acid sequence to specifically hybridize. Loss of efficacy results when the binding of an antisense compound to a target DNA or RNA molecule interferes with the normal function of said target DNA or RNA, and there is a sufficient degree of complementarity to avoid specific binding under conditions where specific binding is desired (i.e., in vivo assays). or in the case of therapeutic treatment under physiological conditions and in the case of an in vitro assay under the conditions under which the assay is performed) the antisense compound is specifically hybridizable when the antisense compound forms non-specific binding to a non-target sequence of.

反义化合物通常用作研究试剂和用于诊断学。例如，能够特异性抑制基因表达的反义寡核苷酸可用于阐明特定基因的功能。反义化合物也用于例如区别生物学途径的各成员的功能。Antisense compounds are commonly used as research reagents and in diagnostics. For example, antisense oligonucleotides capable of specifically inhibiting gene expression can be used to elucidate the function of a particular gene. Antisense compounds are also used, for example, to distinguish the function of individual members of biological pathways.

反义的特异性和灵敏性也用于治疗用途。例如，反义寡核苷酸在动物和人的疾病状态的治疗中已用作治疗部分。已安全和有效地将反义寡核苷酸施用给人，并且目前正进行大量临床试验。因此确定寡核苷酸是可被设定成在治疗细胞、组织和动物特别是人的治疗方案中使用的有用治疗样式。The specificity and sensitivity of antisense also lends itself to therapeutic use. For example, antisense oligonucleotides have been used as therapeutic moieties in the treatment of disease states in animals and humans. Antisense oligonucleotides have been safely and effectively administered to humans, and a large number of clinical trials are currently underway. Oligonucleotides are thus identified as useful therapeutic formats that can be configured for use in regimens for the treatment of cells, tissues and animals, especially humans.

尽管反义寡核苷酸是优选的反义化合物的形式，但本发明还包括其它寡聚反义化合物，包括但不限于寡核苷酸模拟物，例如下面描述的模拟物。根据本发明，反义化合物优选地包含大约8至大约30个核碱基(即，大约8至大约30个连接的碱基)，尽管更长和更短的序列都可用于本发明。特别优选的反义化合物是反义寡核苷酸，更优选的是包含大约12至25个核碱基的寡核苷酸。Although antisense oligonucleotides are the preferred form of antisense compounds, the invention also encompasses other oligomeric antisense compounds, including but not limited to oligonucleotide mimetics such as those described below. According to the invention, antisense compounds preferably comprise from about 8 to about 30 nucleobases (ie, from about 8 to about 30 linked bases), although both longer and shorter sequences are useful in the invention. Particularly preferred antisense compounds are antisense oligonucleotides, more preferably oligonucleotides comprising about 12 to 25 nucleobases.

用于本发明的优选的反义化合物的具体示例包括含有经修饰的主链或非天然的核苷间键合的寡核苷酸。如本说明书中所定义的，具有经修饰的主链的寡核苷酸包括在主链上保留磷原子和在主链上不具有磷原子的寡核苷酸。对于本说明书的目的，在其核苷间主链中不具有磷原子的经修饰的寡核苷酸也可被认为是寡核苷。Specific examples of preferred antisense compounds for use in the present invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides with modified backbones include oligonucleotides that retain phosphorus atoms in the backbone and oligonucleotides that do not have phosphorus atoms in the backbone. For the purposes of this specification, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone may also be considered oligonucleotides.

优选的经修饰的寡核苷酸主链包括，例如，硫代磷酸酯、手性硫代磷酸酯、二硫代磷酸酯、磷酸三酯、氨烷基磷酸三酯、甲基和其它烷基膦酸酯包括3′-亚烷基膦酸酯和手性膦酸酯、次膦酸酯、氨基磷酸酯包括3′-氨基氨基磷酸酯和氨烷基氨基磷酸酯、硫羰氨基磷酸酯、硫羰烷基膦酸酯、硫羰烷基磷酸三酯和具有正常3’-5’连接的boranophosphate、其2′-5′连接的类似物和其具有反向极性的类似物(其中，相邻的核苷单位对以3′-5’至5′-3′或2′-5′至5′-2′连接)。也包括各种盐、混合盐和游离酸形式。Preferred modified oligonucleotide backbones include, for example, phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl and other alkyl groups Phosphonates include 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates include 3'-aminophosphoramidates and aminoalkyl phosphoramidates, thionophosphoramidates, Thioalkyl phosphonates, thionoalkyl phosphate triesters and boranophosphates with normal 3'-5' linkage, analogues thereof with 2'-5' linkage and analogues thereof with reversed polarity (wherein, Adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'). Also included are various salts, mixed salts and free acid forms.

优选的经修饰的其中不包含磷原子的寡核苷酸主链具有由短链烷基或环烷基核苷间键合、混合的杂原子与烷基或环烷基核苷间键合、或一个或多个短链杂原子或杂环核苷间键合形成的主链。这些包括具有吗啉代键合(部分形成于核苷的糖部分)；硅氧烷主链；硫化物、亚砜和砜主链；formacetyl和thioformacetyl主链；methyleneformacetyl和thioformacetyl主链；包含烯烃的主链；氨基磺酸酯主链；亚甲基亚氨基和亚甲基肼基主链；磺酸酯和氨磺酰主链；酰胺主链；和其它具有混合的N、O、S和CH₂组分部分的寡核苷酸主链。Preferred modified oligonucleotide backbones in which phosphorus atoms are not included have short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms with alkyl or cycloalkyl internucleoside linkages, Or one or more short-chain heteroatoms or a backbone formed by linkages between heterocyclic nucleosides. These include those with morpholino linkages (formed in part on the sugar moieties of nucleosides); siloxane backbones; sulfide, sulfoxide, and sulfone backbones; formacetyl and thioformacetyl backbones; methyleneformacetyl and thioformacetyl backbones; backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others with mixed N, O, S, and CH_2- component part of the oligonucleotide backbone.

在其它优选的寡核苷酸模拟物中，用新的基团取代核苷酸单位的糖和核苷间键合(即，主链)。保留碱基单位以用于与合适的核酸靶化合物杂交。一种这样的寡聚化合物，即已显示具有优良的杂交特性的寡核苷酸模拟物，被称作肽核酸(PNA)。在PNA化合物中，寡核苷酸的糖主链被包含酰胺的主链特别是氨基乙基甘氨酸主链取代。保留核碱基并直接或间接地与主链的酰胺部分的氮杂氮原子结合。教导PNA化合物制备的代表性的美国专利包括但不限于美国专利号5,539,082、5,714,331和5,719,262，各在此引用作为参考。其它的PNA化合物的教导可在Nielsen等人，Science 254：1497(1991)中找到。In other preferred oligonucleotide mimetics, the sugar and internucleoside linkages (ie, the backbone) of the nucleotide units are replaced with new groups. The base unit is reserved for hybridization to an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimic that has been shown to have excellent hybridization properties, is known as peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of the oligonucleotide is replaced by an amide-containing backbone, particularly an aminoethylglycine backbone. The nucleobase is retained and bonded directly or indirectly to the aza nitrogen atom of the amide portion of the backbone. Representative US patents that teach the preparation of PNA compounds include, but are not limited to, US Patent Nos. 5,539,082, 5,714,331, and 5,719,262, each of which is incorporated herein by reference. Teachings of other PNA compounds can be found in Nielsen et al., Science 254:1497 (1991).

本发明最优选的实施方案是具有硫代磷酸酯主链的寡核苷酸，和具有杂原子的主链，特别是上面提到的美国专利号5,489,677的-CH₂、--NH--O--CH₂--、--CH₂--N(CH₃)--O--CH₂--[称作亚甲基(甲基亚氨基)或MMI主链]、--CH₂--O--N(CH₃)--CH₂--、--CH₂--N(CH₃)--N(CH₃)--CH₂--和--O--N(CH₃)--CH₂--CH₂--[其中天然的磷酸二酯主链表示为--O--P--O--CH₂--]和上述美国专利号5,602,240的酰胺主链的寡核苷。同样优选的是具有上述美国专利号5,034,506的吗啉代主链结构的寡核苷酸。The most preferred embodiments of the present invention are oligonucleotides with phosphorothioate backbones, and backbones with heteroatoms, particularly_-CH2 , --NH--O of the above-mentioned US Patent No. 5,489,677 --CH₂ --, --CH₂ --N(CH₃ )--O--CH₂ --[called methylene (methylimino) or MMI backbone], --CH₂ -- -O--N(CH₃ )--CH₂ --, --CH₂ --N(CH₃ )--N(CH₃ )--CH₂ -- and --O--N(CH₃ )--_CH2 --_CH2 --[wherein the natural phosphodiester backbone is denoted as --O--P--O--_CH2-- ] and the oligosaccharides of the amide backbones of the aforementioned U.S. Patent No. 5,602,240 nucleosides. Also preferred are oligonucleotides having the morpholino backbone structure of the aforementioned US Patent No. 5,034,506.

经修饰的寡核苷酸也可包含一个或多个被取代的糖部分。优选的寡核苷酸在2’位置包含一个下列基团：OH；F；O-、S-、或N-烷基；O-、S-、或N-链烯基；O-、S-或N-炔基；或O-烷基-0-烷基，其中烷基、链烯基和炔基可以是取代的或非取代的C₁至C₁₀烷基或C₂至C₁₀链烯基和炔基。特别优选的是O[(CH₂)_nO]_mCH₃、O(CH₂)_nOCH₃、O(CH₂)_nNH₂、O(CH₂)_nCH₃、O(CH₂)_nONH₂和O(CH₂)_nON[(CH₂)_nCH₃)]₂，其中n和m为1至大约10。其它优选的寡核苷酸在2’位点包含一个下列基团：C₁至C₁₀低级烷基、取代的低级烷基、烷芳基、芳烷基、O-烷芳基或O-芳烷基、SH、SCH₃、OCN、Cl、Br、CN、CF₃、OCF₃、SOCH₃、SO₂CH₃、ONO₂、NO₂、N₃、NH₂、杂环烷基、杂环烷芳基、氨基烷基氨基、多烷基氨基、取代的甲硅烷基、RNA切割基团、报告基团、插入子(intercalator)、用于提高寡核苷酸的药物动力学特征的基团、或用于提高寡核苷酸的药效动力学特征的基团。优选的修饰包括2′-甲氧基乙氧基(2′-O--CH₂CH₂OCH₃，也称作2′-O-(2-甲氧基乙基)or2′-MOE)(Martin等人，Helv.Chim.Acta 78：486[1995])即，烷氧基烷氧基基团。其它优选的修饰包括2′-二甲基氨基氧基乙氧基(即，O(CH₂)₂ON(CH₃)₂基团)，也称作2′-DMAOE，和2′-二甲基氨基乙氧基乙氧基(在本领域也称作2′-O-二甲基氨基乙氧基乙基或2′-DMAEOE)，即，2′-O--CH₂--O--CH₂--N(CH₂)₂。Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides contain one of the following groups at the 2' position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein alkyl, alkenyl and alkynyl may be substituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl groups and alkynyl groups. Particularly preferred are O[(CH₂ )_n O]_m CH₃ , O(CH₂ )_n OCH₃ , O(CH 2 )_n NH₂ , O(CH₂ )_n CH₃ , O(_{CH 2)n} ONH₂ and O(CH₂ )_n ON[(CH₂ )_n CH₃ )]₂ , where n and m range from 1 to about 10. Other preferred oligonucleotides comprise one of the following groups at the 2' position: C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aryl Alkyl, SH, SCH₃ , OCN, Cl, Br, CN, CF₃ , OCF₃ , SOCH₃ , SO₂ CH₃ , ONO₂ , NO₂ , N₃ , NH₂ , Heterocycloalkyl, Heterocycloalkane Aryl groups, aminoalkylamino groups, polyalkylamino groups, substituted silyl groups, RNA cleavage groups, reporter groups, intercalators, groups for improving the pharmacokinetic characteristics of oligonucleotides, Or groups for improving the pharmacodynamic characteristics of oligonucleotides. Preferred modifications include 2'-methoxyethoxy (2'_- O--_CH2CH2OCH3 , also known as 2'-O-(2-methoxyethyl) or 2'-MOE)₍ Martin et al., Helv. Chim. Acta 78:486 [1995]) ie, alkoxyalkoxy groups. Other preferred modifications include 2'-dimethylaminooxyethoxy (ie, O(_CH2 )_2ON (_CH3 )₂ group), also known as 2'-DMAOE, and 2'-dimethyl ylaminoethoxyethoxy (also known in the art as 2′-O-dimethylaminoethoxyethyl or 2′-DMAEOE), that is, 2′-O--CH₂ --O- -CH₂ --N(CH₂ )₂ .

其它优选的修饰包括2′-甲氧基(2′-O--CH₃)、2′-氨基丙氧基(2′-OCH₂CH₂CH₂NH₂)和2′-氟(2′-F)。也可在寡核苷酸的其它位置上进行类似的修饰，特别是在3’末端核苷酸上或在2’-5’连接的寡核苷酸中的糖的3’位置和5’末端核苷酸的5’位置。寡核苷酸也可以用糖模拟物例如环丁基部分替代pentofuranosyl糖。Other preferred modifications include 2'-methoxy (2'-O--CH₃ ), 2'-aminopropoxy (2'-OCH₂ CH₂ CH₂ NH₂ ) and 2'-fluoro (2'- -F). Similar modifications can also be made at other positions in the oligonucleotide, particularly the 3' position and the 5' end of the sugar on the 3' terminal nucleotide or in 2'-5' linked oligonucleotides The 5' position of the nucleotide. Oligonucleotides can also substitute sugar mimetics such as cyclobutyl moieties for pentofuranosyl sugars.

寡核苷酸也可包括核碱基(通常在本领域简单地称作“碱基”)修饰或取代。如此处所使用的，“未修饰的”或“天然的”核碱基包括嘌呤碱基腺嘌呤(A)和鸟嘌呤(G)，和嘧啶碱基胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。经修饰的核碱基包括其它合成的和天然的核碱基，例如5-甲基胞嘧啶(5-me-C)、5-羟甲基胞嘧啶、黄嘌呤、次黄嘌呤、2-氨基腺嘌呤、腺嘌呤和鸟嘌呤的6-甲基和其它烷基衍生物、腺嘌呤和鸟嘌呤的2-丙基和其它烷基衍生物、2-硫尿嘧啶、2-硫胸腺嘧啶和2-硫胞嘧啶、5-卤代尿嘧啶和胞嘧啶、5-丙炔基尿嘧啶和胞嘧啶、6-偶氮尿嘧啶、胞嘧啶和胸腺嘧啶、5-尿嘧啶(假尿嘧啶)，4-硫尿嘧啶、8-卤代、8-氨基、8-硫、8-硫代烷基、8-羟基和其它8-取代的腺嘌呤和鸟嘌呤、5-卤代特别是5-溴、5-三氟甲基和其它5-取代的尿嘧啶和胞嘧啶、7-甲基鸟嘌呤和7-甲基腺嘌呤、8-氮杂鸟嘌呤和8-氮杂腺嘌呤、7-脱氮鸟嘌呤和7-脱氮腺嘌呤和3-脱氮鸟嘌呤和3-脱氮腺嘌呤。其它核碱基包括公开于美国专利号3,687,808中的那些。这些核碱基中的某些特别地可用于增加本发明的寡聚化合物的结合亲和力。这些核碱基包括5-取代的嘧啶、6-氮杂嘧啶和N-2、N-6和0-6取代的嘌呤，包括2-氨基丙基腺嘌呤、5-杂尿嘧啶和5-丙炔基胞嘧啶。5-甲基胞嘧啶取代物已显示增加核酸双螺旋稳定性0.6-1.2℃并且是目前优选的碱基取代物，当与2′-O-甲氧基乙基糖修饰物结合时更加优选。Oligonucleotides may also include nucleobase (often referred to in the art simply as "base") modifications or substitutions. As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and Uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-amino Adenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2 -thiocytosine, 5-halouracil and cytosine, 5-propynyluracil and cytosine, 6-azouracil, cytosine and thymine, 5-uracil (pseudouracil), 4 -thiouracil, 8-halo, 8-amino, 8-thio, 8-thioalkyl, 8-hydroxy and other 8-substituted adenine and guanine, 5-halo especially 5-bromo, 5-trifluoromethyl and other 5-substituted uracil and cytosine, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deaza Guanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Other nucleobases include those disclosed in US Patent No. 3,687,808. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These nucleobases include 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6, and 0-6 substituted purines, including 2-aminopropyladenine, 5-heterouracil, and 5-propane Alkynecytosine. The 5-methylcytosine substitution has been shown to increase nucleic acid duplex stability by 0.6-1.2°C and is the presently preferred base substitution, even more preferred when combined with a 2'-O-methoxyethyl sugar modification.

本发明的寡核苷酸的另一种修饰包括通过化学方法将一个或多个增强寡核苷酸的活性、细胞分布和细胞吸收的部分或缀合物连接至寡核苷酸。这些部分包括但不限于脂质部分例如胆固醇部分、胆酸、硫醚(例如，己基-S-三苯甲基硫醇)、硫胆固醇(thiocholesterol)、脂肪族链(例如，十二烷二醇或十一烷基残基)、磷脂(例如，二-十六烷基-rac-甘油或1，2-二-O-十六烷基-rac-甘油基-3-H-磷酸三乙基铵)，多胺或聚乙二醇链或或金刚烷乙酸，棕榈基部分，或十八烷基胺或己基氨基-羰基-氧基胆固醇部分。Another modification of the oligonucleotides of the invention involves chemically attaching to the oligonucleotide one or more moieties or conjugates that enhance the activity, cellular distribution, and cellular uptake of the oligonucleotide. These moieties include, but are not limited to, lipid moieties such as cholesterol moieties, cholic acids, thioethers (e.g., hexyl-S-tritylthiol), thiocholesterol, aliphatic chains (e.g., dodecanediol or undecyl residues), phospholipids (e.g., di-hexadecyl-rac-glycerol or 1,2-di-O-hexadecyl-rac-glyceryl-3-H-phosphate triethyl ammonium), polyamine or polyethylene glycol chains or adamantaneacetic acid, palmityl moieties, or stearylamine or hexylamino-carbonyl-oxycholesterol moieties.

相关领域技术员熟知如何产生含有上述修饰的寡核苷酸。本发明不限于上述的反义寡核苷酸。可使用任何合适的修饰或取代。It is well known to those skilled in the relevant art how to generate oligonucleotides containing the above-mentioned modifications. The present invention is not limited to the antisense oligonucleotides described above. Any suitable modification or substitution may be used.

不必在给定的化合物中对所有位置进行统一的修饰，事实上超过一个的前面提到的修饰可被整合入单个化合物中或甚至在寡核苷酸内的单个核苷上。本发明也包括作为嵌合化合物的反义化合物。“嵌合的”反义化合物或“嵌合物”在本发明的上下文中是反义化合物，特别是寡核苷酸，其包含两个或多个化学上不同的区域，各区域由至少一个单体单位(即在寡核苷酸化合物的情况下为核苷酸)构成。这些寡核苷酸通常包含至少一个这样的区域，其中所述寡核苷酸接受修饰以提供寡核苷酸增加的对核酸酶降解的抗性、增加的细胞吸收、和/或增加的对靶核酸的结合亲和力。寡核苷酸的另一区域可用作能够切割RNA：DNA或RNA：RNA杂交物的酶的底物。作为示例，RNA酶H是切割RNA：DNA双螺旋的RNA链的细胞外切核酸酶。因此RNA酶H的作用导致RNA靶的切割，从而大大增强了寡核苷酸抑制基因表达的有效性。因此，与和相同靶区域杂交的硫代磷酸酯脱氧寡核苷酸相比，当使用嵌合寡核苷酸时，通常可用更短的寡核苷酸获得相当的结果。可通过凝胶电泳和(如果需要)本领域已知的相关核酸杂交技术常规地检测RNA靶的切割。It is not necessary to uniformly modify all positions in a given compound, and in fact more than one of the aforementioned modifications may be incorporated into a single compound or even on a single nucleoside within an oligonucleotide. The invention also includes antisense compounds that are chimeric compounds. "Chimeric" antisense compounds or "chimeras" in the context of the present invention are antisense compounds, particularly oligonucleotides, which comprise two or more chemically distinct regions, each composed of at least one Monomeric units (ie nucleotides in the case of oligonucleotide compounds) make up. These oligonucleotides generally comprise at least one region wherein the oligonucleotide has been modified to provide the oligonucleotide with increased resistance to nuclease degradation, increased cellular uptake, and/or increased targeting Nucleic acid binding affinity. Another region of the oligonucleotide can serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. As an example, RNase H is a cellular exonuclease that cleaves the RNA strand of the RNA:DNA duplex. The action of RNase H thus results in cleavage of the RNA target, thereby greatly enhancing the effectiveness of the oligonucleotide to inhibit gene expression. Thus, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used compared to phosphorothioate deoxyoligonucleotides that hybridize to the same target region. Cleavage of RNA targets can be routinely detected by gel electrophoresis and, if desired, related nucleic acid hybridization techniques known in the art.

可以两种或更多种上述的寡核苷酸、经修饰的寡核苷酸、寡核苷和/或寡核苷酸模拟物的复合结构来形成本发明的嵌合反义化合物。Chimeric antisense compounds of the invention can be formed in composite structures of two or more of the oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics described above.

本发明也包括包含如下面描述的本发明的反义化合物的药物组合物和制剂。The invention also includes pharmaceutical compositions and formulations comprising the antisense compounds of the invention as described below.

B.基因治疗法B. Gene therapy

本发明考虑了用于调节本发明的干细胞癌标记表达的任何基因操作的用途。基因操作的示例包括，但不限于，基因敲除(例如，使用例如重组从染色体中除去癌标记基因)、有或无可诱导启动子的反义构建体的表达、异源基因(例如，在可诱导启动子控制下)的加入等。可通过使用任何合适的方法在体外或体内将核酸构建体递送入细胞。合适的方法是将核酸构建体导入细胞以使想要的事件发生(例如，表达反义构建体)的方法。The invention contemplates the use of any genetic manipulation for modulating expression of the stem cell cancer markers of the invention. Examples of genetic manipulation include, but are not limited to, gene knockout (e.g., removal of cancer marker genes from chromosomes using, e.g., recombination), expression of antisense constructs with or without inducible promoters, expression of heterologous genes (e.g., in under the control of an inducible promoter), etc. Nucleic acid constructs can be delivered into cells in vitro or in vivo by using any suitable method. A suitable method is one that introduces a nucleic acid construct into a cell such that a desired event occurs (eg, expression of an antisense construct).

通过各种方法中的任一种实现将携带遗传信息的分子导入细胞中，所述方法包括但不限于定向注射裸露的DNA构建体，用载有所述构建体的金颗粒轰击，和使用例如脂质体、生物聚合体等进行的大分子介导的基因转移。优选的方法使用来源于病毒的基因递送载体，所述病毒包括但不限于，腺病毒、逆转录病毒、痘苗病毒和腺伴随病毒。因为与逆转录病毒相比具有更高的效率，来源于腺病毒的载体是优选的用于在体内将核酸分子转移入宿主细胞内的基因递送载体。已显示腺病毒载体在体内非常有效地将基因转入动物模型的多种实体瘤中和转入免疫缺陷小鼠的人实体瘤异种移植体中。用于基因转移的腺病毒载体和方法的实例描述于PCT公开WO 00/12738和WO 00/09675、美国专利申请号6,033,908、6,019,978、6,001,557、5,994,132、5,994,128、5,994,106、5,981,225、5,885,808、5,872,154、5,830,730和5,824,544，各以其全文在此引用作为参考。Introduction of molecules carrying genetic information into cells is accomplished by any of a variety of methods including, but not limited to, directed injection of a naked DNA construct, bombardment with gold particles loaded with the construct, and use of, for example, Macromolecule-mediated gene transfer by liposomes, biopolymers, etc. Preferred methods use gene delivery vectors derived from viruses including, but not limited to, adenoviruses, retroviruses, vaccinia viruses, and adeno-associated viruses. Adenovirus-derived vectors are preferred gene delivery vehicles for in vivo transfer of nucleic acid molecules into host cells because of their higher efficiency compared to retroviruses. Adenoviral vectors have been shown to be very efficient in vivo for gene transfer into a variety of solid tumors in animal models and into human solid tumor xenografts in immunodeficient mice. Examples of adenoviral vectors and methods for gene transfer are described in PCT Publications WO 00/12738 and WO 00/09675, U.S. Patent Application Nos. 5,824,544, each of which is hereby incorporated by reference in its entirety.

可以多种方法将载体施用给受试者。例如，在本发明的一些实施方案中，使用直接注射将载体施用入肿瘤或与肿瘤相关的组织中。在其它实施方案中，通过血液或淋巴循环进行施用(参见，例如，PCT公开99/02685，以其全文在此引用作为参考)。示例性的腺病毒载体的剂量水平优选地是10⁸至10¹¹个加入到灌流液中的载体颗粒。The vector can be administered to a subject in a variety of ways. For example, in some embodiments of the invention, the vector is administered into a tumor or tumor-associated tissue using direct injection. In other embodiments, administration is via the blood or lymphatic circulation (see, eg, PCT Publication 99/02685, which is hereby incorporated by reference in its entirety). An exemplary adenoviral vector dosage level is preferably¹⁰⁸ to¹⁰¹¹ vector particles added to the perfusate.

C.抗体治疗法C. Antibody therapy

在一些实施方案中，本发明提供了靶向表达本发明干细胞癌标记(例如，显示于表4-8中的那些)的肿瘤的抗体。任何合适的抗体(例如，单克隆抗体、多克隆抗体或合成的抗体)可用于此处公开的治疗方法中。在优选的实施方案中，用于癌症治疗的抗体是人源化的抗体。用于使抗体人源化的方法在本领域是熟知的(参见，例如，美国专利6,180,370、5,585,089、6,054,297和5,565,332；各在此引用作为参考)。In some embodiments, the invention provides antibodies targeted to tumors expressing stem cell cancer markers of the invention (eg, those shown in Tables 4-8). Any suitable antibody (eg, monoclonal, polyclonal, or synthetic) can be used in the methods of treatment disclosed herein. In a preferred embodiment, the antibody used in the treatment of cancer is a humanized antibody. Methods for humanizing antibodies are well known in the art (see, eg, US Patents 6,180,370, 5,585,089, 6,054,297, and 5,565,332; each incorporated herein by reference).

在一些实施方案中，治疗性抗体包括抗本发明的干细胞癌标记而产生的抗体，其中所述抗体被缀合至细胞毒剂。在这些实施方案中，产生不靶向正常细胞的肿瘤特异性治疗剂，从而减少了许多常规化疗方法的有害副作用。对于某些应用，可展望这些治疗剂是这样的药理学试剂，即所述药理学试剂用作用于附着至抗体的有用试剂，特别是细胞毒剂或其它具有杀死内皮细胞或抑制内皮细胞生长或细胞分裂的能力的抗细胞试剂。本发明考虑了任何可缀合至抗体和以活性形式被递送的药理学试剂的用途。示例性的抗细胞试剂包括化疗剂、放射性同位素和细胞毒素。本发明的治疗性抗体可包括多种细胞毒性部分，包括但不限于放射性同位素(例如，碘-131、碘-123、锝(technicium)-99m、铟-111、铼-188、铼-186、镓-67、铜-67、钇-90、碘-125或砹-211)，激素例如类固醇，抗代谢物例如胞嘧啶(例如，阿拉伯糖苷、氟尿嘧啶、氨甲蝶呤或氨基蝶呤；安慈拉环素；丝裂霉素C)，长春花生物碱(例如，秋水仙胺；鬼臼亚乙苷；光神霉素)，和抗肿瘤烷化试剂例如苯丁酸氮芥或美法仑。其它实施方案可包括诸如促凝剂、细胞因子、生长因子、细菌内毒素或细菌内毒素的脂质A部分的试剂。例如，在一些实施方案中，治疗剂包括植物、真菌或细菌来源的毒素例如A链毒素、核糖体灭活蛋白、α-八叠球菌(sarcin)、曲霉菌素、局限曲菌素、核糖核酸酶、白喉毒素或假单胞菌外毒素，仅举少量示例。在一些优选的实施方案中，使用去糖基化的篦麻毒蛋白A链。In some embodiments, a therapeutic antibody comprises an antibody raised against a stem cell cancer marker of the invention, wherein the antibody is conjugated to a cytotoxic agent. In these embodiments, tumor-specific therapeutics are produced that do not target normal cells, thereby reducing the deleterious side effects of many conventional chemotherapy approaches. For certain applications, it is envisioned that these therapeutic agents are pharmacological agents that serve as useful agents for attachment to antibodies, particularly cytotoxic agents or other agents that have the ability to kill endothelial cells or inhibit endothelial cell growth or Anticellular agents for the ability of cells to divide. The present invention contemplates the use of any pharmacological agent that can be conjugated to an antibody and delivered in an active form. Exemplary anticellular agents include chemotherapeutic agents, radioisotopes and cytotoxins. Therapeutic antibodies of the invention may include a variety of cytotoxic moieties including, but not limited to, radioactive isotopes (e.g., iodine-131, iodine-123, technicium-99m, indium-111, rhenium-188, rhenium-186, gallium-67, copper-67, yttrium-90, iodine-125, or astatine-211), hormones such as steroids, antimetabolites such as cytosine (e.g., arabinoside, fluorouracil, methotrexate, or aminopterin; Lacycline; Mitomycin C), vinca alkaloids (eg, colcemid; etoposide; mithramycin), and antineoplastic alkylating agents such as chlorambucil or melphalan . Other embodiments may include agents such as coagulants, cytokines, growth factors, bacterial endotoxins, or the lipid A portion of bacterial endotoxins. For example, in some embodiments, therapeutic agents include toxins of plant, fungal, or bacterial origin such as A-chain toxins, ribosome-inactivating proteins, alpha-sarcin, aspergillins, constrictins, ribonucleic acids Enzyme, Diphtheria toxin or Pseudomonas exotoxin, just to name a few. In some preferred embodiments, deglycosylated ricin A chain is used.

在任何情况下建议，如果想要，可通过使用已知的缀合技术(参见，例如，Ghose等人，Methods Enzymol.，93：280[1983])，以使其按要求在被靶向的肿瘤细胞的位点上靶向、内化、释放或提供到血液组分中的方式，将试剂例如这些试剂成功地缀合到抗体上。In any case it is suggested that, if desired, it be possible to make it in the targeted region by using known conjugation techniques (see, e.g., Ghose et al., Methods Enzymol., 93:280 [1983]). Agents such as these are successfully conjugated to antibodies in such a way that they are targeted, internalized, released or provided at the site of tumor cells into blood components.

例如，在一些实施方案中，本发明提供了被靶向本发明的干细胞癌标记的免疫毒素。免疫毒素是特异性靶向剂(通常是针对肿瘤的抗体或片段)与细胞毒剂例如毒素部分的缀合物。所述靶向剂使毒素指向携带被靶向的抗原的细胞从而选择性地杀死这些细胞。在一些实施方案中，治疗抗体使用提供高度体内稳定性的交联剂(Thorpe等人，Cancer Res.，48：6396[1988])。For example, in some embodiments, the invention provides immunotoxins targeted to the stem cell cancer markers of the invention. Immunotoxins are conjugates of specific targeting agents (usually antibodies or fragments against tumors) with cytotoxic agents such as toxin moieties. The targeting agent directs the toxin to cells bearing the targeted antigen thereby selectively killing those cells. In some embodiments, therapeutic antibodies use cross-linking agents that provide high in vivo stability (Thorpe et al., Cancer Res., 48:6396 [1988]).

在其它实施方案中，特别是涉及实体瘤治疗的实施方案中，设计具有抗肿瘤血管系统(通过抑制血管内皮细胞生长或细胞分裂)的细胞毒性作用或抗细胞作用的抗体。该攻击是想要导致局限于肿瘤的血管崩溃，剥夺肿瘤细胞特别是血管系统末梢的肿瘤细胞的氧气和营养，最终导致细胞死亡和肿瘤坏死。In other embodiments, particularly those involving the treatment of solid tumors, antibodies are designed to have cytotoxic or anticellular effects against tumor vasculature (by inhibiting vascular endothelial cell growth or cell division). The attack is intended to cause the collapse of tumor-confined blood vessels, depriving tumor cells of oxygen and nutrients, especially those at the ends of the vasculature, and ultimately leading to cell death and tumor necrosis.

在优选的实施方案中，将基于抗体的治疗剂配制成如下所述的药物组合物。在优选的实施方案中，施用本发明的抗体组合物导致可测量的癌减小(例如，肿瘤的减小或消除)。In preferred embodiments, antibody-based therapeutics are formulated into pharmaceutical compositions as described below. In preferred embodiments, administration of an antibody composition of the invention results in a measurable reduction in cancer (eg, reduction or elimination of tumors).

C.RNAi治疗法C. RNAi therapy

在其它实施方案中，RNAi用于调节本发明的干细胞癌标记(例如，表4-8中显示的那些)的表达。RNAi代表用于在大多数真核生物包括人中控制外源基因表达的进化保守的细胞防御。RNAi通过双链RNA(dsRNA)引发并导致响应dsRNA的单链靶RNAs同源物的序列特异性mRNA降解。mRNA降解的介导者是小的干扰性RNA双螺旋(siRNA)，其通常在细胞中通过酶切由长的dsRNA产生。siRNA通常在长度上为大约21个核苷酸(例如，长度为21-23个核苷酸)，并且具有特征在于两个核苷酸3’-突出端的碱基配对的结构。在将小RNA，或RNAi导入细胞后，据信所述序列被递送至称作RISC(RNA诱导的沉默复合物)的酶复合物。RISC识别靶并且用内切核酸酶切割之。要指出的是如果更大的RNA序列被递送到细胞，则RNA酶III(Dicer)将更长的dsRNA转化成21-23nt的双链siRNA片段。In other embodiments, RNAi is used to modulate the expression of stem cell cancer markers of the invention (eg, those shown in Tables 4-8). RNAi represents an evolutionarily conserved cellular defense for the control of foreign gene expression in most eukaryotes, including humans. RNAi is initiated by double-stranded RNA (dsRNA) and results in sequence-specific mRNA degradation of homologues of single-stranded target RNAs in response to the dsRNA. The mediators of mRNA degradation are small interfering RNA duplexes (siRNAs), which are normally produced in cells by enzymatic cleavage from long dsRNAs. siRNAs are typically about 21 nucleotides in length (e.g., 21-23 nucleotides in length) and have a structure characterized by base pairing of two nucleotide 3'-overhangs. After a small RNA, or RNAi, is introduced into a cell, it is believed that the sequence is delivered to an enzyme complex called RISC (RNA-induced silencing complex). RISC recognizes the target and cleaves it with an endonuclease. Note that if larger RNA sequences are delivered to cells, RNase III (Dicer) converts longer dsRNAs into double-stranded siRNA fragments of 21-23 nt.

化学合成的siRNA已成为用于在培养的体细胞中进行基因组范围的哺乳动物基因功能分析的强有力的试剂。除了其用于确认基因功能的价值外，siRNA也具有巨大的作为基因特异性治疗剂的潜能(Tuschl和Borkhardt，Molecular Intervent.2002；2(3)：158-67，此处引用作为参考)。Chemically synthesized siRNAs have emerged as powerful reagents for genome-wide functional analysis of mammalian genes in cultured somatic cells. In addition to their value for confirming gene function, siRNAs also have great potential as gene-specific therapeutics (Tuschl and Borkhardt, Molecular Intervent. 2002; 2(3):158-67, incorporated herein by reference).

将siRNA转染入动物细胞导致有效的、长效的特定基因的转录后沉默(Caplen等人，Proc Natl Acad Sci U.S.A.2001；98：9742-7；Elbashir等人，Nature.2001；411：494-8；Elbashir等人，GenesDev.2001；15：188-200：和Elbashir等人，EMBO J.2001；20：6877-88，均在此引用作为参考)。用于使用siRNA进行RNAi的方法和组合物例如描述于U.S.专利6,506,559(此处引用作为参考)。Transfection of siRNA into animal cells results in efficient, long-lasting post-transcriptional silencing of specific genes (Caplen et al., Proc Natl Acad Sci U.S.A. 2001; 98:9742-7; Elbashir et al., Nature. 2001; 411:494- 8; Elbashir et al., GenesDev. 2001; 15:188-200: and Elbashir et al., EMBO J. 2001; 20:6877-88, both incorporated herein by reference). Methods and compositions for RNAi using siRNA are described, for example, in U.S. Patent 6,506,559 (incorporated herein by reference).

siRNA在降低被靶向的RNA的量上非常有效，并且通过伸展蛋白(extension protein)，常常降低至不可检测的水平。所述沉默效应可持续数月，并且具有极高的特异性，因为靶RNA和siRNA中心区域之间的一个核苷酸错配通常足以阻止沉默(Brummelkamp等人，Science 2002；296：550-3；和Holen等人，Nucleic Acids Res.2002；30：1757-66，两者在此引用作为参考)。siRNAs are very effective at reducing the amount of targeted RNA, and through extension proteins, often to undetectable levels. The silencing effect lasts for months and is extremely specific, as a single nucleotide mismatch between the target RNA and the central region of the siRNA is usually sufficient to prevent silencing (Brummelkamp et al., Science 2002;296:550-3 and Holen et al., Nucleic Acids Res. 2002; 30: 1757-66, both of which are incorporated herein by reference).

E.药物组合物E. Pharmaceutical composition

本发明进一步提供药物组合物(例如，包含靶向本发明的干细胞癌标记的小分子、反义物(antisent)、抗体或siRNA)。可以许多方式施用本发明的药物组合物，依赖于想要的是局部还是全身性治疗和待处理的区域。施用可以是局部(包括眼的和至粘膜的(包括阴道和直肠递送))、肺部(例如，通过或粉末或气雾剂的吸入吹入，包括通过喷雾器；气管内的、鼻内的、表皮和经皮的)、经口或肠胃外的施用。肠胃外施用包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内例如鞘内或心室内施用。The invention further provides pharmaceutical compositions (eg, comprising small molecules, antisents, antibodies or siRNAs targeting the stem cell cancer markers of the invention). The pharmaceutical compositions of the invention can be administered in a number of ways, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including ocular and to the mucosa (including vaginal and rectal delivery)), pulmonary (for example, by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal, Epidermal and transdermal), oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intraventricular, administration.

用于局部施用的药物组合物和制剂可包括经皮的贴剂、软膏剂、洗剂、乳膏剂、凝胶、滴剂、栓剂、喷雾剂、液体和粉末。常规的药物载体，水性、粉末或油性的基质，增稠剂等可以是必需的或想要的。Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

用于口服施用的组合物和制剂包括粉末或颗粒、水或非水性介质中的悬浮液或溶液、胶囊、囊剂或片剂。增稠剂、调味剂、稀释剂、乳化剂、分散助剂或粘合剂可以是想要的。Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavourings, diluents, emulsifiers, dispersing aids or binders may be desired.

用于肠胃外、鞘内或心室内施用的组合物和制剂可包括灭菌的水溶液，其还可含有缓冲质、稀释剂和其它合适的添加物，例如但不限于渗透增强剂、载体化合物和其它药物可接受的载体或赋形剂。Compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and Other pharmaceutically acceptable carriers or excipients.

本发明的药物组合物包括但不限于溶液、乳剂和包含脂质体的制剂。这些组合物可从多种组分中产生，所述组分包括但不限于预制的液体、自乳化性固体和自乳化性半固体。Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions can be produced from a variety of components including, but not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semi-solids.

本发明的药物制剂可方便地以单位剂量形式存在，其可根据药物工业熟知的常规技术进行制备。这些技术包括使活性成分与药物载体或赋形剂结合的步骤。通常通过均匀地和紧密地使活性成分与液体载体或细分的固体载体或二者进行结合来制备制剂，然后，如果需要，为产品塑形。The pharmaceutical formulations of the invention may conveniently be presented in unit dosage form, which may be prepared according to conventional techniques well known in the pharmaceutical industry. These techniques include the step of bringing into association the active ingredient with pharmaceutical carriers or excipients. The formulations are generally prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

本发明的组合物可配制成许多可能的剂型中的任一种，例如但不限于片剂、胶囊、液体糖浆、软明胶胶囊、栓剂和灌肠剂。本发明的组合物也可以配制成在水、非水或混合介质中的混悬剂。含水的混悬剂可进一步包含增加混悬剂粘度的物质，所述物质包括例如，羧甲基纤维素钠、山梨糖醇和/或葡聚糖。混悬剂也可以包含稳定剂。Compositions of the present invention may be formulated in any of a number of possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gelatin capsules, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol, and/or dextran. The suspension may also contain stabilizers.

在本发明的一个实施方案中，药物组合物可配制成泡沫使用。药物泡沫包括这些的制剂，例如但不限于乳剂、微乳剂、乳膏剂、胶冻剂和脂质体。尽管在本质上基本相似，但这些制剂在终产物的组分和稠度上产生变化。In one embodiment of the invention, the pharmaceutical composition may be formulated for use as a foam. Pharmaceutical foams include formulations of such as, but not limited to, emulsions, microemulsions, creams, jellies, and liposomes. Although substantially similar in nature, these formulations vary in the composition and consistency of the final product.

在细胞水平增强寡核苷酸吸收的试剂也可以加入到本发明的药物和其它组合物中。例如，阳离子脂质例如lipofectin(美国专利号5,705,188)、阳离子甘油衍生物和聚阳离子分子，例如聚赖氨酸(WO97/30731)，也增加寡核苷酸的细胞吸收。Agents that enhance oligonucleotide uptake at the cellular level may also be added to the pharmaceutical and other compositions of the invention. For example, cationic lipids such as lipofectin (US Patent No. 5,705,188), cationic glycerol derivatives and polycationic molecules such as polylysine (WO97/30731), also increase cellular uptake of oligonucleotides.

本发明的组合物可额外地含有其他通常存在于药物组合物中的添加剂组分。因此，例如，组合物可包含额外的、相容的、药物活性物质，例如止痒药、收敛药、局部麻醉药或抗炎剂，或可包含额外的用于物理配制本发明组合物的各种剂型的材料，例如染料、调味剂、防腐剂、抗氧化剂、遮光剂、增稠剂和稳定剂。然而，这些材料，当加入时，不应当过度地干扰本发明组合物的组分的生物学活性。制剂可以灭菌，如果想要，可与不会有害地与制剂的核酸相互作用的助剂混合，例如，润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、用于影响渗透压的盐、缓冲质、着色剂、调味剂和/或芳香物质等。The compositions of the present invention may additionally contain other additive components usually present in pharmaceutical compositions. Thus, for example, the composition may contain additional, compatible, pharmaceutically active substances, such as antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional individual ingredients for the physical formulation of the compositions of the present invention. formulation materials such as dyes, flavorings, preservatives, antioxidants, opacifiers, thickeners and stabilizers. However, these materials, when added, should not unduly interfere with the biological activity of the components of the compositions of the invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents that do not deleteriously interact with the nucleic acids of the formulation, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure , buffer substances, coloring agents, flavoring agents and/or aromatic substances, etc.

本发明的某些实施方案提供包含(a)一种或多种调节干细胞癌标记的活性的化合物(例如，抗体、小分子、siRNA、反义等)和(b)一种或多种其它化疗剂的药物组合物。这类化疗剂的示例包括，但不限于，抗癌药物例如正定霉素、放线菌素D、多柔比星、博来霉素、丝裂霉素、氮芥、苯丁酸氮芥、美法仑、环磷酰胺，6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷(CA)、5-氟尿嘧啶(5-FU)、氟尿苷(5-FUdR)、氨甲蝶呤(MTX)、秋水仙碱、长春花新碱、长春花碱、鬼臼亚乙苷、替尼泊苷、顺铂和己烯雌酚(DES)。抗炎药物，包括但不限于非类固醇抗炎药和皮质类固醇，和抗病毒药物，包括但不限于利巴韦林、阿糖腺苷、阿昔洛韦和更昔洛韦，也可以与本发明的组合物组合。其它化疗剂也在本发明的范围内。两种或多种组合的化合物可一起使用或顺次使用。Certain embodiments of the invention provide compounds comprising (a) one or more compounds that modulate the activity of stem cell cancer markers (e.g., antibodies, small molecules, siRNA, antisense, etc.) and (b) one or more other chemotherapeutic agents pharmaceutical composition. Examples of such chemotherapeutic agents include, but are not limited to, anticancer drugs such as daunomycin, actinomycin D, doxorubicin, bleomycin, mitomycin, nitrogen mustard, chlorambucil, Melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine (CA), 5-fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate ( MTX), colchicine, vinblastine, vinblastine, etoposide, teniposide, cisplatin, and diethylstilbestrol (DES). Anti-inflammatory drugs, including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribavirin, vidarabine, acyclovir, and ganciclovir, may also be used with this Composition Combination of Invention. Other chemotherapeutic agents are also within the scope of the invention. Two or more compounds in combination may be used together or sequentially.

剂量给药依赖于要治疗的疾病状态的严重性和应答性，治疗过程持续几天至几个月，或直至治愈或实现疾病状况的减弱(例如，肿瘤大小上的减小)。最佳剂量给药方案可根据患者体内药物积累的测量值进行计算。施药医生可容易地确定最佳剂量、剂量给药方法学和重复率。最佳剂量可视单独的寡核苷酸的相对效能而变化，并且通常可基于在体外和体内动物模型中发现有效的EC₅₀或基于此处描述的实施例进行估计。一般地，剂量为每千克体重0.01μg至100μg，可每天、每周、每月或每年给药一次或多次。治疗医生可基于药物在体液或组织中的驻留时间和浓度估计剂量给药的重复率。在成功治疗之后，使受试者进行维持治疗以防止疾病状况复发可以是想要的，其中以维持剂量施用所述寡核苷酸，用量为每千克体重0.01μg至100μg，每天一次或多次，至每20年一次。Dosing depends on the severity and responsiveness of the disease state being treated, and the course of treatment is continued from several days to several months, or until cure or attenuation of the disease state (eg, reduction in tumor size) is achieved. Optimal dosing regimens can be calculated based on measurements of drug accumulation in the patient. Optimal dosages, dosing methodology and repetition rates can be readily determined by the administering physician. Optimal dosages may vary depending on the relative potencies of the individual oligonucleotides, and can generally be estimated based on_EC50s found to be effective in in vitro and in vivo animal models or based on the examples described herein. Generally, the dose is 0.01 μg to 100 μg per kilogram of body weight, which can be administered once or more times per day, week, month or year. The treating physician can estimate the repetition rate of dosing based on the residence time and concentration of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to subject the subject to maintenance therapy to prevent recurrence of the disease condition, wherein the oligonucleotide is administered in a maintenance dose of 0.01 μg to 100 μg per kilogram of body weight, one or more times per day , to once every 20 years.

VIII.表达癌标记基因的转基因动物VIII. Transgenic Animals Expressing Cancer Marker Genes

本发明考虑了产生含有本发明的外源癌标记基因或其突变体和变体(例如，截短或单个核苷酸多态性)或其敲除的转基因动物。在优选的实施方案中，转基因动物表现出与野生型动物相比改变了的表型(例如，增加的或减少的标记物存在)。用于分析这些表型存在或不存在的方法包括但不限于此处描述的方法。在一些优选的实施方案中，转基因动物进一步显示增加的或减少的肿瘤生长或癌症迹象。The present invention contemplates the generation of transgenic animals containing exogenous cancer marker genes of the present invention or mutants and variants thereof (eg, truncations or single nucleotide polymorphisms) or knockouts thereof. In preferred embodiments, transgenic animals exhibit an altered phenotype (eg, increased or decreased presence of a marker) compared to wild-type animals. Methods for analyzing the presence or absence of these phenotypes include, but are not limited to, those described herein. In some preferred embodiments, the transgenic animal further exhibits increased or decreased tumor growth or evidence of cancer.

本发明的转基因动物用于药物(例如，癌症治疗)筛选。在一些实施方案中，将受试化合物(例如，怀疑对治疗癌症有用的药物)和对照化合物(例如，安慰剂)给转基因动物和对照动物施用并评估效果。The transgenic animals of the invention are used for drug (eg, cancer therapy) screening. In some embodiments, a test compound (eg, a drug suspected of being useful in treating cancer) and a control compound (eg, a placebo) are administered to transgenic and control animals and the effect is assessed.

可通过多种方法产生转基因动物。在一些实施方案中，各个发育阶段的胚胎细胞被用于导入转基因以产生转基因动物。根据胚胎细胞的发育阶段使用不同的方法。受精卵是显微注射的最佳的靶。在小鼠中，雄性前核达到直径为大约20微米的大小，所述直径可允许重复注射1-2皮升(p1)DNA溶液。将受精卵用作进行基因转移的靶具有一个主要的优点，即在大多数情况下注射的DNA会在第一次卵裂以前整合入宿主基因组中(Brinster等人，Proc.Natl.Acad.Sci.USA 82：4438-4442[1985])。结果，所有转基因非人动物的细胞将携带整合的转基因。这通常也反映在转基因有效地传递到建立者的子代中，因为50％的生殖细胞将含有转基因。美国专利号4,873,191描述了用于受精卵显微注射的方法；该专利的公开内容以其全文在此引用。Transgenic animals can be produced by a variety of methods. In some embodiments, embryonic cells at various developmental stages are used to introduce transgenes to generate transgenic animals. Different methods are used depending on the developmental stage of the embryonic cells. Fertilized eggs are the best targets for microinjection. In mice, male pronuclei reach a size of approximately 20 microns in diameter, which allows repeated injections of 1-2 picoliters (p1) of DNA solution. The use of fertilized eggs as targets for gene transfer has the major advantage that in most cases the injected DNA will integrate into the host genome before the first cleavage (Brinster et al., Proc. Natl. Acad. Sci. . USA 82: 4438-4442 [1985]). As a result, all cells of the transgenic non-human animal will carry the integrated transgene. This is also usually reflected in the efficient transmission of the transgene to the offspring of the founder, as 50% of the germ cells will contain the transgene. US Patent No. 4,873,191 describes a method for microinjection of fertilized eggs; the disclosure of this patent is incorporated herein in its entirety.

在其它实施方案中，使用逆转录病毒感染将转基因导入非人动物中。在一些实施方案中，通过将逆转录病毒载体注射入卵母细胞的卵周隙中而利用逆转录病毒载体转染卵母细胞(美国专利号6,080,912,在此引用作为参考)。在其它实施方案中，可在体外培养发育中的非人胚胎至胚泡阶段。在此期间，卵裂球可作为逆转录病毒感染的靶(Janenich，Proc.Natl.Acad.Sci.USA 73：1260[1976])。通过酶处理而除去透明带以获得有效的卵裂球感染(Hogan等人，Manipulating the Mouse Embryo，Cold Spring Harbor LaboratoryPress，Cold Spring Harbor，N.Y.[1986])。用于导入转基因的病毒载体系统通常是携带转基因的复制缺陷型逆转录病毒(Jahner等人，Proc.Natl.Acad Sci.USA 82：6927[1985])。通过在单层的产生病毒的细胞上培养卵裂球容易且有效地获得转染(Stewart，等人，EMBO J.，6：383[1987])。In other embodiments, retroviral infection is used to introduce transgenes into non-human animals. In some embodiments, oocytes are transfected with a retroviral vector by injecting the retroviral vector into the perivitelline space of the oocyte (US Patent No. 6,080,912, incorporated herein by reference). In other embodiments, developing non-human embryos can be cultured in vitro to the blastocyst stage. During this time, blastomeres can serve as targets for retroviral infection (Janenich, Proc. Natl. Acad. Sci. USA 73:1260 [1976]). The zona pellucida is removed by enzymatic treatment for efficient blastomere infection (Hogan et al., Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. [1986]). The viral vector system used to introduce the transgene is usually a replication-deficient retrovirus carrying the transgene (Jahner et al., Proc. Natl. Acad Sci. USA 82:6927 [1985]). Transfection is readily and efficiently obtained by culturing blastomeres on a monolayer of virus-producing cells (Stewart, et al., EMBO J., 6:383 [1987]).

可选择地，可在较后阶段进行感染。可将病毒或产生病毒的细胞注射入囊胚腔(Jahner等人，Nature 298：623[1982])。大多数建立者是转基因的嵌合体，因为整合只发生在形成转基因动物的细胞的亚群中。此外，建立者可在基因组中的不同位置包含转基因的各种逆转录病毒插入物，其通常在子代中分离。此外，虽然效率较低，但通过妊娠中期的胚胎的子宫内逆转录病毒感染将转基因导入种系中也是可能的(Jahner等人，同上[1982])。其它本领域已知的使用逆转录病毒或逆转录病毒载体形成转基因动物的方法包括将逆转录病毒颗粒或产生逆转录病毒的经丝裂霉素C处理的细胞显微注射入受精卵或早期胚胎的卵周隙中(PCT国际申请WO 90/08832[1990]，和Haskell和Bowen，Mol.Reprod.Dev.，40：386[1995])。Alternatively, infection can be performed at a later stage. Virus or virus-producing cells can be injected into the blastocoel (Jahner et al., Nature 298:623 [1982]). Most founders are mosaics of the transgene because integration occurs only in the subpopulation of cells that form the transgenic animal. In addition, the founders may contain various retroviral insertions of the transgene at different locations in the genome, which usually segregate in the progeny. Furthermore, although less efficient, it is also possible, although less efficient, to introduce transgenes into the germline by in utero retroviral infection of embryos in the second trimester (Jahner et al., supra [1982]). Other methods known in the art to generate transgenic animals using retroviruses or retroviral vectors include microinjection of retroviral particles or mitomycin C-treated cells producing retroviruses into fertilized eggs or early embryos in the perivitelline space (PCT International Application WO 90/08832 [1990], and Haskell and Bowen, Mol. Reprod. Dev., 40:386 [1995]).

在其它实施方案中，将转基因导入胚胎干细胞中并利用经转染的干细胞形成胚胎。通过在合适的条件下在体外培养植入前胚胎获得ES细胞(Evans等人，Nature 292：154[1981]；Bradley等人，Nature309：255[1984]；Gossler等人，Proc.Acad.Sci.USA 83：9065[1986]；和Robertson等人，Nature 322：445[1986])。通过以本领域已知的多种方法进行的DNA转染可有效地将转基因导入ES细胞，所述方法包括磷酸钙共沉淀、原生质体或原生质球融合、脂质转染法和DEAD-葡聚糖介导的转染。也可通过逆转录病毒介导的转导或通过显微注射将转基因导入ES细胞。在将这些经转染的ES细胞导入胚泡阶段的胚胎的囊胚腔中后，其可形成胚胎并且对所得的嵌合体动物的种系作出贡献(对于此的综述，可参见Jaenisch，Science 240：1468[1988])。在将经转染的ES细胞导入囊胚腔前，可将经转染的ES细胞接受各种选择方案以富集已整合了转基因的ES细胞，假定所述转基因提供了进行该选择的方法。可选择地，可使用聚合酶链式反应筛选已整合了转基因的ES细胞。该技术避免了需要在转移入囊胚腔之前让经转染的ES细胞在合适的选择条件下生长。In other embodiments, a transgene is introduced into embryonic stem cells and the transfected stem cells are used to form embryos. Obtain ES cells by culturing preimplantation embryos in vitro under suitable conditions (Evans et al., Nature 292: 154 [1981]; Bradley et al., Nature 309: 255 [1984]; Gossler et al., Proc. Acad. Sci. USA 83:9065 [1986]; and Robertson et al., Nature 322:445 [1986]). Transgenes can be efficiently introduced into ES cells by DNA transfection by a variety of methods known in the art, including calcium phosphate co-precipitation, protoplast or spheroplast fusion, lipofection, and DEAD-dextrose Sugar-mediated transfection. Transgenes can also be introduced into ES cells by retrovirus-mediated transduction or by microinjection. After introduction of these transfected ES cells into the blastocoel of blastocyst-stage embryos, they can form embryos and contribute to the germline of the resulting chimeric animal (for a review, see Jaenisch, Science 240 : 1468 [1988]). Prior to introducing transfected ES cells into the blastocoel, the transfected ES cells can be subjected to various selection protocols to enrich for ES cells that have integrated the transgene, which is assumed to provide a means for this selection. Alternatively, polymerase chain reaction can be used to screen for ES cells that have integrated the transgene. This technique avoids the need to grow transfected ES cells under suitable selection conditions prior to transfer into the blastocoel.

在其它实施方案中，利用同源重组敲除基因功能或形成缺失突变体(例如，截短的突变体)。用于同源重组的方法描述于美国专利号5,614,396,此处引用作为参考。In other embodiments, homologous recombination is used to knock out gene function or create deletion mutants (eg, truncated mutants). Methods for homologous recombination are described in US Patent No. 5,614,396, incorporated herein by reference.

实验experiment

提供下列实施例以证明和进一步举例说明本发明的某些优选的实施方案和方面，而不应被解释为限定本发明范围。The following examples are provided to demonstrate and further illustrate certain preferred embodiments and aspects of the invention and should not be construed as limiting the scope of the invention.

在下面的实验公开内容中，使用下列缩写：N(正常)、M(摩尔浓度)、mM(毫摩尔浓度)、μM(微摩尔浓度)、mol(摩尔)、mmol(毫摩尔)、μmol(微摩尔)、nmol(纳摩尔)、pmol(皮摩尔)、g(克)、mg(毫克)、μg(微克)、ng(纳克)、l或L(升)、ml(毫升)、μl(微升)、cm(厘米)、mm(毫米)、μm(微米)、nm(纳米)和℃(摄氏度)。In the experimental disclosure below, the following abbreviations are used: N (normal), M (molar), mM (millimolar), μM (micromolar), mol (mole), mmol (millimolar), μmol ( Micromole), nmol (nanomole), pmol (picomole), g (gram), mg (milligram), μg (microgram), ng (nanogram), l or L (liter), ml (milliliter), μl (microliters), cm (centimeters), mm (millimeters), μm (micrometers), nm (nanometers), and °C (degrees Celsius).

                        实施例1Example 1

          建立和分析实体瘤细胞异种移植体模型Establishment and Analysis of Solid Tumor Cell Xenograft Models

该实施例描述了使用来自人的人实体瘤细胞在小鼠中产生肿瘤和分析这些肿瘤。This example describes the generation of tumors in mice and the analysis of these tumors using human solid tumor cells from humans.

材料和方法Materials and methods

制备小鼠。通过腹膜内注射0.2ml氯胺酮/赛拉嗪(4ml体积中300mg氯胺酮和20mg赛拉嗪。每20g小鼠使用0.02ml该溶液)麻醉8周大小的雌性NOD-SCID小鼠。使用HBSS稀释至200μl。然后通过腹膜内注射(每1kg小鼠30mg依托泊苷剂量，在无血清HBSS中稀释至200μl终注射体积)用VP-16(依托泊苷)处理小鼠。同时，使用套管针将雌激素小球放置在小鼠颈背的皮下。在该过程5天后进行所有肿瘤注射/移植。在下列方法中，如上所述麻醉小鼠。Prepare mice. Eight week old female NOD-SCID mice were anesthetized by intraperitoneal injection of 0.2 ml ketamine/xylazine (300 mg ketamine and 20 mg xylazine in a volume of 4 ml. 0.02 ml of this solution was used per 20 g mouse). Dilute to 200 μl with HBSS. Mice were then treated with VP-16 (etoposide) by intraperitoneal injection (30 mg etoposide dose per 1 kg mouse, diluted to a final injection volume of 200 μl in serum-free HBSS). Simultaneously, place estrogen pellets subcutaneously on the nape of the mouse using a trocar. All tumor injections/implantations were performed 5 days after the procedure. In the following methods, mice were anesthetized as described above.

原发肿瘤样品移植。为移植新鲜样品，在手术后1小时内获取人乳腺肿瘤样品。用剪刀将肿瘤切割成小块，然后用刀片将小块切碎产生2×2mm大小碎片。在无菌条件下在冰上在加有20％胎牛血清(FBS)的无菌RPMI 1640培养基中进行切割。在移植前用无血清HBSS清洗肿瘤碎片。然后在中腹区域产生2mm切口，并用套管针将一至二块小肿瘤碎片移植入右上和左上乳房脂肪垫(正好在两边第二乳头下面)区域。用6-0缝线在MFP-Nipple周围包裹两次以使其将移植的碎片保持在原位。5天后拆除缝线。使用Nexaban封闭切口，每周监控小鼠肿瘤生长。Transplantation of primary tumor samples. For transplantation of fresh samples, human breast tumor samples were obtained within 1 hour of surgery. Tumors were cut into small pieces with scissors and then minced with a razor blade to produce 2 x 2 mm size fragments. Cutting was performed under sterile conditions on ice in sterile RPMI 1640 medium supplemented with 20% fetal bovine serum (FBS). Tumor debris was washed with serum-free HBSS before transplantation. A 2 mm incision was then made in the mid-abdominal region, and one or two small tumor fragments were implanted with a trocar into the upper right and upper left breast fat pad (just below the second nipple on both sides) area. Wrap around the MFP-Nipple twice with 6-0 sutures to hold the grafted pieces in place. The sutures were removed after 5 days. The incisions were closed using Nexaban, and tumor growth in mice was monitored weekly.

胸膜渗出液注射。为进行胸膜渗出液注射，在thorocentesis后立刻获取细胞并用无血清HBSS清洗。然后将细胞悬浮在无血清RPMI/Matrigel混合物(1∶1体积)中，然后使用18G针头注射到右上方和左上方的乳房垫内。通常注射0.2ml含有1-2百万个细胞的溶液。用Nexaban封住针头注射的位置以防细胞渗漏。Injection of pleural effusion. For pleural effusion injection, cells were harvested immediately after thorocentesis and washed with serum-free HBSS. Cells were then suspended in a serum-free RPMI/Matrigel mixture (1:1 volume) and injected into the upper right and upper left breast pads using an 18G needle. Typically 0.2 ml of a solution containing 1-2 million cells is injected. The needle injection site was sealed with Nexaban to prevent cell leakage.

肿瘤细胞的单细胞悬浮液的制备。在用胶原蛋白酶消化之前，将异种移植的肿瘤或原发人肿瘤切成小块并用灭菌的刀片完全切割。为获得单细胞悬浮液，然后将HBSS溶液中的超纯胶原蛋白酶III(每ml200-250U胶原蛋白酶)与胸膜渗出液细胞或所得的肿瘤碎片混合并使其在37℃下温育3-4小时。每隔15-20分钟用10ml移液器进行吸打。在温育结束时，将细胞通过45μm的尼龙膜过滤并用RPMI-20％FBS清洗，然后用HBSS清洗两次。然后将要注射的细胞悬浮在HBSS/Matrigel混合物(1∶1体积)中并如上所述注射到乳房脂肪垫区域。用Nexaban封闭注射部位。Preparation of single-cell suspensions of tumor cells. Xenografted tumors or primary human tumors were minced and completely dissected with a sterile razor blade prior to digestion with collagenase. To obtain a single-cell suspension, ultrapure collagenase III (200-250 U collagenase per ml) in HBSS solution was then mixed with pleural effusion cells or resulting tumor fragments and allowed to incubate at 37 °C for 3-4 Hour. Pipette with a 10ml pipette every 15-20 minutes. At the end of the incubation, cells were filtered through a 45 μm nylon membrane and washed with RPMI-20% FBS followed by two washes with HBSS. Cells to be injected were then suspended in a HBSS/Matrigel mixture (1:1 volume) and injected into the mammary fat pad area as described above. Seal the injection site with Nexaban.

细胞染色以进行流式细胞术。对细胞进行计数然后转移至5ml管中，用含有2％的热失活牛血清(HICS)的HBSS清洗两次(在1000rpm下5min)，然后重新悬浮于100μl(每10⁶个细胞)含有2％HICS的HBSS中。加入5mlSandoglobin溶液(1mg/ml)并在冰上冰浴10分钟，然后所述样品用HBSS 2％HICS清洗两次并重新悬浮于100ml(每10⁶个细胞)的HBBS 2％HICS。然后加入抗体(使用合适的稀释度/抗体)并在冰上温育20分钟，然后用HBSS 2％HICS清洗两次。当需要时，通过重新悬浮于100μl(每10⁶个细胞)的HBSS 2％HICS中进行二抗加入，然后加入1-4ml二抗(视二抗及其浓度而定)，接着进行20分钟温育。当使用链霉抗生物素步骤时，将细胞重新悬浮于100ml(每10⁶个细胞)的HBBS 2％HICS中，然后加入1μl缀合指定的荧光染料的链霉抗生物素，接着进行20分钟温育。用HBSS 2％热失活的胎牛血清(HICS)清洗细胞两次并重新悬浮于0.5ml(每百万个细胞)含有7AAD(1mg/ml终浓度)的HBSS 2％HICS中。Cells were stained for flow cytometry. The cells were counted and then transferred to a 5ml tube, washed twice with HBSS containing 2% heat-inactivated bovine serum (HICS) (5min at 1000rpm), then resuspended in 100μl (per¹⁰⁶ cells) containing 2 %HICS in HBSS. After adding 5 ml of Sandoglobin solution (1 mg/ml) and cooling on ice for 10 minutes, the samples were washed twice withHBSS 2% HICS and resuspended in 100 ml (per 10⁶ cells) of HBBS 2% HICS. Antibody was then added (use appropriate dilution/antibody) and incubated on ice for 20 minutes, followed by two washes withHBSS 2% HICS. When needed, secondary antibody addition was performed by resuspending in 100 μl (per¹⁰ cells) ofHBSS 2% HICS, followed by addition of 1-4 ml of secondary antibody (depending on secondary antibody and its concentration), followed by 20 min incubation. education. When using the streptavidin step, resuspend the cells in 100 ml (per¹⁰⁶ cells) of HBBS 2% HICS, then add 1 μl of streptavidin conjugated to the indicated fluorescent dye, followed by 20 min Incubation. Cells were washed twice withHBSS 2% heat-inactivated fetal calf serum (HICS) and resuspended in 0.5 ml (per million cells) ofHBSS 2% HICS containing 7AAD (1 mg/ml final concentration).

流式细胞术。所使用的抗体是抗CD44(APC，PE或生物素)、抗CD24(PE或FITC)、抗B38.1(APC)、抗ESA-FITC(Biomeda，CA)、抗H2Kd(Santa Cruz Products，Santa Cruz，CA)。谱系标记抗体是抗-CD2、-CD3-CD10、-CD16、-CD18、-CD31、-CD64和-CD140b。除非特别指出，抗体购自Pharmingen(San Diego，CA)。将抗体直接缀合到各种荧光团上(依赖于测试)。在所有测试中，通过在流式细胞术期间除去H²K^d+(I类MHC)细胞或Lineage⁺细胞除去小鼠细胞和/或Lineage⁺细胞。通过使用存活染料7-AAD除去死细胞。在FACSVantage(Becton Dickinson，San Jose，CA)上进行流式细胞术。使用侧向散射(Side scatter)和正向散射(forward scatter)特征除去细胞双联体。常规地分选细胞两次和就纯度对细胞重新进行分析，纯度通常高于95％。Flow Cytometry. Antibodies used were anti-CD44 (APC, PE or biotin), anti-CD24 (PE or FITC), anti-B38.1 (APC), anti-ESA-FITC (Biomeda, CA), anti-H2Kd (Santa Cruz Products, Santa Cruz, CA). Lineage marker antibodies were anti-CD2, -CD3-CD10, -CD16, -CD18, -CD31, -CD64 and -CD140b. Antibodies were purchased from Pharmingen (San Diego, CA) unless otherwise noted. Antibodies are directly conjugated to various fluorophores (assay dependent). In all tests, mouse cells^{and/or Lineage+ cells were removed by removing H2Kd+ (MHC class I) cells or Lineage+cellsduringflow} cytometry. Dead cells were removed by using the survival dye 7-AAD. Flow cytometry was performed on a FACSVantage (Becton Dickinson, San Jose, CA). Cell doublets were removed using side scatter and forward scatter features. Cells were routinely sorted twice and re-analyzed for purity, which was usually greater than 95%.

在实体瘤中，已证实在体外克隆发生测定^{21-24，101-103}中只有少部分肿瘤细胞能够形成集落。此外，在异种移植模型中通常必须移植大量细胞以形成肿瘤。对这些观察现象的一个可能解释是肿瘤内的每一个细胞具有增殖和形成新肿瘤的能力但单个细胞完成这些测定中的必需步骤的概率却很小。另一种可能的解释是只有极少的、表型不同的细胞亚群具有明显增殖和形成新肿瘤的能力，但在这种亚群内的细胞这样做的效率非常高²⁵。为区分这些可能性，需要在这些肿瘤中鉴定克隆发生细胞，所述细胞具有区别这些细胞与其它非致瘤性细胞的标记。这可以在急性髓样白血病(AML)中实现，其中已证实，在NOD/SCID无免疫应答的小鼠中持续地富集具有克隆发生活性的特异性的白血病细胞(表达类似正常造血干细胞的标记)亚群，而其它癌细胞丧失了克隆发生活性^104-106。这些测试还未在实体瘤中报道过。In solid tumors^, only a minority of tumor cells have been shown to be able to form colonies in in vitro clonogenic assays21-24,101-103. Furthermore, in xenograft models it is often necessary to transplant a large number of cells to form a tumor. One possible explanation for these observations is that every cell within a tumor has the ability to proliferate and form new tumors but the probability of a single cell completing the necessary steps in these assays is small. Another possible explanation is that only a small, phenotypically distinct subpopulation of cells has the apparent ability to proliferate and form new tumors, but cells within this subpopulation do so with very high efficiency²⁵ . To distinguish between these possibilities, it is necessary to identify clonogenic cells in these tumors that have markers that distinguish these cells from other non-tumorigenic cells. This can be achieved in acute myeloid leukemia (AML), where it has been shown that in NOD/SCID immunocompromised mice there is a sustained enrichment of specific leukemic cells with clonogenic activity (expressing markers similar to normal hematopoietic stem cells). ) subpopulation, while other cancer cells lost clonogenic activity^104-106 . These tests have not been reported in solid tumors.

为研究实体瘤异质性的机制，培育了NOD/SCID免疫缺陷小鼠模型的修饰小鼠模型，在所述小鼠模型中人乳腺癌在小鼠乳房脂肪垫⁹⁹中有效地增殖。在本申请中，已显示实体瘤含有不同的具有专有的在小鼠中形成肿瘤的能力的细胞群体。这些细胞称作致瘤性细胞或癌启始细胞，因为其持续地形成肿瘤，而其它癌细胞群体失去了能够形成肿瘤的细胞。已鉴定了可区分这些细胞群体的细胞表面标记。这些发现提供了乳腺肿瘤生物学的新模型，在所述模型中确定的细胞亚群驱动肿瘤发生，以及产生肿瘤细胞异质性。该致瘤性癌细胞群体的预定鉴定使得能够鉴定在这些细胞中表达的分子，然后可用所述分子作为靶以除去该关键性癌细胞群体。To investigate the mechanism of solid tumor heterogeneity, a modified mouse model of the NOD/SCID immunodeficient mouse model in which human breast cancer efficiently proliferates in the mouse mammary fat^pad99 was generated. In the present application, it has been shown that solid tumors contain distinct cell populations with an exclusive ability to form tumors in mice. These cells are called tumorigenic or cancer-initiating cells because they continue to form tumors while other cancer cell populations lose tumor-forming cells. Cell surface markers have been identified that distinguish these cell populations. These findings provide a new model of breast tumor biology in which defined cell subsets drive tumorigenesis and generate tumor cell heterogeneity. Predetermined identification of this tumorigenic cancer cell population enables the identification of molecules expressed in these cells that can then be used as targets to remove this critical cancer cell population.

肿瘤样品和移植率。将获自9个不同患者的原发或转移位点的人乳腺癌样品(称为肿瘤1-9；T1-T9)全部移植到NOD/SCID小鼠中(表1)。在一种情况下，从原发乳腺肿瘤(T2)获得癌细胞，而在其它情况下细胞获自转移的胸膜渗出液(T1，T3-T9)。在其已在小鼠中传代一次或两次(称作传代1&2)后，对细胞进行一些检验，而其它检验则对直接获至患者的未传代的新鲜或冷冻肿瘤样品进行。当使用来自在小鼠中传代的肿瘤的人癌症细胞时，通过除去H2K⁺细胞[小鼠组织相容性I类(MHC)]来除去污染的小鼠细胞。Tumor samples and engraftment rates. Human breast cancer samples (designated tumors 1-9; T1-T9) from primary or metastatic sites obtained from 9 different patients were all transplanted into NOD/SCID mice (Table 1). In one case, cancer cells were obtained from the primary breast tumor (T2), while in the other cases cells were obtained from metastatic pleural effusions (T1, T3-T9). Some assays were performed on cells after they had been passaged once or twice in mice (referred to aspassage 1 & 2), while others were performed on unpassaged fresh or frozen tumor samples obtained directly to patients. When using human cancer cells from tumors passaged in mice, contaminating mouse cells were removed by removing H2K⁺ cells [mouse histocompatibility class I (MHC)].

                              表1   肿瘤   来源   小鼠中形成   小鼠中传代   诊断   1   肿瘤转移   是   是   浸润性导管癌   T2   乳腺原发   是   是   腺癌   T3   肿瘤转移   是   是   浸润性小叶癌   T4   肿瘤转移   是   不是   浸润性小叶癌   T5   肿瘤转移   是   是   浸润性小叶癌   T6   肿瘤转移   是   是   炎性乳腺癌   T7   肿瘤转移   是   是   浸润性小叶癌   T8   肿瘤转移   是   是   炎性乳腺癌   T9   肿瘤转移   是   是   腺癌Table 1 the tumor source formed in mice passage inmice diagnosis 1 tumor metastasis yes yes invasive ductal carcinoma T2 primary breast yes yes Adenocarcinoma T3 tumor metastasis yes yes invasive lobular carcinoma T4 tumor metastasis yes no invasive lobular carcinoma T5 tumor metastasis yes yes invasive lobular carcinoma T6 tumor metastasis yes yes inflammatory breast cancer T7 tumor metastasis yes yes invasive lobular carcinoma T8 tumor metastasis yes yes inflammatory breast cancer T9 tumor metastasis yes yes Adenocarcinoma

表1提供了移植人乳腺癌至NOD/SCID小鼠中的结果。用未分选的T1和T3细胞和2mm的T2碎片注射小鼠。如图1中所描述的通过流式细胞仪分离来自T4-T9的细胞。所有9种受试肿瘤全部移植入NOD/SCID小鼠模型中。除了T2是原发乳腺肿瘤外，所有其它肿瘤都是转移的。除了T4，所有肿瘤在小鼠中都进行系列传代。Table 1 provides the results of transplantation of human breast cancer into NOD/SCID mice. Mice were injected with unsorted T1 and T3 cells and 2 mm T2 fragments. Cells from T4-T9 were isolated by flow cytometry as described in Figure 1. All nine tested tumors were transplanted into the NOD/SCID mouse model. All tumors are metastatic except T2 which is the primary breast tumor. All tumors, except T4, were serially passaged in mice.

致瘤性标记的鉴定。在有关各种细胞表面标记(包括CD44、CD24和B38.1)的表达上乳腺癌细胞是异质的。CD24和CD44是附着分子，而B38.1已被描述为乳腺/卵巢癌特异性标记^{9，107，108}。为确定这些标记是否能够区别致瘤性细胞和非致性细胞，使用流式细胞仪分离对来自第一代T1或T2细胞的各标记呈阳性或阴性的细胞。当注射各群体的2×10⁵-8×10⁵个细胞时，所有CD44⁺细胞(8/8)、B38.1⁺细胞(8/8)或CD24^-/low细胞(12/12)的注射在注射后12周内产生可见的肿瘤，但CD44^-细胞(0/8)或B38.1^-细胞(0/8)注射没有产生可检测的肿瘤(表2)。尽管通过触诊在用CD24⁺细胞注射的部位没有检测到肿瘤，但通过尸检发现在用CD24⁺细胞注射的12只小鼠中的2只在注射位点上确实含有小肿瘤。这些肿瘤很可能产生自不可避免地污染分选的CD24⁺细胞的1-3％的CD24-细胞或来自具有减少的增殖能力(表2)的CD24⁺细胞。因为CD44⁺细胞是独有的B38.1⁺，在随后的检验中我们集中研究CD44和CD24标记物。Identification of tumorigenic markers. Breast cancer cells are heterogeneous with respect to the expression of various cell surface markers, including CD44, CD24 and B38.1. CD24 and CD44 are attachment molecules, while B38.1 has been described as a breast/ovarian cancer-specific^{marker9,107,108} . To determine whether these markers could distinguish tumorigenic from non-tumorigenic cells, cells that were positive or negative for each marker from first passage T1 or T2 cells were isolated using flow cytometry. When 2×10⁵ -8×10⁵ cells of each population were injected, all CD44⁺ cells (8/8), B38.1⁺ cells (8/8) or CD24^−/low cells (12/12) Injections produced visible tumors within 12 weeks post-injection, but CD44^- cell (0/8) or B38.1^- cell (0/8) injections did not produce detectable tumors (Table 2). Although no tumor was detectable by palpation at the site of injection with CD24⁺ cells, 2 of the 12 mice injected with CD24⁺ cells did contain small tumors at the injection site by necropsy. These tumors likely arose from CD24- cells that inevitably contaminate the 1-3% of sorted CD24⁺ cells or from CD24⁺ cells with reduced proliferative capacity (Table 2). Because CD44⁺ cells are exclusively B38.1⁺ , we focused on CD44 and CD24 markers in subsequent assays.

基于对已经在小鼠中传代多次的肿瘤的分析，发现了几种与正常细胞类型(谱系标记；CD2、CD3、CD10、CD16、CD18、CD31、CD64和CD140b)相关的抗原不在癌细胞中表达。通过从未传代或早期传代的肿瘤细胞中除去Lineage⁺细胞，除去了正常人白细胞、内皮细胞、间皮细胞和成纤维细胞。通过显微镜检查，Lineage^-肿瘤细胞具有致瘤性细胞(图6)的表型。Based on the analysis of tumors that have been passaged multiple times in mice, several antigens associated with normal cell types (lineage markers; CD2, CD3, CD10, CD16, CD18, CD31, CD64, and CD140b) were found not in cancer cells Express. Normal human leukocytes, endothelial cells, mesothelial cells and fibroblasts were removed by removing Lineage⁺ cells from unpassed or early passaged tumor cells. By microscopic examination, Lineage^- tumor cells had the phenotype of tumorigenic cells (Figure 6).

                 表2   肿瘤/注射   细胞/注射  8×10⁵ 5×10⁵  2×10⁵   传代的T1   CD44-   0/2  0/2   -   CD44+   2/2  2/2   -   B38.1-   0/2  0/2   -   B38.1+   2/2  2/2   -   CD24+   -  -   1/6   CD24-   -  -   6/6   传代的T2   CD44-   0/2  0/2   -   CD44+   2/2  2/2   -   B38.1-   0/2  0/2   -   B38.1+   2/2  2/2   -   CD24+   -  -   1/6   CD24-   -  -   6/6Table 2 tumor/injection cells/injection 8×10⁵ 5×10⁵ 2×10⁵ passaged T1 CD44- 0/2 0/2 - CD44+ 2/2 2/2 - B38.1- 0/2 0/2 - B38.1+ 2/2 2/2 - CD24+ - - 1/6 CD24- - - 6/6 passaged T2 CD44- 0/2 0/2 -CD44+ 2/2 2/2 - B38.1- 0/2 0/2 - B38.1+ 2/2 2/2 - CD24+ - - 1/6 CD24- - - 6/6

表2显示通过如图1中所描述的流式细胞仪分离的细胞和就注射入NOD/SCID小鼠乳房脂肪垫内后形成肿瘤的能力进行测定的结果，所述分离基于指定的标记的表达。在12周中，通过观察和触诊每周对小鼠肿瘤进行检查，然后对小鼠进行尸检以在注射部位查找肿瘤(所述肿瘤太小以至不能触诊)。对每一群体标示出形成的肿瘤的数目/进行注射的数目。除了来自CD24⁺群体的肿瘤只能依赖尸检检测外，所有肿瘤都很容易地由目视观察和触诊发现。Table 2 shows the results of cells isolated by flow cytometry as described in Figure 1 and assayed for their ability to form tumors after injection into the mammary fat pad of NOD/SCID mice, the isolation being based on the expression of the indicated markers . Mice were examined weekly for tumors by observation and palpation during 12 weeks, and mice were then necropsied to look for tumors at the site of injection (which were too small to be palpated). The number of tumors formed/injections performed is indicated for each population. All tumors were readily detected by visual inspection and palpation, with the exception of tumors from the CD24⁺ population, which could only rely on autopsy detection.

依赖于肿瘤，在肿瘤或胸膜渗出液中11％至35％的Lineage^-癌细胞是CD44⁺CD24^-/low(图4a-1f)。将CD44⁺CD24^-/lowLineage^-细胞或其它分离自9位患者的Lineage^-癌细胞群体注射到小鼠的乳房脂肪垫中(表3)。当注射未分选的、传代的T1或T2细胞时，5×10⁴个细胞一致地产生肿瘤，但10⁴个细胞只在少数情况下产生肿瘤。相反地，少至10³个T1或T2 CD44⁺CD24^-/lowLineage^-细胞在所有情况下(表3)产生肿瘤。在T1和T2中，高达2×10⁴个CD44⁺Lineage^-但非CD24⁺的细胞不能形成肿瘤。这些数据暗示相对于未分级分离的肿瘤细胞，就在NOD/SCID小鼠内形成肿瘤的能力而言，CD44⁺CD24^-/lowLineage^-群体被富集了10-50倍。无论CD44⁺CD24^-/lowLineage^-细胞分离自传代的肿瘤(T1、T2、T3)还是分离自直接获自患者的未传代癌细胞(T1、T4-T6、T8、T9)，就致瘤性活性而言它们是富集的。注意T7是9个经研究的癌症中仅有的一个不满足该模式(图4f)的癌细胞。除了T7外，在未传代和传代的肿瘤中的CD24⁺Lineage^-癌细胞都不能形成新肿瘤(表3)。因此，异种移植和未传代患者的肿瘤由相似的表型各异的癌细胞类型群体组成，并且在两种情况下只有CD44⁺CD24^-/lowLineage^-细胞具有增殖形成新肿瘤(p＜0.001)的能力。Depending on the tumor, 11% to 35% of Lineage^- cancer cells in tumor or pleural effusion were CD44⁺ CD24^-/low (Fig. 4a-1f). CD44⁺ CD24^-/low Lineage^- cells or other Lineage^- cancer cell populations isolated from 9 patients were injected into the mammary fat pad of mice (Table 3). When injected with unsorted, passaged T1 or T2 cells, 5 x¹⁰⁴ cells consistently produced tumors, but¹⁰⁴ cells produced tumors only in a few cases. In contrast, as few as 10³ T1 or T2 CD44⁺ CD24^−/low Lineage⁻ cells produced tumors in all cases (Table 3). In T1 and T2, up to 2 x 10⁴ CD44⁺ Lineage^- but not CD24⁺ cells failed to form tumors. These data suggest that the CD44⁺ CD24^-/low Lineage^- population is enriched 10-50 fold relative to unfractionated tumor cells for their ability to form tumors in NOD/SCID mice. Whether CD44⁺ CD24^-/low Lineage^- cells were isolated from passaged tumors (T1, T2, T3) or from unpassaged cancer cells obtained directly from patients (T1, T4-T6, T8, T9), tumorigenicity They are enriched in terms of activity. Note that T7 was the only cancer cell among the 9 cancers studied that did not fit this pattern (Fig. 4f). With the exception of T7, CD24^+Lineage- cancer cells in both unpassaged and passaged tumors were unable to form new tumors (Table 3). Thus, tumors from xenografted and unpassaged patients consisted of similar phenotypically diverse populations of cancer cell types, and in both cases only CD44⁺ CD24^-/low Lineage^- cells proliferated to form new tumors (p<0.001) Ability.

                                                           表3   每次注射的细胞数   5×10⁵   10⁵   5×10⁴   2×10⁴   10⁴   5×10³   10³   500   200   100   小鼠传代1   未分选的   8/8   8/8   10/10   3/12   0/12   CD44⁺CD24⁺   0/10   0/10   0/14   0/10   CD44⁺CD24^-/low   10/10   10/10   14/14   10/10   CD44⁺CD24^-/lowESA⁺   10/10^*   4/4   4/4   1/6   CD44⁺CD24^-/lowESA^-   0/10^*   0/4   0/4   0/6   小鼠传代2   CD44⁺CD24⁺   0/9   CD44⁺CD24^-/low   9/9   患者肿瘤细胞   CD44⁺CD24⁺   0/3   0/4   0/8   1/13   0/2   CD44⁺CD24^-/low   3/3   4/4   11/13   1/1   CD44⁺CD24^-/lowESA⁺   2/2   2/2   CD44⁺CD24^-/lowESA^-   2/2^#   0/2table 3 Number of cells per injection 5×10⁵ 10⁵ 5×10⁴ 2×10⁴ 10⁴ 5×10³ 10³ 500 200 100mouse passage 1 Unsorted 8/8 8/8 10/10 3/12 0/12 CD44⁺ CD24⁺ 0/10 0/10 0/14 0/10 CD44⁺ CD24-^/low 10/10 10/10 14/14 10/10 CD44⁺ CD24^-/low ESA⁺ 10/10^* 4/4 4/4 1/6 CD44⁺ CD24^-/low ESA^- 0/10^* 0/4 0/4 0/6mouse passage 2 CD44⁺ CD24⁺ 0/9 CD44⁺ CD24-^/low 9/9 patient tumor cells CD44⁺ CD24⁺ 0/3 0/4 0/8 1/13 0/2 CD44⁺ CD24-^/low 3/3 4/4 11/13 1/1 CD44⁺ CD24^-/low ESA⁺ 2/2 2/2 CD44⁺ CD24^-/low ESA^- 2/2^# 0/2

如表3中所显示的，在ESA⁺CD44⁺CD24^-/low群体中高度富集了致瘤性乳腺癌细胞。从第一代(称为小鼠1代)肿瘤1、肿瘤2和肿瘤3、第二代肿瘤3(称作小鼠2代)、以及6个不同患者的未传代细胞，T1、T4、T5、T6、T8和T9(称作患者肿瘤细胞)中分离细胞。如图1中所描述的通过流式细胞仪分离CD44⁺CD24⁺Lineage^-群体和CD44⁺CD24^-/lowLineage^-细胞。将指定数目的各表型细胞注射入NOD/SCID小鼠的乳腺中。通过经修饰的最大似然分析方法计算的致瘤性细胞的频率是大约5/10⁵，如果单个致瘤性细胞能够形成肿瘤，并且每个移植的致瘤性细胞产生肿瘤¹⁰⁹。因此，该计算可能低估致瘤性细胞的频率，因为其没有考虑细胞-细胞的相互作用和可能影响移植的局部环境因素。除了显示的标记外，在所有检验中所有分选的细胞都是Lineage^-，并且就B38.1+进一步选择来自T1、T2和T3的致瘤性细胞。在4-6.5个月中每周对小鼠进行观察，或直至小鼠因肿瘤得病。#由T5ESA^-CD44⁺CD24^-/lowLineage^-细胞形成的肿瘤推迟了2-4周。*在这些检验中注射2,000个细胞。As shown in Table 3, tumorigenic breast cancer cells were highly enriched in the ESA⁺ CD44⁺ CD24-^/low population. From the first generation (referred to as mouse passage 1)tumor 1,tumor 2 andtumor 3, second generation tumor 3 (referred to as mouse passage 2), and unpassaged cells from 6 different patients, T1, T4, T5 , T6, T8 and T9 (referred to as patient tumor cells) isolated cells. CD44⁺ CD24⁺ Lineage^- populations and CD44⁺ CD24^-/low Lineage^- cells were separated by flow cytometry as described in Figure 1 . The indicated numbers of cells of each phenotype were injected into the mammary glands of NOD/SCID mice. The frequency of tumorigenic cells calculated by the modified maximum likelihood analysis method is approximately 5/10⁵ if a single tumorigenic cell is capable of forming a tumor and each transplanted tumorigenic cell produces a tumor¹⁰⁹ . Therefore, this calculation may underestimate the frequency of tumorigenic cells because it does not take into account cell-cell interactions and local environmental factors that may affect transplantation. All sorted cells were Lineage⁻ in all assays except for the markers shown, and tumorigenic cells from T1, T2 and T3 were further selected for B38.1+. Mice were observed weekly for 4-6.5 months or until mice became diseased by tumors. #Tumor formation by T5ESA^- CD44⁺ CD24^-/low Lineage^- cells is delayed by 2-4 weeks. *2,000 cells were injected in these assays.

图1显示致瘤性细胞的分离。使用流式细胞仪分离在NOD/SCID小鼠中进行致瘤性检验的肿瘤1(a，b)、肿瘤3(c)、肿瘤5(d)、肿瘤6(e)和肿瘤7细胞(f)的亚群。T1(b)和T3(c)已在NOD/SCID小鼠中传代(P)一次，而其余细胞是冷冻的或在从患者中取出后直接获得的非冷冻样品(UP)。用抗CD44、CD24、谱系标记和小鼠-H2K(用于获自小鼠的传代的肿瘤)的抗体和7AAD对细胞进行染色。从所有分析中除去死亡细胞(7AAD+)、小鼠细胞(H2K⁺)和Lineage⁺正常细胞。图1中的各图描述了活的人Lineage^-癌细胞的CD24和CD44染色模式，并且显示了作为癌细胞/各样品中所有细胞的百分比的方框标记的致瘤性癌细胞群体的频率。Figure 1 shows the isolation of tumorigenic cells. Tumor 1 (a, b), tumor 3 (c), tumor 5 (d), tumor 6 (e) andtumor 7 cells (f) tested for tumorigenicity in NOD/SCID mice were separated by flow cytometry ) subgroup. T1(b) and T3(c) had been passaged once in NOD/SCID mice (P), while the remaining cells were either frozen or obtained as unfrozen samples (UP) directly after removal from the patient. Cells were stained with antibodies against CD44, CD24, lineage markers and mouse-H2K (for passaged tumors obtained from mice) and 7AAD. Dead cells (7AAD+), mouse cells (H2K⁺ ) and Lineage⁺ normal cells were removed from all analyses. The panels in Figure 1 depict CD24 and CD44 staining patterns of live human Lineage^- cancer cells and show the frequency of the box-marked tumorigenic cancer cell population as a percentage of cancer cells/all cells in each sample.

在其中三个肿瘤中，通过分离CD44⁺CD24^-/low群体的ESA⁺亚群可能进一步富集致瘤性活性。ESA(上皮特异性抗原，Ep-CAM)在过去曾被用于区别上皮癌细胞和良性反应性间皮细胞¹¹⁰。当从传代的T1中分离ESA⁺CD44⁺CD24^-/lowLineage^-细胞时，在注射后5-6个月期间少至200个细胞一致地形成大约1cm左右的肿瘤，而2000个ESA^-CD44⁺CD24^-/lowLineage^-细胞或20,000个CD44⁺CD24⁺细胞总是不能形成肿瘤(表3)。一万个未分选的细胞仅在12只小鼠中的3只中形成肿瘤。这暗示着ESA⁺CD44⁺CD24^-/lowLineage^-群体相对未分级分离的肿瘤细胞(表3)，形成肿瘤的能力富集了超过50倍。ESA⁺CD44⁺CD24^-/lowLineage^-群体占第一代T1细胞(2.5-5％的癌细胞)的2-4％。来自未传代的T5细胞的ESA⁺CD44⁺CD24^-/lowLineage^-群体(0.6％的癌细胞)与ESA^-CD44⁺CD24^-/lowLineage^-细胞相比致瘤性活性也被富集了，但ESA⁺和ESA^-级分都具有一些致瘤性活性(表3)。在未传代的T5细胞中，低至1000个ESA⁺CD44⁺CD24^-/lowLineage^-细胞一致地形成肿瘤。In three of these tumors, tumorigenic activity might be further enriched by segregating the ESA⁺ subpopulation of the CD44⁺ CD24-^/low population. ESA (Epithelial Specific Antigen, Ep-CAM) has been used in the past to differentiate epithelial cancer cells from benign reactive mesothelial cells¹¹⁰ . When ESA⁺ CD44⁺ CD24^-/low Lineage^- cells were isolated from passaged T1, as few as 200 cells consistently formed tumors around 1 cm during 5-6 months after injection, while 2000 ESA^- CD44⁺ CD24^-/low Lineage^- cells or 20,000 CD44⁺ CD24⁺ cells were always unable to form tumors (Table 3). Ten thousand unsorted cells formed tumors in only 3 of 12 mice. This implies that the ESA⁺ CD44⁺ CD24^-/low Lineage^- population is more than 50-fold enriched in tumor-forming ability relative to unfractionated tumor cells (Table 3). The ESA⁺ CD44⁺ CD24^-/low Lineage^- population accounts for 2-4% of first generation T1 cells (2.5-5% of cancer cells). ESA⁺ CD44⁺ CD24^-/lowLineage -population (0.6% of cancer cells) from unpassaged T5 cells was also enriched for tumorigenic activity compared to ESA^- CD44⁺ CD24^-/low Lineage^- cells, but Both ESA⁺ and^ESA- fractions had some tumorigenic activity (Table 3). In unpassaged T5 cells, as low as 1000 ESA⁺ CD44⁺ CD24^-/low Lineage^- cells consistently formed tumors.

为了确定细胞群体的致瘤性不同是否是由于细胞周期的不同造成的，通过流式细胞仪分析群体。来自T1的致瘤性和非致瘤性癌细胞的细胞周期状况的比较表明两者都表现相似的细胞周期分布(图2a、2b)。因此，没有一个群体富集了处于特定的细胞周期阶段的细胞，并且在异种移植模型中，非致瘤性细胞至少能够进行有限数量的分裂。To determine whether the differences in tumorigenicity of the cell populations were due to differences in the cell cycle, the populations were analyzed by flow cytometry. Comparison of the cell cycle profiles of tumorigenic and non-tumorigenic cancer cells from T1 showed that both exhibited similar cell cycle distributions (Fig. 2a, 2b). Thus, neither population was enriched for cells at a specific cell cycle stage, and non-tumorigenic cells were able to undergo at least a limited number of divisions in xenograft models.

图2显示致瘤性和非致瘤性乳腺癌细胞的DNA含量。通过DNA含量(20)的hoechst33342染色确定ESA⁺CD44⁺CD24^-/lowLineage^-致瘤性细胞(a)和分离自T1的其它Lineage^-非致瘤性癌细胞(b)的细胞周期状态。致瘤性和非致瘤性细胞群体表现出相似的细胞周期分布。Figure 2 shows the DNA content of tumorigenic and non-tumorigenic breast cancer cells. Cell cycle status of ESA⁺ CD44⁺ CD24^-/low Lineage^- tumorigenic cells (a) and other Lineage^- non-tumorigenic cancer cells (b) isolated from T1 was determined by hoechst33342 staining for DNA content (20). Tumorigenic and non-tumorigenic cell populations exhibit similar cell cycle distributions.

在接种6个月后，通过组织学检查20,000致瘤性CD44⁺CD24^-/lowLineage^-细胞和20,000CD44⁺CD24⁺Lineage^-细胞的注射部位。CD44⁺CD24^-/lowLineage^-注射部位含有直径大约1cm的肿瘤，而CD44⁺CD24⁺Lineage^-注射部分不含有可检测的肿瘤(图6c)。通过组织学在CD44⁺CD24⁺Lineage^-注射部位(图3a)只看到正常的小鼠乳房组织，但CD44⁺CD24^-lowLineage^-细胞形成的肿瘤包含通过苏木精和曙红染色切片(图3b)判断为恶性肿瘤细胞的细胞。甚至在16-29周后对来自58只小鼠的CD44⁺CD24⁺Lineage^-注射部位(各施用1,000-50,000个细胞)进行检查时，没有检测到肿瘤。此外，致瘤性和非致瘤性群体在形态学上是不能区别的。来自传代和未传代肿瘤的Lineage^-细胞的致瘤性和非致瘤性亚群包含＞95％的被Wright染色或Papanicolaou染色和显微镜观察判断为癌细胞的细胞。通过组织学，CD44⁺CD24^-/lowLineage^-细胞和剩下的Lineage^-细胞具有上皮癌细胞的表型(图3d，3e)。Six months after inoculation, the injection site of 20,000 tumorigenic CD44⁺ CD24^−/low Lineage⁻ cells and 20,000 CD44⁺ CD24⁺ Lineage⁻ cells was examined histologically. CD44⁺ CD24^-/low Lineage^- injection sites contained tumors approximately 1 cm in diameter, whereas CD44⁺ CD24^+Lineage -injected sections contained no detectable tumors (Fig. 6c). Only normal mouse mammary tissue was^seen by histology at the CD44^+CD24+ Lineage^- injection site (Fig^. 3b) Cells judged to be malignant tumor cells. Even when CD44⁺ CD24⁺ Lineage^-injection sites from 58 mice (1,000-50,000 cells administered each) were examined after 16-29 weeks, no tumors were detected. Furthermore, tumorigenic and non-tumorigenic populations were morphologically indistinguishable. Tumorogenic and non-tumorigenic subpopulations of Lineage^- cells from passaged and unpassaged tumors contained >95% of cells judged to be cancerous by Wright staining or Papanicolaou staining and microscopic observation. By histology, CD44⁺ CD24^-/low Lineage^- cells and the remaining Lineage^- cells had the phenotype of epithelial cancer cells (Fig. 3d, 3e).

图3显示来自CD24⁺注射部位(a)的组织学结果，(20x物镜放大)表明只有正常小鼠组织，而CD24^-/low注射部位(b)，(40x物镜放大)含有恶性肿瘤细胞。(c)在小鼠中CD44⁺CD24^-/1owLineage^-注射部位具有代表性肿瘤，但在CD44⁺CD24⁺Lineage^-注射部分没有。用Papanicolaou染色对T3细胞进行染色并进行显微检查(100x物镜)。非致瘤性(c)和致瘤性(d)群体都包含具有致瘤性表型(具有大细胞核和明显的核仁)的细胞。Figure 3 shows the histological results from the CD24⁺ injection site (a), (20x objective magnification) showing only normal mouse tissue, while the CD24-^/low injection site (b), (40x objective magnification) contained malignant tumor cells. (c) Representative tumors at CD44⁺ CD24-^/1ow Lineage^- injected sites in mice, but not in CD44⁺ CD24⁺ Lineage^- injected sections. T3 cells were stained with Papanicolaou stain and examined microscopically (100x objective). Both non-tumorigenic (c) and tumorigenic (d) populations contain cells with a tumorigenic phenotype with large nuclei and prominent nucleoli.

致瘤性群体能够产生发现于起始肿瘤中的表型异质性。少数CD44⁺CD24^-/lowLineage^-致瘤性细胞产生新肿瘤的能力使人联想起正常干细胞的器官发生能力。正常干细胞自我更新并产生具有减少的增殖潜能的表型各异的细胞。为检测致瘤性乳腺癌细胞是否也表现这些特性，将产生自200ESA⁺CD44⁺CD24^-/lowLineage^-T1或1,000CD44⁺CD24^-/lowLineage^-T2细胞的肿瘤分离并通过流式细胞仪进行分析。ESA、CD44或CD24在次生肿瘤中的异质性表达模式类似于其所起源的肿瘤的(图7a、7b和7e、7f相比)表型复杂性。在这些次生肿瘤内，CD44⁺CD24^-/1owLineage^-细胞仍保持致瘤性，而其它Lineage^-癌细胞仍保持非致瘤性(表3)。因此致瘤性细胞产生另外的CD44⁺CD24^-/lowLineage^-致瘤性细胞和产生表型各异的非致瘤性细胞，所述细胞概括了所述致瘤性细胞所起源的原发肿瘤的复杂性。这些来自T1、T2和T3的CD44⁺CD24^-/lowLineage^-致瘤性细胞通过在小鼠中经历4轮肿瘤形成已进行系列传代，在各代中产生类似的结果，没有显著减少的致瘤性迹象。这些观察暗示CD44⁺CD24^-/lowLineage^-致瘤性癌细胞进行类似于正常干细胞自我更新和分化的过程。Oncogenic populations are capable of generating the phenotypic heterogeneity found in the starting tumor. The ability of a small number of CD44⁺ CD24^-/low Lineage^- tumorigenic cells to generate new tumors is reminiscent of the organogenic capacity of normal stem cells. Normal stem cells self-renew and give rise to phenotypically diverse cells with reduced proliferative potential. To test whether tumorigenic breast cancer cells also exhibit these properties, tumors arising from 200ESA⁺ CD44⁺ CD24^-/low Lineage^- T1 or 1,000 CD44⁺ CD24^-/low Lineage^- T2 cells were isolated and analyzed by flow cytometry analyze. The heterogeneous expression pattern of ESA, CD44 or CD24 in secondary tumors was similar to the (compare Figures 7a, 7b and 7e, 7f) phenotypic complexity of the tumors from which they originated. Within these secondary tumors, CD44⁺ CD24^-/1ow Lineage^- cells remained tumorigenic, while other Lineage^- cancer cells remained non-tumorigenic (Table 3). Thus tumorigenic cells give rise to additional CD44⁺ CD24^-/low Lineage^- tumorigenic cells and to non-tumorigenic cells of phenotype that recapitulate the primary tumor from which the tumorigenic cells originated complexity. These CD44⁺ CD24^-/low Lineage^- tumorigenic cells from T1, T2, and T3 have been serially passaged by undergoing 4 rounds of tumor formation in mice, producing similar results at each passage without significant reduction in tumorigenicity sexual signs. These observations imply that CD44⁺ CD24^-/low Lineage^- tumorigenic cancer cells undergo processes similar to normal stem cell self-renewal and differentiation.

图4显示产生自CD44⁺CD24^-/1owLineage^-细胞的肿瘤的表型多样性。图描述了来自肿瘤1(a，c和e)或肿瘤2(b，d和f)的活的人Lineage^-癌细胞的CD24和CD44或ESA染色模式。T1 CD44⁺Lineage^-细胞(a)或T2 Lineage^-细胞(b)获自已在NOD/SCID小鼠中传代一次的肿瘤。分离来自T1的ESA⁺CD44⁺CD24^-/lowLineage^-致瘤性细胞(c)或来自T2的CD44⁺CD24^-/lowLineage^-致瘤性细胞(d)并注射入NOD/SCID小鼠的乳腺中。图版(e)和(f)描述了产生自这些细胞的肿瘤的分析。在两种情况下，致瘤性细胞型成含有与在原始肿瘤中观察到的相似的表型多样的细胞。Figure 4 shows the phenotypic diversity of tumors arising from CD44⁺ CD24^-/1ow Lineage^- cells. Graphs depict CD24 and CD44 or ESA staining patterns of live human Lineage^- carcinoma cells from tumor 1 (a, c and e) or tumor 2 (b, d and f). T1 CD44⁺ Lineage^- cells (a) or T2 Lineage^- cells (b) were obtained from tumors that had been passaged once in NOD/SCID mice. ESA⁺ CD44⁺ CD24^-/low Lineage^- tumorigenic cells from T1 (c) or CD44⁺ CD24^-/low Lineage^- tumorigenic cells from T2 (d) were isolated and injected into the mammary glands of NOD/SCID mice middle. Panels (e) and (f) depict the analysis of tumors arising from these cells. In both cases, tumorigenic cells typified into diverse cells containing a phenotype similar to that observed in the original tumor.

Wnt途径基因在乳腺癌肿瘤细胞中的表达。Frizzled蛋白是Wnt家族的生长/存活因子的受体。在一些正常的干细胞中，已知Wnt在增殖、存活和分化中发挥作用。在某些情况下，刺激Wnt可提高干细胞自我更新。当激活时，Wnt诱导β连环蛋白的稳定性。使用抗β连环蛋白的抗体的流式细胞术证实肿瘤1细胞表达该蛋白(图5)。免疫组织化学显示β连环蛋白位于细胞质中和核中，表明所述蛋白是活化的(数据未显示)。不同的Wnt蛋白特异性地激活不同的frizzled受体(44)。因为Wnt信号传导途径似乎在正常和乳腺癌细胞的增殖(14，27)中发挥至关重要的作用，所以检查Wnt途径基因在肿瘤1致瘤性细胞和非致瘤性细胞中的表达(图5)。为进行该检查，分离100个ESA⁺B38.1⁺CD24^-/lowLineage^-(致瘤性)或非致瘤性细胞。进行使用针对各frizzled蛋白的嵌套引物的RT-PCR。这些结果表明致瘤性细胞表达frizzled2和6，而非致瘤性细胞表达frizzled2和7(图5)。这些检验已重复两次，结果一致。然后，确定由乳腺癌细胞表达的Wnt家族成员。从10,000个干细胞和非致瘤性细胞中分离RNA。由于存在超过20个已知的Wnt家族成员，使在乳腺癌肿瘤中分析特定Wnts的表达非常困难。因此使用识别所有已知Wnt基因的简并引物进行RT-PCR并克隆和对所得的cDNA进行测序。令人惊奇的是，我们仅能够检测非致瘤性细胞(图5)的cDNA表达。这在十个细胞的水平上进行RT-PCR得到证实。在十个致瘤性样品的九个中检测到frizzled6，而在10个非致瘤性细胞样品中只有一个被检测到。克隆cDNA，测序表明这些细胞表达Wnt 3A、4、7A、7B、10B和11。Wnt信号参与乳腺癌细胞和正常内皮细胞的生长。尽管不必理解本发明如何实施，但这暗示非致瘤性细胞通过刺激乳腺癌干细胞和通过Wnt途径形成血管来促进肿瘤形成。本模型非常符合已知的观察：即与使用单个细胞(22)相反，使用组织碎片培养乳腺癌要容易得多。Expression of Wnt pathway genes in breast cancer tumor cells. Frizzled proteins are receptors for growth/survival factors of the Wnt family. In some normal stem cells, Wnts are known to play a role in proliferation, survival and differentiation. In certain instances, stimulating Wnt can enhance stem cell self-renewal. When activated, Wnt induces the stabilization of β-catenin. Flow cytometry using an antibody against β-catenin confirmed thattumor 1 cells expressed the protein (Fig. 5). Immunohistochemistry showed that β-catenin was localized in the cytoplasm and in the nucleus, indicating that the protein was active (data not shown). Different Wnt proteins specifically activate different frizzled receptors (44). Because the Wnt signaling pathway appears to play a crucial role in the proliferation of normal and breast cancer cells (14, 27), the expression of Wnt pathway genes in tumorigenic and non-tumorigenic cells oftumor 1 was examined (Fig. 5). For this examination, 100 ESA⁺ B38.1⁺ CD24^−/low Lineage⁻ (tumorigenic) or non-tumorigenic cells were isolated. RT-PCR using nested primers for each frizzled protein was performed. These results indicate that tumorigenic cells express frizzled2 and 6, whereas non-tumorigenic cells express frizzled2 and 7 (Fig. 5). These tests have been repeated twice with consistent results. Then, the Wnt family members expressed by the breast cancer cells were identified. RNA isolation from 10,000 stem and non-tumorigenic cells. Profiling the expression of specific Wnts in breast cancer tumors is difficult due to the existence of more than 20 known Wnt family members. RT-PCR was therefore performed using degenerate primers recognizing all known Wnt genes and the resulting cDNA was cloned and sequenced. Surprisingly, we were only able to detect cDNA expression in non-tumorigenic cells (Figure 5). This was confirmed by RT-PCR at the level of ten cells. frizzled6 was detected in nine out of ten tumorigenic samples, while it was detected in only one out of 10 non-tumorigenic cell samples. Cloning of cDNAs and sequencing showed that these cells expressedWnt 3A, 4, 7A, 7B, 10B and 11. Wnt signaling is involved in the growth of breast cancer cells and normal endothelial cells. Although it is not necessary to understand how the invention works, it is suggested that non-tumorigenic cells promote tumor formation by stimulating breast cancer stem cells and forming blood vessels through the Wnt pathway. This model fits well with the known observation that breast cancer is much easier to grow using tissue fragments as opposed to using single cells (22).

图5显示Wnt(左图)和frizzled(右图)的表达。关于左图，使用简并Wnt引物和分离自10,000个指定类型的细胞的RNA进行RT-PCR。+或-表示是否使用RT。右图，从100个通过图1中所述的流式细胞仪分离的乳腺癌细胞或乳腺癌干细胞中分离RNA。通过使用嵌套引物进行RT-PCR以检测指定的mRNA。省略RT的对照RT-PCR反应是阴性。Figure 5 shows the expression of Wnt (left panel) and frizzled (right panel). For the left panel, RT-PCR was performed using degenerate Wnt primers and RNA isolated from 10,000 cells of the indicated types. + or - indicates whether to use RT. Right panel, RNA isolation from 100 breast cancer cells or breast cancer stem cells isolated by flow cytometry as described in Figure 1. RT-PCR was performed using nested primers to detect the indicated mRNAs. Control RT-PCR reactions omitting RT were negative.

为确定fizzled蛋白表达的RT-PCR结果，用从肿瘤1、肿瘤2和肿瘤3癌干细胞制备的cDNA探测Affymetrix微阵列。所有三种肿瘤表达Frizzled2&6。此外，肿瘤2&3似乎表达frizzled4。To confirm the RT-PCR results of fizzled protein expression, cDNAs prepared fromtumor 1,tumor 2 andtumor 3 cancer stem cells were probed with Affymetrix microarrays. All three tumors expressed Frizzled2&6. Furthermore,tumors 2 & 3 appear to express frizzled4.

来自肿瘤的正常细胞的分离。然后努力确定是否可从肿瘤中分离足够的正常细胞以用这些细胞进行分子研究。通过流式细胞仪分离来自患者肿瘤(大小接近3cm)的正常成纤维细胞和内皮细胞。2％的肿瘤细胞是CD31⁺内皮细胞，8％的是CD140b⁺成纤维细胞(图6)。当1/45的肿瘤用于流式细胞仪时收集9,000个成纤维细胞和2,000个内皮细胞。通过推断，可以从完整的肿瘤中分离大约90,000个内皮细胞和405,000个成纤维细胞。Isolation of normal cells from tumors. Efforts were then made to determine whether enough normal cells could be isolated from the tumor to use them for molecular studies. Normal fibroblasts and endothelial cells from patient tumors (approximately 3 cm in size) were isolated by flow cytometry. 2% of tumor cells were CD31⁺ endothelial cells and 8% were CD140b⁺ fibroblasts (Fig. 6). When 1/45 of the tumors were used for flow cytometry, 9,000 fibroblasts and 2,000 endothelial cells were collected. By extrapolation, approximately 90,000 endothelial cells and 405,000 fibroblasts could be isolated from intact tumors.

图6显示正常肿瘤成纤维细胞和内皮细胞的分离。如方法部分中描述的一样分离肿瘤，用标记有抗-CD2、-CD3、-CD16、CD18、-CD45、-CD64和抗-B38.1-APC(以分别除去造血细胞和肿瘤细胞)、抗-CD140b-PE和抗-CD31-FITC的抗体的细胞色素对肿瘤细胞进行染色。A：方框表示针对成纤维细胞的分选门控，所述成纤维细胞是Lineage^-CD31^-CD140b⁺细胞。B：方框表示针对内皮细胞的分选门控，所述内皮细胞是CD31⁺Lineage^-细胞。Figure 6 shows the isolation of normal tumor fibroblasts and endothelial cells. Tumors were isolated as described in the methods section and treated with anti-CD2, -CD3, -CD16, CD18, -CD45, -CD64 and anti-B38.1-APC (to remove hematopoietic and tumor cells, respectively), anti- Cytochrome staining of tumor cells with CD140b-PE and anti-CD31-FITC antibody. A: Boxes indicate sorting gates for fibroblasts, which are Lineage⁻ CD31⁻ CD140b⁺ cells. B: Boxes indicate sorting gates for endothelial cells, which are CD31⁺ Lineage^- cells.

用腺病毒载体感染乳腺癌干细胞。因为异种移植的肿瘤只能在组织培养中短暂培养，常规的转染方法通常不能用于基因表达研究，只有病毒载体具有有效地转导乳腺癌干细胞的潜能。因此，对腺病毒载体感染T1乳腺癌干细胞的能力进行检验。为进行该检验，用0，50，500或5,000LacZ腺病毒颗粒感染10,000个乳腺癌干细胞或对照MCF-7细胞。图7显示，我们可容易地转导超过90％的所述干细胞并且使用腺病毒使其比对照MCF-7细胞更容易受到感染。这表明我们可使用腺病毒载体用重组基因转导所述干细胞。Infection of breast cancer stem cells with adenoviral vectors. Because xenografted tumors can only be cultured transiently in tissue culture, conventional transfection methods often cannot be used for gene expression studies, and only viral vectors have the potential to efficiently transduce breast cancer stem cells. Therefore, the ability of adenoviral vectors to infect T1 breast cancer stem cells was examined. For this assay, 10,000 breast cancer stem cells or control MCF-7 cells were infected with 0, 50, 500 or 5,000 LacZ adenoviral particles. Figure 7 shows that we could easily transduce over 90% of the stem cells and make them more susceptible to infection than control MCF-7 cells using adenovirus. This demonstrates that we can transduce the stem cells with recombinant genes using adenoviral vectors.

图7显示用腺病毒载体感染乳腺癌干细胞。使用流式细胞仪分离CD44⁺CD241^-/lowLineage^-细胞。用0，或500，或5,000个LacZ腺病毒颗粒/细胞感染肿瘤1干细胞或对照MCF-7细胞。两天后，用X-gal对细胞进行染色。注意，肿瘤1干细胞容易被腺病毒载体感染。Figure 7 shows infection of breast cancer stem cells with adenoviral vectors. CD44⁺ CD241^-/low Lineage^- cells were isolated using flow cytometry.Tumor 1 stem cells or control MCF-7 cells were infected with 0, or 500, or 5,000 LacZ adenoviral particles/cell. Two days later, cells were stained with X-gal. Note thatTumor 1 stem cells are susceptible to infection with adenoviral vectors.

下列数据描述了已进行的研究造血干细胞的工作。其说明了基本的干细胞特征，其也展示干细胞的分离如何使人们第一次表征这些细胞，然后进行分子和生物化学研究以在功能上表征其。The following data describe the work that has been done to study hematopoietic stem cells. It illustrates basic stem cell characteristics, and it also shows how the isolation of stem cells allows one to characterize these cells for the first time, followed by molecular and biochemical studies to characterize them functionally.

成熟的干细胞数目受到严格的调控。造血干细胞(HSC)动态平衡的调控仍未获得很好的理解。我们筛选与鼠种系之间在长期重建性HSCs或骨髓中限制性祖先的数目上的差异相关的基因多态性。在AKR/J小鼠中，HSCs和其骨髓中的限制性祖先的数目和频率都高于C57BL/Ka-Thy-1.1小鼠。C57BL/Ka-Thy-1.1等位基因是部分显性的。位于17号染色体上的基因座(包括H-2复合物)显著地与长期自我更新的HSCs频率连锁但未显示与限制性祖先的频率连锁的证据。相反地，1号染色体基因座表现暗示性的与限制性祖先的频率连锁但与HSC频率不连锁。这表明在体内HSCs和限制性祖先的频率存在不同的遗传决定子。当与C57BL背景杂交时，AKR/J的17号染色体基因座不足以增力HSC频率。这暗示着要影响HSC频率，该基因座的产物可能依赖于与非连锁的修饰基因座的相互作用。本发明表明在动物中干细胞增殖在严格的遗传调控之下。The number of mature stem cells is tightly regulated. The regulation of hematopoietic stem cell (HSC) homeostasis is still not well understood. We screened for gene polymorphisms associated with differences between the murine germlines in the number of long-term reconstituted HSCs or restricted progenitors in the bone marrow. The number and frequency of HSCs and their restricted progenitors in the bone marrow were higher in AKR/J mice than in C57BL/Ka-Thy-1.1 mice. The C57BL/Ka-Thy-1.1 allele is partially dominant. Loci located on chromosome 17, including the H-2 complex, were significantly linked to the frequency of long-term self-renewing HSCs but showed no evidence of linkage to the frequency of restricted progenitors. In contrast, thechromosome 1 locus exhibited suggestive linkage to the frequency of restricted ancestry but not to HSC frequency. This suggests that there are distinct genetic determinants of the frequency of HSCs and restricted progenitors in vivo. The chromosome 17 locus of AKR/J was insufficient to augment HSC frequency when crossed to a C57BL background. This implies that to affect HSC frequency, the product of this locus may depend on interactions with non-linked modifying loci. The present invention demonstrates that stem cell proliferation in animals is under strict genetic control.

造血干细胞的基因组分析。造血干细胞(HSCs)具有自我更新能力和多谱系发育潜能。控制HSCs自我更新的分子机制仍远未明了。进行使用生物信息和阵列杂交技术以分析HSCs中基因表达特征谱的系统性方法。为富集在未定型细胞谱系中优势表达的mRNAs，从高度富集的HSCs群体以及干细胞和早期多能祖细胞(MPP)的混合群体中产生54000个cDNA克隆，并排列在尼龙膜(巨阵列或高密度阵列)上，用来源于成熟谱系细胞(包括脾、胸腺和骨髓)的cDNA探针进行减除。选择具有极弱杂交信号的5,000个cDNA克隆进行测序和使用玻璃载玻片上微阵列进一步分析。使用微阵列分析对两个细胞群体HSCs和MPP细胞进行差式基因表达比较。HSCs具有自我更新的能力，而MPP细胞已失去自我更新的能力。鉴定由富集的HSCs和MPP细胞群体差异表达的大量基因。这些包括转录因子、信号传导分子和以前未知的基因。Genomic analysis of hematopoietic stem cells. Hematopoietic stem cells (HSCs) possess self-renewal ability and multi-lineage developmental potential. The molecular mechanisms governing the self-renewal of HSCs are still far from understood. A systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs was performed. To enrich for mRNAs predominantly expressed in uncommitted cell lineages, 54,000 cDNA clones were generated from highly enriched populations of HSCs and mixed populations of stem cells and early multipotent progenitors (MPPs) and arrayed on nylon membranes (macroarray or high-density arrays), subtraction was performed with cDNA probes derived from mature lineage cells, including spleen, thymus, and bone marrow. 5,000 cDNA clones with very weak hybridization signals were selected for sequencing and further analysis using microarrays on glass slides. Differential gene expression comparisons of the two cell populations, HSCs and MPP cells, were performed using microarray analysis. HSCs have the ability of self-renewal, while MPP cells have lost the ability of self-renewal. A large number of genes differentially expressed by enriched populations of HSCs and MPP cells were identified. These include transcription factors, signaling molecules and previously unknown genes.

HSC自我更新需要Bmi-1。HSCs的基因表达分析使得我们能够鉴定对自我更新潜在重要的基因。在分析基因表达数据后，我们开始机制研究以鉴定重要的干细胞调节基因。干细胞生物学中最重要的问题是理解调节HSCs自我更新的机制，该机制是动物终生保持血细胞发生所必需的。我们发现成年和E14.5胎儿小鼠和成人造血干细胞表达原癌基因bmi-1。胎儿肝HSCs数目，如通过流式细胞仪测量的，在失去功能的bmi-1小鼠中是正常的，并且bmi-1^-/-HSCs能够正常地向趋化因子梯度迁移。在出生后的bmi-1^-/-小鼠中，HSCs的数目，但不是早期祖先细胞的数目，显著减少。当移植入致死性辐射的受体中时，获自bmi-1^-/-小鼠的胎儿肝和骨髓细胞都只能够短暂地对血细胞发生作出贡献。bmi-1^-/-小鼠中没有可检测的成熟造血干细胞的自我更新，表明存在细胞自主缺陷。该研究表明bmi-1的表达是产生自我更新成熟造血干细胞所必需的。参见Park等人，″Bmi-1 is required formaintenance of adult self-renewing hematopoietic stemcells″Nature(2003)的原稿。Bmi-1 is required for HSC self-renewal. Gene expression analysis of HSCs allowed us to identify genes potentially important for self-renewal. After analyzing the gene expression data, we initiated mechanistic studies to identify important stem cell regulatory genes. The most important question in stem cell biology is understanding the mechanisms that regulate the self-renewal of HSCs, which is required to maintain hematopoiesis throughout the life of the animal. We found that adult and E14.5 fetal mice and adult hematopoietic stem cells express the proto-oncogene bmi-1. Fetal liver HSCs numbers, as measured by flow cytometry, were normal in non-functional bmi-1 mice, and bmi-1^-/- HSCs were able to migrate normally towards chemokine gradients. In postnatal bmi-1^-/- mice, the number of HSCs, but not early progenitor cells, was significantly reduced. Both fetal liver and bone marrow cells obtained from bmi-1^-/- mice were only transiently able to contribute to hematopoiesis when transplanted into lethally irradiated recipients. There is no detectable self-renewal of mature hematopoietic stem cells in bmi-1^-/- mice, suggesting a defect in cell autonomy This study demonstrates that bmi-1 expression is required for the generation of self-renewing mature hematopoietic stem cells. See the manuscript of Park et al., "Bmi-1 is required for maintenance of adult self-renewing hematopoietic stem cells" Nature (2003).

概述：由本实验室发展的异种移植模型使可能在细胞水平进行人乳腺癌细胞的分析。尽管已证明癌细胞系可用于许多研究，但细胞系经改变适应由组织培养施予的独特条件并且其许多特性明显地与患者的肿瘤^91，109中的癌细胞不同。最近，在切除术之前的原发乳腺癌肿瘤的大小已明显减少。这使得使用患者样品进行生物学和生物化学研究变得困难。可以预期描述于初步结果中的异种移植模型改善了该问题。初步结果表明异种移植似乎包括了在原始患者的肿瘤中看到的表型和生物学多样性。尽管由于环境因素导致在小鼠和人肿瘤中可能存在一些差异，但此处描述的NOD/SCID模型是可获得的最佳人乳腺癌模型。结果表明在该异种移植模型中乳腺癌细胞可靠地移植并在早期代中反映了发现于原始人肿瘤中的细胞和生物学多样性。这些检验也显示不同的癌细胞群体可能在其形成肿瘤的能力上不同。Overview: The xenograft model developed by our laboratory enables the analysis of human breast cancer cells at the cellular level. Although cancer cell lines have proven useful in many studies, cell lines are adapted to the unique conditions imposed by tissue culture and many of their properties are distinct from cancer cells in a patient's^tumor91,109 . Recently, the size of primary breast cancer tumors prior to resection has been markedly reduced. This makes it difficult to conduct biological and biochemical studies using patient samples. The xenograft model described in the preliminary results can be expected to ameliorate this issue. Preliminary results suggest that xenografts appear to include the phenotypic and biological diversity seen in the original patient's tumor. Although there may be some differences between mouse and human tumors due to environmental factors, the NOD/SCID model described here is the best human breast cancer model available. The results demonstrate that breast cancer cells engraft reliably in this xenograft model and mirror the cellular and biological diversity found in original human tumors at early passages. These tests also showed that different populations of cancer cells may differ in their ability to form tumors.

                       实施例2Example 2

        表征人乳腺癌肿瘤中的Wnt/β-连环蛋白途径Characterization of the Wnt/β-catenin pathway in human breast cancer tumors

该实施例描述了人们是如何使用上述的异体移植模型表征人乳腺癌中的Wnt/β-连环蛋白途径。Wnt/β-连环蛋白途径在正常干细胞的增殖和自我更新中发挥作用。尽管显著百分比的人乳腺癌似乎具有该重要途径的组成型活性，与结肠癌不同，还未明确阐明该途径在人^84-89的该疾病的病理学中发挥怎样的作用。上述异种移植模型可用于在人乳腺癌肿瘤中表征该途径的生物学后果。直接使用在从患者取出后的癌细胞和早期传代异种移植肿瘤进行这些检验。This example describes how one characterized the Wnt/β-catenin pathway in human breast cancer using the xenograft model described above. The Wnt/β-catenin pathway plays a role in the proliferation and self-renewal of normal stem cells. Although a significant percentage of human breast cancers appear to have constitutive activity of this important pathway, unlike colon cancer, it has not been clearly elucidated how this pathway plays a role in the pathology of this disease in^humans84-89 . The xenograft model described above can be used to characterize the biological consequences of this pathway in human breast cancer tumors. These assays are performed using cancer cells and early passage xenograft tumors directly after removal from the patient.

Wnt/frizzled/β-连环蛋白信号传导途径在多个患者肿瘤中的功能。原理：几乎90％的直肠癌包含导致β-连环蛋白激活的突变。最普遍的突变是在APC基因上或β-连环蛋白自身^43，111的突变，所述APC基因参与靶向β-连环蛋白的降解。这些后者突变阻止了降解。尽管在许多乳腺肿瘤中癌细胞似乎具有组成型β-连环蛋白⁸⁴活性，与直肠癌相反，在APC基因或β-连环蛋白自身上的突变只占这些病例^84-89的6-10％。在乳腺癌细胞中研究Wnt/β-连环蛋白信号传导途径应当导致给该疾病的病理发生带来新的知识。存在大量的被认为差异地与不同Frizzled受体^{43，65，69，78，112}结合的Wnt蛋白。只有Wnts的亚群和经推断Frizzled受体，可激活β-连环蛋白。通常，β-连环蛋白结合细胞膜上的E-钙粘着蛋白。细胞质β-连环蛋白与APC和Axin蛋白形成复合物并有助于通过GSK3β^{87，88，111}磷酸化β-连环蛋白。然后通过遍在蛋白降解途径降解磷酸化的β-连环蛋白。然而，在通过Wnt激活Frizzled受体后，β-连环蛋白得到稳定。然后将所述蛋白转移至核内，在那里其与LGLS/BCL9、PYGO和TCF蛋白形成复合物以激活转录^113，114。我们相信我们的异种移植模型和细胞测定法是对理解该至关重要的途径来说独特和强大的工具。我们分析了具有组成型β-连环蛋白信号传导的肿瘤和10个不具此途径的肿瘤。这些研究给Wnt途径被激活的机制和在人乳腺癌中该激活的后果带来新的知识。Function of the Wnt/frizzled/β-catenin signaling pathway in multiple patient tumors. Rationale: Almost 90% of rectal cancers contain mutations that lead to β-catenin activation. The most prevalent mutations are on the APC gene, which is involved in targeting β-catenin for degradation, or on β-catenin^itself43,111 . These latter mutations prevent degradation. Although cancer cells appear to have constitutive β-^catenin84 activity in many breast tumors, in contrast to rectal cancers, mutations in the APC gene or β-catenin itself account for only^6-10 % of these cases84-89. Study of the Wnt/β-catenin signaling pathway in breast cancer cells should lead to new knowledge about the pathogenesis of this disease. There^are a large number of Wnt proteins that are thought to bind differentially to different Frizzled receptors43,65,69,78,112. Only a subset of Wnts and, putatively, Frizzled receptors, activate β-catenin. Normally, β-catenin binds E-cadherin on cell membranes. Cytoplasmic β-catenin forms a complex with APC and Axin proteins and contributes to the phosphorylation of β-catenin by^{GSK3β87,88,111} . Phosphorylated β-catenin is then degraded by the ubiquitin degradation pathway. However, upon activation of Frizzled receptors by Wnt, β-catenin is stabilized. The protein is then translocated into the nucleus where it forms a complex with LGLS/BCL9, PYGO and TCF proteins to activate^{transcription113,114} . We believe our xenograft models and cellular assays are unique and powerful tools for understanding this critical pathway. We analyzed tumors with constitutive β-catenin signaling and 10 tumors without this pathway. These studies bring new knowledge to the mechanism by which the Wnt pathway is activated and the consequences of this activation in human breast cancer.

在小鼠中，各种Wnt蛋白的异常表达导致乳腺肿瘤的形成，而在人中在乳腺癌细胞中激活的β-连环蛋白与周期蛋白D1的表达和不良预后^{78，84，115，116}相关。然而，还不知道持续的β-连环蛋白信号传导是否是致瘤性乳腺癌细胞形成肿瘤所必需的。存在几种组成型β-连环蛋白信号传导可在人乳腺癌中发挥的可能作用。第一，其可能是致瘤性癌细胞连续增殖和/或存活所必需的。第二，其可能是肿瘤起始所必需的，但随后突变避开了对β-连环蛋白信号传导的需要。第三，由于下激靶例如周期蛋白D1的激活使其可能使癌细胞对化学治疗法更具抗性。第四，组成型β-连环蛋白信号传导加速了癌细胞生长，但不是致瘤性所必需的。最后，β-连环蛋白在肿瘤形成中的作用可能在具有和不具有组成型β-连环蛋白活性的肿瘤中会有所不同。例如，前者肿瘤可能需要β-连环蛋白信号传导但后者肿瘤可能需要来自其它细胞的Wnt信号或其可能不依赖于β-连环蛋白，因为其具有组成型的下游靶例如c-myc和/或周期蛋白D1的活性。此处描述的检验通过使用新的人癌症异种移植模型设计用来区别这些可能性之间的差异。数据显示异种移植模型基本上具有人乳腺肿瘤的特征。因此，该模型允许我们尽可能在生理学条件下在从头形成的人肿瘤中研究Wnt途径。In mice, aberrant expression of various Wnt proteins leads to mammary tumor formation, whereas in humans activated β-catenin in breast cancer cells is associated with cyclin D1 expression and poor^{prognosis78,84,115,116} . However, it was not known whether sustained β-catenin signaling was required for tumor formation by tumorigenic breast cancer cells. There are several possible roles that constitutive β-catenin signaling may play in human breast cancer. First, it may be required for the continued proliferation and/or survival of tumorigenic cancer cells. Second, it may be required for tumor initiation, but then mutated to circumvent the requirement for β-catenin signaling. Third, cancer cells may be made more resistant to chemotherapy due to the activation of downstimulatory targets such as cyclin D1. Fourth, constitutive β-catenin signaling accelerates cancer cell growth but is not required for tumorigenicity. Finally, the role of β-catenin in tumorigenesis may differ in tumors with and without constitutive β-catenin activity. For example, the former tumor may require β-catenin signaling but the latter tumor may require Wnt signaling from other cells or it may not be dependent on β-catenin because it has constitutive downstream targets such as c-myc and/or Cyclin D1 activity. The assay described here was designed to discriminate between these possibilities by using a new human cancer xenograft model. The data show that the xenograft model essentially has the characteristics of human breast tumors. Thus, this model allows us to study the Wnt pathway in de novo human tumors as far as possible under physiological conditions.

β-连环蛋白是分离自多个患者的癌细胞形成肿瘤所必需的吗？此处的检验确定β-连环蛋白途径是否负责乳腺癌细胞的生长或激活是否不是肿瘤形成所必需的但确实增加了所述癌细胞增殖的速率。尽管异种移植肿瘤似乎与人肿瘤非常相似，但一段时间的选择压力产生经改变适应小鼠环境的肿瘤。这样的肿瘤中在一些方面与组成原始人肿瘤的癌细胞不同。我们鉴定来自5个不同异种移植肿瘤和5个未传代的具有激活的β-连环蛋白(通过免疫组织化学检测在细胞质和/或细胞核中表达的)的肿瘤的癌细胞以及来自5个异种移植肿瘤和5个未传代的不具有激活的β-连环蛋白(通过免疫组织化学检测，与细胞结合表达的)的肿瘤的癌细胞。我们选择对重要预测特征是异质的肿瘤，所述特征包括雌激素受体/孕酮受体(ER/PgR)、原发肿瘤和转移的肿瘤、野生型和突变体p53以及Her2/neu的扩增。Is β-catenin required for tumor formation in cancer cells isolated from multiple patients? The assay here determines whether the β-catenin pathway is responsible for the growth of breast cancer cells or whether activation is not necessary for tumor formation but does increase the rate at which the cancer cells proliferate. Although xenograft tumors appear to closely resemble human tumors, a period of selective pressure produces tumors that have been altered to adapt to the mouse environment. Such tumors differ in several respects from the cancer cells that make up the original human tumor. We identified cancer cells from 5 different xenograft tumors and 5 unpassaged tumors with activated β-catenin expressed in the cytoplasm and/or nucleus by immunohistochemistry and from 5 xenograft tumors and 5 unpassaged cancer cells of tumors without activated β-catenin (expressed in association with cells by immunohistochemistry). We selected tumors that were heterogeneous for important predictive features including estrogen receptor/progesterone receptor (ER/PgR), primary and metastatic tumors, wild-type and mutant p53 and Her2/neu Amplify.

为鉴定具有组成型活性的β-连环蛋白的细胞，我们利用下列观察：其导致β-连环蛋白的稳定和所述蛋白在细胞质和细胞核中的积累。当不被激活时，β-连环蛋白与质膜结合。因此我们使用免疫组织化学分析来自各肿瘤的乳腺癌细胞群体以确定β-连环蛋白的亚细胞定位和使用流式细胞仪确定由各细胞群体表达的β-连环蛋白的量。为进行之，我们使用流式细胞仪从多个肿瘤中分离Lineage^-癌细胞。使用存活的冷冻异种移植或患者肿瘤细胞进行该分析。然后用抗β-连环蛋白-FITC抗体染色以进行免疫组织化学检测和使用抗体厂商的方案进行流式细胞术分析(Transduction Laboratories)。具有激活的β-连环蛋白的细胞具有所述蛋白的细胞质/细胞核定位和增加的水平。To identify cells with constitutively active β-catenin, we took advantage of the observation that this leads to stabilization of β-catenin and accumulation of the protein in the cytoplasm and nucleus. When not activated, β-catenin is associated with the plasma membrane. We therefore analyzed breast cancer cell populations from each tumor using immunohistochemistry to determine the subcellular localization of β-catenin and flow cytometry to determine the amount of β-catenin expressed by each cell population. To do this, we used flow cytometry to isolate Lineage^- cancer cells from multiple tumors. This analysis was performed using viable frozen xenografts or patient tumor cells. Immunohistochemical detection was then performed by staining with anti-β-catenin-FITC antibody and flow cytometry analysis (Transduction Laboratories) using the antibody manufacturer's protocol. Cells with activated β-catenin have cytoplasmic/nuclear localization and increased levels of the protein.

为确定β-连环蛋白信号传导在肿瘤发生中的作用，用含有显性失活(dn)的TCF4-IRES-GFP迷你基因的腺病毒载体或慢病毒载体或对照GFP病毒(为详细了解病毒的构建和应用，参见¹¹⁷)感染从20个肿瘤的各肿瘤中分离的Lineage^-癌细胞。腺病毒载体短暂地表达dnTCF4 1-3周，而慢病毒载体永久地表达dnTCF4。通过使用dnTCF4迷你基因(来自Eric Fearon的礼物)已制备dnTCF4腺病毒。dnTCF4与β-连环蛋白形成复合物从而抑制通过激活的β-连环蛋白的转录反式激活。要指出的是dnTCF4阻断来自所有介导β-连环蛋白信号传导(Eric Fearon，私人通讯)的TCF家族成员的信号传导。进行有限稀释检验以确定经转导的细胞在体外形成集落和在体内形成肿瘤的能力。使用从患者或人肿瘤中分离的癌细胞以流式细胞仪进行此处的检验。通过除去谱系混合物以除去正常细胞，可测量(如下面在目的2B中描述的对正常基质细胞对致瘤性细胞生长的可能贡献进行分析)由癌症细胞在组织培养中形成的集落和在小鼠中形成的肿瘤。为确定β-连环蛋白信号传导在癌细胞生长和存活性上发挥的作用，用dnTCF4病毒(腺病毒或慢病毒载体)和对照病毒感染来自各肿瘤的5组1,000、5,000、20,000、50,000和100,000Lineage^-癌细胞，在体外在含有Notch配体Delta的培养基中培养，并确定形成的集落的数目。用细胞角质蛋白在对照组织培养板中的集落染色以确定其产生自致瘤性细胞96。在感染后两天，用荧光显微镜检查以确定大于90％的细胞被所述病毒转导。类似地，进行体内有限稀释检验以确定dnTCF4病毒是否影响从不同患者分离的癌细胞形成肿瘤。在感染后，通过流式细胞仪分离10组5,000、20,000、50,000和100,000Lineage^-癌细胞，然后用dnTCF4腺病毒或对照腺病毒进行感染。将经感染的细胞注射入NOD/SCID小鼠的乳腺中。然后我们确定在各组中需要用来形成肿瘤的癌细胞数目、各组中形成肿瘤所需的时间、各组生长速率和各组中形成的肿瘤大小。这允许我们确定β-连环蛋白是否是具有或不具有组成型激活的β-连环蛋白的癌细胞形成肿瘤所必需的。To determine the role of β-catenin signaling in tumorigenesis, adenoviral vectors or lentiviral vectors containing a dominant negative (dn) TCF4-IRES-GFP minigene or control GFP virus (for details on viral Construction and Applications, see¹¹⁷ ) Infected Lineage^- cancer cells isolated from each of the 20 tumors. Adenoviral vectors express dnTCF4 transiently for 1-3 weeks, while lentiviral vectors express dnTCF4 permanently. The dnTCF4 adenovirus has been prepared by using the dnTCF4 minigene (a gift from Eric Fearon). dnTCF4 forms a complex with β-catenin to inhibit transcriptional transactivation by activated β-catenin. It is noted that dnTCF4 blocks signaling from all TCF family members that mediate β-catenin signaling (Eric Fearon, personal communication). Limiting dilution assays were performed to determine the ability of transduced cells to form colonies in vitro and tumors in vivo. The assays herein are performed by flow cytometry using cancer cells isolated from patient or human tumors. Colonies formed by cancer cells in tissue culture and in mice can be measured (as described below in Objective 2B to analyze the possible contribution of normal stromal cells to tumorigenic cell growth) by removing the lineage mixture to remove normal cells. tumors formed in. To determine the role of β-catenin signaling in cancer cell growth and viability, five groups of 1,000, 5,000, 20,000, 50,000, and 100,000 cells from each tumor were infected with dnTCF4 virus (either adenovirus or lentivirus vector) and a control virus. Lineage^- cancer cells were cultured in vitro in media containing the Notch ligand Delta and the number of colonies formed was determined. Colonies in control tissue culture plates were stained with cytokeratin to confirm their origin from tumorigenic cells96. Two days after infection, fluorescence microscopy was used to confirm that greater than 90% of the cells were transduced by the virus. Similarly, in vivo limiting dilution assays were performed to determine whether dnTCF4 virus affects tumor formation in cancer cells isolated from different patients. After infection, 10 groups of 5,000, 20,000, 50,000 and 100,000 Lineage^- cancer cells were isolated by flow cytometry, and then infected with dnTCF4 adenovirus or control adenovirus. Infected cells were injected into the mammary glands of NOD/SCID mice. We then determined the number of cancer cells required to form tumors in each group, the time required to form tumors in each group, the growth rate in each group, and the size of tumors formed in each group. This allowed us to determine whether β-catenin is required for tumor formation by cancer cells with or without constitutively activated β-catenin.

随后的检验依赖于体内和体外有限稀释检验的结果。如果β-连环蛋白转录反式激活的抑制阻止了肿瘤形成或减慢肿瘤生长，那么我们开始检验下游β-连环蛋白靶例如周期蛋白D1或c-myc是否是致瘤性^{84，85，118}所必需的。为进行该检验，我们用对照或dnTCF4腺病毒以及对照gfp载体、c-myc-IRES-gfp逆转录病毒载体、细胞周期蛋白D1-IRES-rfp逆转录病毒载体或myc-IRES-gfp和细胞周期蛋白D1-IRES-rfp逆转录病毒载体两者感染通过流式细胞仪分离的Lineage^-群体和感染细胞。通过流式细胞仪分离感染的细胞，然后将10组5,000、10,000、20,000、50,000或100,000各检验组的Lineage^-癌细胞注射入小鼠中。每周分析小鼠的肿瘤形成和各受试组的生长速率。这允许我们确定增强的c-myc和/或细胞周期蛋白的表达是否将细胞从β-连环蛋白信号传导的抑制中挽救出来。Subsequent testing relies on the results of in vivo and in vitro limiting dilution assays. If inhibition of β-catenin transcriptional transactivation prevented tumor formation or slowed tumor growth, we set out to examine whether downstream β-catenin targets such as cyclin D1 or c-myc were^{tumorigenic84,85,118} required. For this assay, we used control or dnTCF4 adenovirus together with control gfp vector, c-myc-IRES-gfp retroviral vector, cyclin D1-IRES-rfp retroviral vector or myc-IRES-gfp and cell cycle The protein D1-IRES-rfp retroviral vector both infects Lineage^- populations and infects cells isolated by flow cytometry. Infected cells were isolated by flow cytometry, and then 10 groups of 5,000, 10,000, 20,000, 50,000 or 100,000 Lineage^- cancer cells of each test group were injected into mice. Mice were analyzed weekly for tumor formation and growth rate for each test group. This allowed us to determine whether enhanced expression of c-myc and/or cyclins rescued cells from inhibition of β-catenin signaling.

如果β-连环蛋白的抑制对肿瘤的形成没有任何明确的作用，那么我们首先确定两种显性失活的病毒是否抑制dnTCF4迷你基因的表达。如果不是，我们使用另一种方法抑制β-连环蛋白途径。除了RNA-i和反义方法^119-122以外，过量表达Axin(将β-连环蛋白靶向降解)可用于抑制β-连环蛋白^66，75。如果β-连环蛋白信号传导被抑制并且对肿瘤形成影响最小或没有影响，那么我们确定对癌症干细胞是否产生更细微的变化。周期蛋白D1的表达(其表达由β-连环蛋白诱导)涉及对化疗的抗性。因此，我们在dnTCF4诱导或对照癌干细胞注射入小鼠中5天后用阿霉素(8mg/kg)或泰素(60mg/kg)处理小鼠以确定β-连环蛋白的抑制是否增强化疗的效果。如上所述确定对肿瘤形成和肿瘤生长速度的影响。If inhibition of β-catenin did not have any clear effect on tumor formation, we first determined whether the two dominant negative viruses inhibited the expression of the dnTCF4 minigene. If not, we use another approach to inhibit the β-catenin pathway. In addition to RNA-i and antisense approaches^119-122 , overexpression of Axin (which targets β-catenin for degradation) can be used to inhibit β-^catenin66,75 . If β-catenin signaling was inhibited with minimal or no effect on tumor formation, we determined whether more subtle changes were produced on cancer stem cells. Expression of cyclin D1, whose expression is induced by β-catenin, is involved in resistance to chemotherapy. Therefore, we treated mice with doxorubicin (8 mg/kg) or taxol (60 mg/kg) 5 days after injection of dnTCF4-induced or control cancer stem cells into mice to determine whether inhibition of β-catenin enhanced the effect of chemotherapy . Effects on tumor formation and tumor growth rate were determined as described above.

预期的结果。尽管大量乳腺肿瘤中癌细胞具有组成型活性的β-连环蛋白信号传导途径，但仍不知道该途径是否是恶性肿瘤转化所必需的。如果Wnt/β-连环蛋白途径是癌细胞形成肿瘤所必需的，那么显性失活抑制剂可阻止癌细胞形成肿瘤的能力。如果组成型β-连环蛋白信号传导在恶性肿瘤转化后增强肿瘤细胞生长，但不是肿瘤形成所必需的，那么显性失活抑制剂可减慢所述肿瘤细胞的生长但不阻止肿瘤的形成。如果肿瘤起始后的癌基因突变使细胞不依赖于Wnt途径，那么显性失活抑制剂不影响肿瘤的形成或生长。最后，Wnt途径的组成型激活可能对针对凋亡的抗性作出贡献，并因此使细胞对化疗产生抗性。expected result. Although cancer cells in a large number of breast tumors have a constitutively active β-catenin signaling pathway, it is unknown whether this pathway is required for malignant transformation. If the Wnt/β-catenin pathway is required for cancer cells to form tumors, then a dominant negative inhibitor could block the ability of cancer cells to form tumors. If constitutive β-catenin signaling enhances tumor cell growth after malignant transformation but is not required for tumor formation, a dominant negative inhibitor can slow the growth of the tumor cells without preventing tumor formation. If oncogene mutations after tumor initiation render cells independent of the Wnt pathway, dominant negative inhibitors do not affect tumor formation or growth. Finally, constitutive activation of the Wnt pathway may contribute to resistance to apoptosis and thus render cells resistant to chemotherapy.

在小鼠癌症模型中，在用这些基因转化的癌细胞中c-ras或c-myc活性的短暂抑制导致致瘤性^123，124的永久丧失。如果这对β-连环蛋白信号传导也是如此，那么通过腺病毒对信号的短暂抑制可抑制肿瘤的形成。如果β-连环蛋白信号传导的抑制可抑制致瘤性，同时细胞保持存活并且β-连环蛋白信号传导的恢复能使其形成肿瘤，那么腺病毒载体减慢肿瘤形成，而慢病毒载体抑制肿瘤的形成。如果β-连环蛋白信号传导增加增殖的速率但不负责致瘤性，那么两种病毒载体都延缓肿瘤的形成和减慢肿瘤的生长。如果一些肿瘤依赖于β-连环蛋白信号传导而另外一些依赖其它途径或具有β-连环蛋白信号传导的组成型活性的下游效应器，那么一些肿瘤受到病毒载体的影响而其它的则不受影响。在本目的中描述的检验允许我们使用具有人肿瘤特点的独特模型回答这些至关重要的问题。这些检验第一次在从头形成的人乳腺癌中描述了β-连环蛋白信号传导的生物学功能。In mouse cancer models, transient inhibition of c-ras or c-myc activity in cancer cells transformed with these genes resulted in permanent loss of^{tumorigenicity123,124} . If this is true for β-catenin signaling as well, transient inhibition of signaling by adenovirus could inhibit tumor formation. If inhibition of β-catenin signaling suppresses tumorigenicity while cells remain viable and restoration of β-catenin signaling allows them to form tumors, then adenoviral vectors slow tumor formation, while lentiviral vectors inhibit tumor growth. form. If β-catenin signaling increases the rate of proliferation but is not responsible for tumorigenicity, both viral vectors delay tumor formation and slow tumor growth. If some tumors are dependent on β-catenin signaling and others are dependent on other pathways or have constitutively active downstream effectors of β-catenin signaling, some tumors are affected by viral vectors while others are not. The assays described in this objective allow us to answer these crucial questions using a unique model with characteristics of human tumors. These assays describe the biological function of β-catenin signaling for the first time in de novo human breast cancer.

可使用其它包膜制备慢病毒，只要发现其能有效地^125，156感染细胞。Other envelopes can be used^to prepare lentiviruses as long as they are found to efficiently125,156 infect cells.

要指出的是使用慢病毒载体，感染效率可能只在30-70％的范围内。这意味着大量可形成肿瘤的肿瘤细胞仍然存在。然而，如果β-连环蛋白信号传导的抑制抑制了肿瘤的形成，那么所产生的肿瘤不能表达gfP。使用流式细胞仪在用dnTCF4和对照病毒感染的肿瘤中测量表达gfp的细胞。如果β-连环蛋白确实在肿瘤形成中发挥作用，那么从dnTCF4组产生的肿瘤具有显著减少的这些细胞。It is to be noted that with lentiviral vectors, infection efficiencies may only be in the range of 30-70%. This means that a large number of tumor cells that can form tumors are still present. However, if inhibition of β-catenin signaling suppresses tumor formation, the resulting tumors cannot express gfP. GFP-expressing cells were measured in tumors infected with dnTCF4 and control virus using flow cytometry. If β-catenin does play a role in tumor formation, tumors generated from the dnTCF4 group had significantly fewer of these cells.

β-连环蛋白信号传导的抑制改变致瘤性乳腺癌细胞的表型吗？一个用于分离致瘤性和非致瘤性乳腺癌细胞的能提供信息的标记是CD44。有趣地，CD44是通过β-连环蛋白上调转录的靶基因中的一个基因，上皮干细胞，但不是其分化的后代，被认为表达该标记物^83，127。我们预计β-连环蛋白信号传导的抑制导致致瘤性癌细胞的分化并导致其丧失CD44的表达。我们进一步预测CD44^-非致瘤性癌细胞不具有活性β-连环蛋白。为检验这一点，我们使用流式细胞仪从肿瘤1、肿瘤2和肿瘤3中分离ESA⁺CD44⁺CD24^-/lowLineage^-癌细胞并用dnTCF4腺病毒或对照腺病毒感染其。将所述细胞培养在含有可溶性Delta的培养基中。我们已发现该培养基允许致瘤性细胞在组织培养中生长1-3周。在体外在3周的时间内观察所述细胞的生长。此外，在感染后1、3和7天，通过流式细胞仪就ESA、CD44和CD24的表达对dnTCF4腺病毒或对照腺病毒感染的细胞进行分析。Does inhibition of β-catenin signaling alter the phenotype of tumorigenic breast cancer cells? An informative marker for the separation of tumorigenic and non-tumorigenic breast cancer cells is CD44. Interestingly, CD44 is one of the genes targeted for upregulated transcription by β-catenin, and epithelial stem cells, but not their differentiated progeny, are thought to express this^marker83,127 . We expected that inhibition of β-catenin signaling would lead to differentiation of tumorigenic cancer cells and lead to their loss of CD44 expression. We further predict that CD44^- non-tumorigenic cancer cells do not have active β-catenin. To test this, we isolated ESA⁺ CD44⁺ CD24^−/low Lineage⁻ cancer cells fromTumor 1,Tumor 2 andTumor 3 using flow cytometry and infected them with dnTCF4 adenovirus or control adenovirus. The cells were cultured in medium containing soluble Delta. We have found that this medium allows growth of tumorigenic cells in tissue culture for 1-3 weeks. The growth of the cells was observed in vitro over a period of 3 weeks. In addition, cells infected with dnTCF4 adenovirus or control adenovirus were analyzed by flow cytometry for the expression of ESA, CD44 and CD24 at 1, 3 and 7 days after infection.

然后，我们确定在致瘤性癌细胞，CD44⁺癌细胞或CD44^-癌细胞中的β-连环蛋白信号传导是否不同。为检验之，我们使用流式细胞仪从肿瘤1、肿瘤2和肿瘤3中分离ESA⁺CD44⁺CD24^1-/lowLineage^-致瘤性癌细胞、CD44⁺癌细胞和CD44^-非致瘤性癌细胞。用已缀合有APC的抗β-连环蛋白抗体对各细胞群进行染色。通过荧光显微镜分析各细胞群以确定β-连环蛋白是否与膜结合(非组成型活化的)，和通过流式细胞仪确定细胞中所述蛋白的量。β-连环蛋白的水平与活性相关。此外，我们使用商业可购得的识别磷酸化的和非磷酸化的β-连环蛋白的抗体。磷酸化形式标志着要进行降解而非磷酸化形式是活性的^18，129。这些检验使我们能够确定CD44的表达和β-连环蛋白信号传导是否在患者的癌细胞中相关。We then determined whether β-catenin signaling differs in tumorigenic, CD44⁺ or^CD44− cancer cells. To test this, we used flow cytometry to isolate ESA⁺ CD44⁺ CD24^1-/low Lineage^- tumorigenic cancer cells, CD44⁺ cancer cells and CD44^- non-tumorigenic cancer cells fromtumor 1,tumor 2, andtumor 3 cell. Each cell population was stained with an anti-β-catenin antibody to which APC had been conjugated. Each cell population was analyzed by fluorescence microscopy to determine whether β-catenin was membrane bound (not constitutively active), and by flow cytometry to determine the amount of the protein in the cells. Levels of β-catenin correlate with activity. In addition, we used commercially available antibodies recognizing phosphorylated and non-phosphorylated β-catenin. The phosphorylated form is marked for degradation and the non-phosphorylated form is active^18,129 . These assays allowed us to determine whether CD44 expression and β-catenin signaling were correlated in the patient's cancer cells.

CD44是一个允许区分致瘤性癌细胞和非致瘤性癌细胞的最佳标记物。因为CD44通过β-连环蛋白转录激活，所以抑制β-连环蛋白信号传导导致CD44的下调。CD44 is an optimal marker that allows the distinction of tumorigenic and non-tumorigenic cancer cells. Because CD44 is transcriptionally activated by β-catenin, inhibition of β-catenin signaling results in downregulation of CD44.

Frizzled蛋白的差异表达影响乳腺癌干细胞在肿瘤1中的命运吗？数据显示在肿瘤1中，致瘤性干细胞表达frizzled 2和6，而非致瘤性赘生性细胞表达Wnt3、4、7A、7B、10B和11。这暗示着在该特定肿瘤中存在旁分泌系统，其中非致瘤性细胞可能驱动癌干细胞的增殖。初步的数据表明在肿瘤1中，致瘤性干细胞表达frizzled 2和6，而非致瘤性赘生性细胞表达frizzled 2和7。Frizzled基因的差异表达可能在癌细胞的命运决定上发挥作用。其它的可能性是这些基因的差异表达是分化或永生性的函数但不直接在该肿瘤中调控细胞命运决定。该亚目标区分这些可能性之间的差别。Does differential expression of Frizzled proteins affect the fate of breast cancer stem cells intumor 1? Data showed that intumor 1, tumorigenic stem cells expressedfrizzled 2 and 6, while non-tumorigenic neoplastic cells expressed Wnt3, 4, 7A, 7B, 10B, and 11. This implies the existence of a paracrine system in this particular tumor, in which non-tumorigenic cells may drive the proliferation of cancer stem cells. Preliminary data suggest that intumor 1, tumorigenic stem cells express frizzled 2 and 6, whereas non-tumorigenic neoplastic cells express frizzled 2 and 7. The differential expression of Frizzled gene may play a role in the fate determination of cancer cells. Other possibilities are that differential expression of these genes is a function of differentiation or immortality but does not directly regulate cell fate decisions in this tumor. This subgoal differentiates between these possibilities.

肿瘤1致瘤性细胞表达frizzled 6而非致瘤性癌细胞表达frizzled 7。Frizzled 6可能增强而frizzled 7可能抑制癌细胞的增殖或自我更新。为检验这种可能性，在体外和体内进行克隆发生测定。用表达frizzled 6-IRES-GFP或frizzled 7-IRES-GFP的慢病毒载体感染肿瘤1致瘤性和非致瘤性癌细胞。使用慢病毒而不是腺病毒是因为前者病毒可感染和稳定地转导高比例的原代细胞，而腺病毒转导通常是短暂的。可以想像frizzled 6的表达为癌细胞提供自我更新的能力。如果是这样，用含有frizzled 6-IRES-GFP迷你基因的慢病毒载体感染干细胞和/或非致瘤性细胞可增强所述干细胞的致瘤性或允许先前的非致瘤性细胞形成肿瘤。相反地，frizzled 7的增强表达可以抑制致瘤性。在用frizzled或对照病毒感染后，进行有限稀释检验以确定增强的各基因表达是否改变各癌细胞群体形成肿瘤的能力。Tumor 1 tumorigenic cells express frizzled 6 but not tumorigenic cancer cells express frizzled 7. Frizzled 6 may enhance andfrizzled 7 may inhibit the proliferation or self-renewal of cancer cells. To test this possibility, clonogenic assays were performed in vitro and in vivo.Tumor 1 tumorigenic and non-tumorigenic cancer cells were infected with lentiviral vectors expressing frizzled 6-IRES-GFP or frizzled 7-IRES-GFP. Lentivirus was used rather than adenovirus because the former virus infects and stably transduces a high proportion of primary cells, whereas adenovirus transduction is usually transient. It is conceivable that the expression offrizzled 6 provides cancer cells with the ability to self-renew. If so, infection of stem cells and/or non-tumorigenic cells with lentiviral vectors containing the frizzled 6-IRES-GFP minigene could enhance tumorigenicity of said stem cells or allow previously non-tumorigenic cells to form tumors. Conversely, enhanced expression of frizzled 7 suppressed tumorigenicity. Following infection with frizzled or control virus, limiting dilution assays were performed to determine whether enhanced expression of each gene altered the ability of each cancer cell population to form tumors.

这些检验使我们能够确定增强的frizzled 6的表达是否增强干细胞的增殖和/或自我更新，或frizzled 7的表达是否抑制致瘤性癌细胞增殖和/或自我更新。为检验这种可能性，我们通过流式细胞仪从各肿瘤中分离致瘤性ESA⁺CD44⁺CD24^-/lowLineage^-癌细胞和其它Lineage^-、非致瘤性癌细胞。首先，使用抗β-连环蛋白抗体进行免疫组织化学以确定在致瘤性和非致瘤性细胞中活性β-连环蛋白的量的差异。然后，我们确定致瘤性和非致瘤性细胞¹²⁸中磷酸化(失活的)的和非磷酸化(活性的)的β-连环蛋白的量。These assays allowed us to determine whether enhanced expression offrizzled 6 enhances proliferation and/or self-renewal of stem cells, or whether expression offrizzled 7 inhibits proliferation and/or self-renewal of tumorigenic cancer cells. To test this possibility, we isolated tumorigenic ESA⁺ CD44⁺ CD24^-/low Lineage^- cancer cells and other Lineage^- , non-tumorigenic cancer cells from each tumor by flow cytometry. First, immunohistochemistry was performed using an anti-β-catenin antibody to determine differences in the amount of active β-catenin in tumorigenic and non-tumorigenic cells. We then determined the amount of phosphorylated (inactive) and non^- phosphorylated (active) β-catenin in tumorigenic and non-tumorigenic cells128.

然后，设计体外测定以确定各基因对组织培养中的致瘤性和非致瘤性癌细胞形成集落的影响。通过流式细胞仪分离后，用相同MOI的frizzled 6/GFP、frizzled 7/GRP或对照GFP病毒感染各细胞群体。In vitro assays were then designed to determine the effect of each gene on colonization of tumorigenic and non-tumorigenic cancer cells in tissue culture. After separation by flow cytometry, each cell population was infected with the same MOI of frizzled 6/GFP, frizzled 7/GRP or control GFP virus.

将100、500、1,000和5,000个细胞的三份培养物置于组织培养基中。对总的GFP⁺集落数以及在第3、7、14、21和28天的总的集落数和GFP⁺集落数进行计数。在21天结束时，我们试图传代细胞以确定特定frizzled基因的表达是否影响自我更新。Triplicate cultures of 100, 500, 1,000, and 5,000 cells were placed in tissue culture medium. The total number of GFP⁺ colonies and the number of total and GFP⁺ colonies ondays 3, 7, 14, 21 and 28 were counted. At the end of the 21 days, we attempted to passage the cells to determine whether the expression of specific frizzled genes affected self-renewal.

确定增强的各frizzled基因对赘生性细胞在NOD/SCID小鼠中形成肿瘤的能力的影响。通常，需要200个肿瘤1细胞来形成肿瘤。因此，frizzled 6、frizzled 7或对照GFP慢病毒被用于感染50、100、500、1,000、5,000和10,000个致瘤性癌细胞或非致瘤性癌细胞。将所述细胞注射入免疫缺陷小鼠中。监控需要用来形成肿瘤的细胞数目和肿瘤生长速度。在肿瘤达到1厘米大小后，将其切割并通过流式细胞仪分析GFP的表达。通过比较由GFP病毒和frizzled/GFP病毒感染的细胞的百分比，我们能够估计感染的效率和后者病毒对增殖的影响。这些检验重复三次。The effect of enhanced frizzled genes on the ability of neoplastic cells to form tumors in NOD/SCID mice was determined. Typically, 200Tumor 1 cells are required to form a tumor. Therefore, frizzled 6, frizzled 7, or control GFP lentiviruses were used to infect 50, 100, 500, 1,000, 5,000, and 10,000 tumorigenic or non-tumorigenic cancer cells. The cells were injected into immunodeficient mice. The number of cells needed to form a tumor and the rate of tumor growth are monitored. After tumors reached a size of 1 cm, they were dissected and analyzed for GFP expression by flow cytometry. By comparing the percentage of cells infected by GFP virus and frizzled/GFP virus, we were able to estimate the efficiency of infection and the effect of the latter virus on proliferation. These tests were repeated three times.

预测的结果：在肿瘤1中，不同细胞群体表达不同frizzled蛋白，非致瘤性细胞似乎优选地表达Wnt蛋白。这暗示着某些非致瘤性细胞群体通过Wnts提高肿瘤的形成。如果β-连环蛋白信号传导在非致瘤细胞中下调而在致瘤性亚群中是激活的，这可以通过分别在非致瘤性和致瘤性癌细胞中免疫组化分析磷酸化&非磷酸化的β-连环蛋白的表达模式来进行检测。如果不存在特定的frizzled/GFP病毒的影响，那么在各组中将有相似百分比的细胞表达GFP，并且在形成肿瘤所需要的细胞数目上没有差异。如果特定frizzled病毒减少或增加致瘤性或增殖，那么用frizzled/GFP病毒感染的肿瘤将分别具有更少的或更多的GFP⁺细胞和/或将需要更多或更少的细胞来形成肿瘤。Predicted results: Intumor 1, different cell populations expressed different frizzled proteins, and non-tumorigenic cells appeared to preferentially express Wnt proteins. This implies that certain non-tumorigenic cell populations enhance tumor formation through Wnts. If β-catenin signaling is downregulated in non-tumorigenic cells but activated in tumorigenic subpopulations, this can be determined by immunohistochemical analysis of phosphorylated & non-tumorigenic cells in non-tumorigenic and tumorigenic cancer cells, respectively. Expression patterns of phosphorylated β-catenin were detected. If there were no specific frizzled/GFP virus influence, a similar percentage of cells would express GFP in each group and there would be no difference in the number of cells required to form tumors. If a particular frizzled virus reduces or increases tumorigenicity or proliferation, then tumors infected with frizzled/GFP viruses will have fewer or more GFP⁺ cells respectively and/or will require more or fewer cells to form tumors .

如果必要，使用基于猫科动物白血病慢病毒的载体系统。该后者载体有效地转导非复制细胞，并且导致延长的转基因表达。我们可使用tet可诱导的侧翼连接基因隔离子的dnTCF-IRES-GFP慢病毒或对照GFP慢病毒感染细胞。在收获肿瘤前的1-2天，激活转基因。收获GFP⁺乳腺癌干细胞并移植到NOD/SCID小鼠的乳腺中。我们继续在小鼠中诱导转基因的表达，我们能够就细胞形成肿瘤的能力对其进行监控。If necessary, use a feline leukemia lentivirus-based vector system. This latter vector efficiently transduces non-replicating cells and results in prolonged transgene expression. We can infect cells with a tet-inducible dnTCF-IRES-GFP lentivirus or a control GFP lentivirus flanked by a gene isolator. 1-2 days before harvesting the tumors, activate the transgene. GFP⁺ breast cancer stem cells were harvested and transplanted into the mammary glands of NOD/SCID mice. We went on to induce expression of the transgene in mice, and we were able to monitor the cells for their ability to form tumors.

在分离自具有和不具有组成型激活的β-连环蛋白的癌的癌细胞中β-连环蛋白信号传导途径不同。原理：与直肠癌不同，只在少数乳腺癌细胞中检测β-连环蛋白信号传导途径的突变。然而，这些研究只集中于APC和β-连环蛋白。在该目的中，我们仔细地研究了各肿瘤中的β-连环蛋白途径，在特定目的1A中对所述肿瘤在生物学水平上进行了分析。The β-catenin signaling pathway differs in cancer cells isolated from carcinomas with and without constitutively activated β-catenin. Rationale: Unlike rectal cancer, mutations in the β-catenin signaling pathway were detected in only a minority of breast cancer cells. However, these studies only focused on APC and β-catenin. In this objective we have carefully studied the β-catenin pathway in individual tumors which were analyzed at the biological level in specific objective 1A.

Wnt途径在从不同肿瘤中分离的癌细胞中会不同吗？在这些实验中，我们表征在各肿瘤中的Wnt/β-连环蛋白。为进行该目的，我们使用RT-PCR扩增由癌细胞表达的β-连环蛋白、各frizzled蛋白、低密度脂质白相关的Wnt受体、APC、TCF家族成员、Axin和Bcl-9的编码序列，所述癌细胞来自具有组成型激活的β-连环蛋白的10个肿瘤中的各肿瘤。对表达的基因的RT-PCR产物进行测序以确定在任一个基因中是否存在突变。通过独立RT-PCR样品的重复测序证实任何可能的突变基因。如果发现突变，我们确定所述突变是否导致Wnt/β-连环蛋白途径的组成型激活。为进行该目的，将突变的基因-IRES-GFP克隆入pCDNA3真核生物表达载体中。例如，如果我们发现突变体frizzled 2，那么用突变体frizzled 2-IRES-GFP表达载体或对照IRES-GFP载体转染HEK 293细胞(所述细胞不具有激活的B-连环蛋白¹³⁰)。用抗β-连环蛋白-PE抗体对细胞进行染色然后用荧光显微镜观察以确定突变体frizzled6是否导致β-连环蛋白的细胞质/细胞核定位，表示信号传导的激活。该测定使我们能够确定β-连环蛋白途径的组分的突变是否在人乳腺癌干细胞中导致异常的信号传导。Does the Wnt pathway differ in cancer cells isolated from different tumors? In these experiments, we characterized Wnt/β-catenin in each tumor. For this purpose, we used RT-PCR to amplify the coding for β-catenin, individual frizzled proteins, LDL-associated Wnt receptors, APC, TCF family members, Axin and Bcl-9 expressed by cancer cells sequence from each of the 10 tumors with constitutively activated β-catenin. RT-PCR products of the expressed genes were sequenced to determine if mutations were present in any of the genes. Any possible mutated genes were confirmed by repeated sequencing of independent RT-PCR samples. If mutations were found, we determined whether the mutations resulted in constitutive activation of the Wnt/β-catenin pathway. For this purpose, the mutated gene-IRES-GFP was cloned into the pCDNA3 eukaryotic expression vector. For example, if we found mutant frizzled 2, HEK 293 cells (which do not have activated B-catenin¹³⁰ ) were transfected with mutant frizzled 2-IRES-GFP expression vector or control IRES-GFP vector. Cells were stained with an anti-β-catenin-PE antibody and visualized by fluorescence microscopy to determine whether mutant frizzled6 resulted in cytoplasmic/nuclear localization of β-catenin, indicating activation of signaling. This assay allowed us to determine whether mutations in components of the β-catenin pathway lead to aberrant signaling in human breast cancer stem cells.

预期结果。尽管在大量乳腺癌肿瘤的癌细胞中观察到组成型激活的β-连环蛋白，但其机制仍不清楚。在通过这些研究检测的不同的肿瘤细胞中信号传导途径存在差异。如果在Wnt受体或β-连环蛋白修饰者中存在突变，那么测序研究可检测该差异。如果自分泌刺激存在，那么我们可看到癌细胞表达其中一种Wnt配体。expected outcome. Although constitutively activated β-catenin is observed in cancer cells of a large number of breast cancer tumors, the mechanism remains unclear. There are differences in signaling pathways among the different tumor cells examined by these studies. If mutations are present in Wnt receptors or β-catenin modifiers, sequencing studies can detect this difference. If autocrine stimulation is present, we can see that cancer cells express one of the Wnt ligands.

在一些肿瘤中由不同肿瘤细胞群体表达的Wnt驱动乳腺癌细胞生长吗？也许比任何其它类型的癌症更象这样，乳腺癌肿瘤包含异质性正常细胞群体，包括间充质(基质)细胞、炎症细胞和内皮细胞，所述细胞与恶性肿瘤细胞相互作用以调节肿瘤生长和入侵。目的是开始弄清楚Wnt途径在这些相互作用中的作用。我们假设正常基质成分(包括间充质和内皮细胞)产生不同的影响肿瘤细胞增殖和入侵的Wnt。只分析未传代的肿瘤，因为异种移植的肿瘤预期已渗入了正常小鼠的基质细胞并且小鼠细胞的分析太复杂。通过流式细胞仪纯化这些细胞允许在不首先将所述细胞进行组织培养的情况下对这些细胞进行分子和生物学分析。这是特别重要的，因为已知正常细胞在体外培养时会改变基因表达。Do Wnts expressed by different tumor cell populations in some tumors drive breast cancer cell growth? Perhaps more like this than any other type of cancer, breast cancer tumors contain a heterogeneous population of normal cells, including mesenchymal (stromal) cells, inflammatory cells, and endothelial cells, which interact with malignant cells to regulate tumor growth and invasion. The goal is to start to figure out the role of the Wnt pathway in these interactions. We hypothesized that normal stromal components, including mesenchymal and endothelial cells, produce different Wnts that affect tumor cell proliferation and invasion. Only unpassaged tumors were analyzed because xenografted tumors were expected to have infiltrated the stromal cells of normal mice and the analysis of mouse cells was too complicated. Purification of these cells by flow cytometry allows molecular and biological analysis of these cells without first subjecting the cells to tissue culture. This is especially important because normal cells are known to alter gene expression when cultured in vitro.

正常的基质细胞被认为在乳腺癌细胞的增殖中发挥作用。癌细胞之间的细胞-细胞相互作用也可能对肿瘤生长作出贡献。Wnt信号传导是一条正常组织细胞用于相互对话的主要途径。因此，理解该途径是如何在肿瘤中被调控的非常重要。特定Wnt蛋白可激活特定frizzled受体。一些frizzled受体通过β-连环蛋白传递信号，而其它通过不同的途径传递信号。为了弄清楚肿瘤内的各种肿瘤细胞群体是如何通过该途径可能与致瘤性乳腺癌细胞对话的，我们必须首先确定来自多个患者肿瘤的正常细胞和癌细胞表达何种frizzled和Wnt基因。因此，我们鉴定由各正常细胞和分离自5个患者的肿瘤样品(具有组成型β-连环蛋白信号传导)的癌细胞和来自5个患者肿瘤(不具有组成型激活的该蛋白)的癌细胞的群体表达的Wnt途径基因。Normal stromal cells are thought to play a role in the proliferation of breast cancer cells. Cell-cell interactions between cancer cells may also contribute to tumor growth. Wnt signaling is a major pathway that normal tissue cells use to talk to each other. Therefore, it is important to understand how this pathway is regulated in tumors. Certain Wnt proteins activate certain frizzled receptors. Some frizzled receptors signal through β-catenin, while others signal through a different pathway. To understand how various tumor cell populations within a tumor might be talking to tumorigenic breast cancer cells through this pathway, we had to first determine which frizzled and Wnt genes were expressed by normal and cancer cells from multiple patient tumors. We therefore identified cancer cells from each normal cell and tumor samples isolated from 5 patients (with constitutive β-catenin signaling) and cancer cells from 5 patient tumors (without constitutively activated this protein). Population of expressed Wnt pathway genes.

因为我们的证据表明在不同的癌细胞群体中Wnt和frizzled基因的表达不同，因此在癌中分离不同表型的细胞亚群进行这些检验是非常重要的。这是因为明显致瘤性的细胞群体是少数群体，并且这些细胞表达的基因可能在分析中被忽略。因此，使用流式细胞仪从患者的原始肿瘤中分离致瘤性和非致瘤性乳腺癌细胞以及正常的内皮细胞和成纤维细胞。如初步结果和目的的1中所描述的一样进行该分离，从35,000个各群体细胞的库中分离RNA，然后进行线性扩增以制备足够的探针用于微阵列分析^131-135。为确定发现于各肿瘤中的各细胞群体表达的frizzled和Wnt基因，我们检测包含Wnt和frizzled基因(新的U133芯片具有大多数这些基因)的affymetrix微阵列芯片(每种细胞类型3个芯片)。Because of our evidence that expression of Wnt and frizzled genes differs in different cancer cell populations, it is important to isolate subpopulations of cells with different phenotypes in cancer for these tests. This is because cell populations that are clearly tumorigenic are a minority, and genes expressed by these cells may have been overlooked in the analysis. Therefore, tumorigenic and non-tumorigenic breast cancer cells, as well as normal endothelial cells and fibroblasts, were isolated from the patient's original tumor using flow cytometry. This isolation was performed as described in Preliminary Results andObjective 1, RNA was isolated from pools of 35,000 cells of each population, and then linearly amplified to prepare sufficient probes for microarray^{analysis131-135} . To determine which frizzled and Wnt genes were expressed by each cell population found in each tumor, we assayed an affymetrix microarray chip (3 chips per cell type) containing Wnt and frizzled genes (the new U133 chip has most of these genes) .

通过不同癌细胞群体的定量RT-PCR证实结果，所述癌细胞分离自在癌细胞中具有和不具有激活的β-连环蛋白的原发肿瘤。进行实时RT-PCR以确定不同的正常和赘生性肿瘤细胞群体中各frizzled和Wnt基因的表达水平。为进行该反应，我们制备用于检测这些基因中的每一个基因的PCR引物。各套引物跨越至少一个外显子以使RT-PCR可用于检测不同肿瘤细胞群体中mRNA的表达。使用流式细胞仪分离在各肿瘤中鉴定的致瘤性细胞群体。然后使用实时PCR测量在微阵列分析(参阅综述¹³⁶)中鉴定的分别由各细胞群体表达的各Wnt途径相关RNAs。为进行实时PCR基因表达分析，从3×10⁴细胞(通过流式细胞仪分离的)纯化mRNA。通过Ribogreen RNA定量方法(Molecular Probes，Eugene，OR)将部分RNA用于直接测量RNA的量，和通过Taqman实时RT-PCR测定将部分RNA用于测量rRNA和GAPDH表达(对照管家基因)。综合起来，这些对照测量使我们能够标准化不同细胞群体¹³⁶之间目的基因的表达。尽管更少的细胞可用于该测定中，但分离自3×10⁴细胞的RNA的分析应当产生更精确的基因表达测量值。Results were confirmed by quantitative RT-PCR of different cancer cell populations isolated from primary tumors with and without activated β-catenin in cancer cells. Real-time RT-PCR was performed to determine the expression levels of each frizzled and Wnt gene in different normal and neoplastic tumor cell populations. To perform this reaction, we prepared PCR primers for the detection of each of these genes. Each set of primers spans at least one exon so that RT-PCR can be used to detect mRNA expression in different tumor cell populations. The tumorigenic cell populations identified in each tumor were isolated using flow cytometry. Real-time PCR was then used to measure the individual Wnt pathway-associated RNAs expressed by each cell population identified in the microarray analysis (see review¹³⁶ ). For real-time PCR gene expression analysis, mRNA was purified from 3×10⁴ cells (isolated by flow cytometry). A portion of the RNA was used to directly measure the amount of RNA by the Ribogreen RNA quantification method (Molecular Probes, Eugene, OR), and a portion of the RNA was used to measure rRNA and GAPDH expression (control housekeeping gene) by the Taqman real-time RT-PCR assay.^Taken together, these control measurements allowed us to normalize the expression of the gene of interest between different cell populations. Although fewer cells can be used in this assay, analysis of RNA isolated from 3 x¹⁰⁴ cells should yield more precise gene expression measurements.

当被各不相同的Wnt基因刺激时，就激活β-连环蛋白和转化细胞的能力对由来自各肿瘤的不同癌细胞群体表达的各frizzled受体进行分析，所述Wnt基因由肿瘤内的不同细胞群体表达。使用两个生物学系统进行这些研究。第一，我们使用HBK细胞通过由致瘤性细胞表达的frizzled蛋白来检验经鉴定的Wnts激活β-连环蛋白的能力，所述HEK293细胞用各单个的在该筛选中鉴定的frizzled进行转染。其次，我们使用乳房上皮细胞系以确定特定的Wnt或frizzled基因是否能够转化所述细胞系。Individual frizzled receptors expressed by different cancer cell populations from each tumor were analyzed for their ability to activate β-catenin and transform cells when stimulated by different Wnt genes within the tumor. Cell population expression. These studies were performed using two biological systems. First, we tested the ability of the identified Wnts to activate β-catenin by frizzled proteins expressed by tumorigenic cells using HBK cells transfected with each individual frizzled identified in this screen. Second, we used mammary epithelial cell lines to determine whether specific Wnt or frizzled genes were able to transform the cell lines.

为测量由乳腺癌细胞表达的不同Wnt和Frizzled蛋白的生物化学功能，我们使用Gazit等人¹³⁰描述的瞬时转染测定。在该测定中，用frizzled迷你基因或对照迷你基因和TCF-荧光素酶或对照报告迷你基因瞬时转染HEK293T细胞。为检测特定Wnt蛋白刺激β-连环蛋白信号传导的能力，用由各种肿瘤细胞群体表达的各Wnt基因转染第二组HEK 293T细胞。将frizzled转染的细胞与Wnt转染的细胞混合以测量由乳腺癌干细胞表达的特定frizzled受体的旁分泌激活是否激活β-连环蛋白(当用由各种肿瘤细胞群体中的一种表达的特定Wnt蛋白刺激时)。To measure the biochemical functions of the different Wnt and Frizzled proteins expressed by breast cancer cells, we used the transient transfection assay described by Gazit et^al . In this assay, HEK293T cells are transiently transfected with a frizzled minigene or a control minigene and a TCF-luciferase or a control reporter minigene. To test the ability of specific Wnt proteins to stimulate β-catenin signaling, a second group of HEK 293T cells were transfected with each Wnt gene expressed by the various tumor cell populations. Frizzled-transfected cells were mixed with Wnt-transfected cells to measure whether paracrine activation of specific frizzled receptors expressed by breast cancer stem cells activates β-catenin (when compared with β-catenin expressed by one of the various tumor cell populations). when stimulated by a specific Wnt protein).

使用C57MG细胞系确定由特定Wnts激活的特定frizzled受体是否导致形态学转化¹³⁷。当这些细胞暴露于Wnt-1、Wnt-2、Wnt-3A、Wnt-6和Wnt-7A，其进行形态学转化，但暴露于Wnt4、Wnt-5A、Wnt-5B和Wnt-7B时不进行形态学转化。这些数据暗示着非转化性Wnts与转化性Wnts信号传导不同，或其通过不由C57MG细胞表达的不同受体发送信号。因此，为全面表征由患者肿瘤癌细胞表达何种不同frizzled和Wnt蛋白的功能，我们必须首先确定由C57MG细胞表达何种frizzled基因。用迷你基因转染细胞，所述迷你基因表达任何由致瘤性乳腺癌细胞但不是由C57MG细胞表达的frizzled基因。然后，将细胞在经致死性辐射的成纤维细胞或用单个Wnt基因转染的HEK 293T细胞存在的情况下进行培养，所述Wnt基因由不同的肿瘤细胞群体表达。如Shimizu¹³⁸描述的一样分析所述细胞的形态学转化。The C57MG cell line was used to determine whether specific frizzled receptors activated by specific Wnts lead to morphological transformation¹³⁷ . These cells undergo morphological transformation when exposed to Wnt-1, Wnt-2, Wnt-3A, Wnt-6, and Wnt-7A, but not when exposed to Wnt4, Wnt-5A, Wnt-5B, and Wnt-7B Morphological transformation. These data imply that non-transforming Wnts signal differently than transforming Wnts, or that they signal through different receptors not expressed by C57MG cells. Therefore, to fully characterize the function of which different frizzled and Wnt proteins are expressed by the patient's tumor cancer cells, we must first determine which frizzled genes are expressed by C57MG cells. Cells were transfected with minigenes expressing any frizzled genes expressed by tumorigenic breast cancer cells but not by C57MG cells. Cells were then cultured in the presence of lethally irradiated fibroblasts or HEK 293T cells transfected with a single Wnt gene expressed by different tumor cell populations. The cells were analyzed for morphological transformation as described by Shimizu¹³⁸ .

接着，我们在体内表征来自不同患者肿瘤的癌细胞对由肿瘤细胞产生的不同Wnts的应答。Wnt蛋白通常发现于细胞外基质并且难以以可溶性的形式制备。因此，我们制备对照HEK 293细胞系，所述细胞系表达由存在于2个患者肿瘤中的各种类型的肿瘤细胞产生的各Wnts。为进行该实验，我们首先分析HEK 293细胞以确定其是否组成型地产生任何一种Wnt蛋白。其次，我们用由患者肿瘤细胞产生的各Wnts稳定转染HEK 293细胞。为确定乳腺癌细胞中Wnt通过其各配体在体内产生的刺激的作用，将0、10、50、100、200、500和1,000个肿瘤1干细胞与500,000个致死性辐射的对照293细胞或用一个或多个相关Wnt迷你基因转染的293细胞混合，然后注射入免疫缺陷的小鼠中。每种注射使用5只小鼠。然后每周监控小鼠的肿瘤形成。如果特定Wnt刺激自我更新的细胞分裂，那么，需要更少的细胞启动肿瘤和/或更快地形成肿瘤。相反地，如果所述配体诱导定型分化，那么需要更多的细胞形成肿瘤和/或需要花费更长的时间形成肿瘤。Next, we characterized in vivo the response of cancer cells from different patient tumors to the different Wnts produced by the tumor cells. Wnt proteins are usually found in the extracellular matrix and are difficult to produce in soluble form. Therefore, we generated control HEK 293 cell lines expressing the respective Wnts produced by various types of tumor cells present in 2 patient tumors. To perform this experiment, we first analyzed HEK 293 cells to determine whether they constitutively produced any of the Wnt proteins. Second, we stably transfected HEK 293 cells with individual Wnts produced by patient tumor cells. To determine the role of Wnt stimulation in vivo by its respective ligands in breast cancer cells, 0, 10, 50, 100, 200, 500, and 1,000Tumor 1 stem cells were compared with 500,000 lethally irradiated control 293 cells or with 293 cells transfected with one or more relevant Wnt minigenes were pooled and injected into immunodeficient mice. Five mice were used for each injection. Mice were then monitored weekly for tumor formation. If specific Wnts stimulate self-renewing cell division, then fewer cells are needed to initiate tumors and/or tumors form faster. Conversely, if the ligand induces committed differentiation, more cells are required to form the tumor and/or it takes longer for the tumor to form.

预期结果。肿瘤中癌细胞与正常基质细胞的相互作用被认为是肿瘤形成和转移³³的关键因素。Wnt途径是正常组织中细胞通讯⁶⁵的一个中心途径。因此这些通讯可能在肿瘤中得到一定程度的保持。在本说明书中描述的模型第一次使得能够用患者肿瘤细胞进行这些研究。如果基质细胞确实通过Wnt信号传导提高肿瘤生长，那么各种基质细胞群体产生特异性的Wnts，所述特异性Wnt为致瘤性癌细胞提供增殖信号。expected outcome. The interaction of cancer cells with normal stromal cells in tumors is considered a key factor in tumor formation and^metastasis . The Wnt pathway is a central pathway of cellular^{communication65} in normal tissues. These communications may therefore be maintained to some extent in tumors. The model described in this specification enables, for the first time, these studies to be performed with patient tumor cells. If stromal cells indeed enhance tumor growth through Wnt signaling, various stromal cell populations produce specific Wnts that provide proliferative signals to tumorigenic cancer cells.

为将这些问题减小到最低水平，用不同的细胞数目以三次重复进行所有检验。使用已知数量的对照RNA的表达构建标准曲线以分析数据(参见综述¹³⁶)。如果必要，制备新的PCR引物，或用识别mRNA不同部分的基因特异性引物进行RT(寡聚dT引物最初用于RT反应)。To minimize these problems, all assays were performed in triplicate with different cell numbers. A standard curve was constructed using the expression of known quantities of control RNA to analyze the data (see review¹³⁶ ). If necessary, prepare new PCR primers, or perform RT with gene-specific primers that recognize different parts of the mRNA (oligo-dT primers were originally used for RT reactions).

总结：这些检测第一次全面详细地描述了在致瘤性乳腺癌细胞群体(直接得自多个患者肿瘤)中β-连环蛋白途径在体内被激活的机制和这种激活在从头形成的乳腺癌细胞中的生物学后果。Summary: These assays provide the first comprehensive and detailed description of the mechanisms by which the β-catenin pathway is activated in vivo in tumorigenic breast cancer cell populations (directly obtained from multiple patient tumors) and how this activation occurs in de novo mammary glands. Biological consequences in cancer cells.

                        实施例3Example 3

            β-连环蛋白在致瘤性细胞中的定位Localization of β-catenin in tumorigenic cells

在正常的造血细胞中，只在干细胞区室中发现细胞核β-连环蛋白。Reya等人进一步证实β-连环蛋白信号传导是正常干细胞自我更新所必需的。最近完全的β-连环蛋白在致瘤性和非致瘤性肿瘤1乳腺癌细胞中的亚细胞定位分析进一步支持这个概念。通常，β-连环蛋白在癌细胞中的亚细胞分布是异质性的。在一些细胞中，所述蛋白主要位于外膜，而在其它细胞中主要在细胞核。所述蛋白的亚细胞分布在致瘤性和非致瘤性癌细胞中是不同的。β-连环蛋白主要位于非致瘤性癌细胞的细胞质中，而其主要位于致瘤性细胞(图8)的细胞核中。当被Wnt信号激活时，β-连环蛋白从细胞膜转移至细胞核中，从而激活下游靶基因，这些数据支持Wnt信号传导在乳腺癌干细胞自我更新中发挥作用的假说。In normal hematopoietic cells, nuclear β-catenin is found only in the stem cell compartment. Reya et al. further demonstrated that β-catenin signaling is required for normal stem cell self-renewal. The recent complete subcellular localization analysis of β-catenin in tumorigenic andnon-tumorigenic tumor 1 breast cancer cells further supports this concept. In general, the subcellular distribution of β-catenin in cancer cells is heterogeneous. In some cells, the protein is predominantly located in the outer membrane, while in others it is predominantly in the nucleus. The subcellular distribution of the protein is different in tumorigenic and non-tumorigenic cancer cells. β-catenin is mainly located in the cytoplasm of non-tumorigenic cancer cells, whereas it is mainly located in the nucleus of tumorigenic cells (Figure 8). When activated by Wnt signaling, β-catenin translocates from the cell membrane into the nucleus, thereby activating downstream target genes, and these data support the hypothesis that Wnt signaling plays a role in breast cancer stem cell self-renewal.

图8显示β-连环蛋白的亚细胞定位。使用FITC标记的抗β-连环蛋白抗体对(A)结肠癌细胞，所述细胞具有组成型激活的β-连环蛋白，(B)非致瘤性T1乳腺癌细胞，和(C)致瘤性乳腺癌细胞进行染色。如AI-Hajj等人在PNAS手稿中所描述的通过流式细胞仪分离致瘤性和非致瘤性癌细胞。要指出的是β-连环蛋白主要位于结肠癌细胞和乳腺癌干细胞的细胞核中，但其主要位于非致瘤性细胞的表面。Figure 8 shows the subcellular localization of β-catenin. (A) colon cancer cells with constitutively activated β-catenin, (B) non-tumorigenic T1 breast cancer cells, and (C) tumorigenic cells using FITC-labeled anti-β-catenin antibody Breast cancer cells were stained. Tumorigenic and non-tumorigenic cancer cells were isolated by flow cytometry as described in the PNAS manuscript by AI-Hajj et al. It is to be noted that β-catenin is mainly localized in the nuclei of colon cancer cells and breast cancer stem cells, but it is mainly localized on the surface of non-tumorigenic cells.

为开始弄清楚β-连环蛋白信号传导在乳腺癌中的生物学后果，我们已在几个细胞系中检测了我们的显性失活TCF-4(dTCF4)腺病毒载体。这些腺病毒抑制β-连环蛋白信号传导。用dTCF4腺病毒或对照腺病毒(空载体)感染两个不同的乳腺癌细胞系即SKBR3和MCF7以及胃肠道癌细胞系RKO。感染后4天，确定各组中存活的细胞数目。如图9所显示的，用dTCF4腺病毒而不是对照腺病毒感染的乳腺癌细胞死亡。这些数据显示Wnt途径确实在人乳腺癌中发挥作用。To begin to understand the biological consequences of β-catenin signaling in breast cancer, we have tested our dominant negative TCF-4 (dTCF4) adenoviral vector in several cell lines. These adenoviruses inhibit β-catenin signaling. Two different breast cancer cell lines, SKBR3 and MCF7, and the gastrointestinal cancer cell line RKO were infected with dTCF4 adenovirus or control adenovirus (empty vector). Four days after infection, the number of surviving cells in each group was determined. As shown in Figure 9, breast cancer cells infected with dTCF4 adenovirus but not control adenovirus died. These data show that the Wnt pathway does indeed play a role in human breast cancer.

图9显示β-连环蛋白信号传导在癌细胞中的抑制，用对照腺病毒(空载体)或表达显性失活TCF4迷你基因(dTCF4)的腺病毒载体感染SKBR3细胞(A)、MCF7细胞(B)和RKO细胞(C)的三份重复培养物。随着病毒浓度的增加，SKBR3细胞和MCF7细胞，但不是RKO细胞，失去存活能力。要注意的是导致细胞死亡的病毒滴度是用对照GFP病毒有效地感染大多数靶细胞所需要的滴度(数据未显示)。本实验已进行了重复并取得相似结果。Figure 9 shows the inhibition of β-catenin signaling in cancer cells, SKBR3 cells (A), MCF7 cells ( B) and triplicate cultures of RKO cells (C). With increasing virus concentration, SKBR3 cells and MCF7 cells, but not RKO cells, lost viability. Note that the virus titer leading to cell death was that required to efficiently infect most target cells with control GFP virus (data not shown). This experiment has been repeated with similar results.

β-连环蛋白主要位于致瘤性而不是非致瘤性癌细胞的细胞核内的观察结果和β-连环蛋白信号传导的抑制影响了一些乳腺癌细胞系的生存力的观察结果一起显示：和正常干细胞一样，Wnt信号可在癌干细胞的自我更新中发挥作用。The observation that β-catenin is predominantly localized in the nucleus of tumorigenic but not non-tumorigenic cancer cells, together with the observation that inhibition of β-catenin signaling affects the viability of some breast cancer cell lines: and normal Like stem cells, Wnt signaling may play a role in the self-renewal of cancer stem cells.

                        实施例4Example 4

                    鉴定干细胞癌标记Identification of Stem Cell Cancer Markers

本实施例描述了如何使用微阵列筛选鉴定各种干细胞癌标记。处理这些筛选的结果，差异表达的基因的名字报道于表4-8(参见上面)。This example describes how microarray screening was used to identify various stem cell cancer markers. Processing the results of these screens, the names of differentially expressed genes are reported in Tables 4-8 (see above).

为了产生基因表达谱，先分离人乳腺致瘤性细胞。从人乳腺肿瘤或正常组织中积累一系列样品。如下制备这些样品。将三种传代的乳腺瘤(来自患者1、2、3的乳腺瘤细胞)移植到小鼠中，各种肿瘤移植到3个小鼠中以产生三个重复肿瘤。然后从这些肿瘤中分离乳腺致瘤性细胞。将两个或三个来自三个患者SUM、PE13、PE15的未传代乳腺瘤进行标记并分选出致瘤性细胞(TG)或非致瘤性细胞(NTG)。PE15-TG和PE15-NTG都是三份重复。两个或三个正常乳腺样品来自乳腺减小患者。用流式细胞仪分离乳腺上皮细胞(乳房)并用于微阵列。从结肠患者新鲜收集两个或三个正常结肠样品。用流式细胞仪分离结肠上皮细胞(结肠)并用于微阵列。从骨髓供体中收集两个或三个正常干细胞样品(正常骨髓)。用流式细胞仪分离造血干细胞(HSC)。从下列各种细胞类型制备探针，以用于微阵列分析。To generate gene expression profiles, human breast tumorigenic cells were first isolated. A series of samples were accumulated from human breast tumor or normal tissue. These samples were prepared as follows. Three passages of mammary tumors (mammary tumor cells frompatients 1, 2, 3) were transplanted into mice, and each tumor was transplanted into 3 mice to generate three replicate tumors. Breast tumorigenic cells were then isolated from these tumors. Two or three unpassaged breast tumors from three patients SUM, PE13, PE15 were labeled and sorted for tumorigenic (TG) or non-tumorigenic (NTG) cells. Both PE15-TG and PE15-NTG are triplicates. Two or three normal breast samples were obtained from patients with reduced breasts. Mammary epithelial cells (breast) were isolated by flow cytometry and used for microarrays. Two or three normal colon samples were freshly collected from colon patients. Colonic epithelial cells (colon) were isolated by flow cytometry and used for microarrays. Two or three samples of normal stem cells (normal bone marrow) are collected from a bone marrow donor. Hematopoietic stem cells (HSCs) were isolated by flow cytometry. Probes were prepared from the various cell types listed below for microarray analysis.

为了进行各种微阵列筛选，使用Affymetrix HG-U133基因芯片。使用标准化的基因表达强度以产生收集在许多大表格中的数据。处理这些表中的结果并将结果用于产生表4、5、6、7a、7b、7c、7d和8，所述表提供了被发现进行差异表达的基因的名字。对于表4-6，通过鉴定基因分选候选癌标记，所述基因在未传代的乳腺致瘤性细胞中的表达与非致瘤性细胞或正常干细胞(HSC)的相比，增加或减少了超过1.5倍。表6只显示那些在UPTG和UPNTG相比中发现下调的基因。表4只显示那些在UPTG和UPNTG相比中发现上调的基因。表5只显示那些在UPTG和HSC相比中发现上调的基因。对于表7a、7b、7c和7d，通过标准的T-检验从更大的表中产生癌标记。基于T分值＜0.01和比例超过2倍对这些表进行分选。表7a只显示那些在UPTG和HSC相比中发现上调的基因。表7b只显示那些在UPTG和HSC相比中发现下调的基因。表7c只显示那些在PTG和HSC相比中上调的基因。表7d只显示那些在PTG和HSC相比中下调的基因。For various microarray screenings, Affymetrix HG-U133 gene chips were used. Normalized gene expression intensities were used to generate data collected in many large tables. The results in these tables were processed and used to generate Tables 4, 5, 6, 7a, 7b, 7c, 7d and 8, which provide the names of genes found to be differentially expressed. For Tables 4-6, candidate cancer markers were sorted by identifying genes whose expression in unpassaged breast tumorigenic cells was increased or decreased compared to non-tumorigenic cells or normal stem cells (HSCs) More than 1.5 times. Table 6 shows only those genes that were found to be down-regulated in UPTG compared to UPNTG. Table 4 shows only those genes found to be upregulated in UPTG compared to UPNTG. Table 5 shows only those genes found to be upregulated in UPTG compared to HSC. For Tables 7a, 7b, 7c and 7d, cancer markers were generated from larger tables by standard T-tests. The tables were sorted on the basis of T-scores <0.01 and proportions more than 2-fold. Table 7a shows only those genes found to be upregulated in UPTG compared to HSC. Table 7b shows only those genes found to be down-regulated in UPTG compared to HSC. Table 7c shows only those genes that were upregulated in PTG compared to HSC. Table 7d shows only those genes that were downregulated in PTG compared to HSC.

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所有上面说明书中提到的出版物和专利在此处引用作为参考。各种本发明描述的方法和系统的修饰和变化对本领域技术人员来说是显而易见的，并且不背离本发明的范围和精神。尽管本发明已使用优选的特定实施方案进行描述，但应当理解本发明不应当过度地限定于这些特定的实施方案中。事实上，各种描述的用于进行本发明的模式的修饰，只要其对本领域技术人员来说是显而易见的，就在下列权利要求的范围之内。All publications and patents mentioned in the above specification are incorporated herein by reference. Various modifications and variations of the methods and systems described herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described using preferred specific embodiments, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the following claims.

Claims (21)

Translated fromChinese

1.检测实体瘤干细胞的方法，其包括：1. A method for detecting solid tumor stem cells, comprising:a)提供受试者的组织样品，和a) provide a tissue sample from the subject, andb)在确定实体瘤干细胞在所述组织样品中存在或不存在的条件下在所述组织样品中检测至少一种来自表4-8的干细胞癌标记。b) detecting at least one stem cell cancer marker from Tables 4-8 in said tissue sample under conditions that determine the presence or absence of solid tumor stem cells in said tissue sample.2.权利要求1的方法，其中所述检测包括确定所述至少一种干细胞癌标记的表达水平。2. The method of claim 1, wherein said detecting comprises determining the expression level of said at least one stem cell cancer marker.3.权利要求1的方法，其中所述检测包括检测所述至少一种干细胞癌标记的mRNA表达。3. The method of claim 1, wherein said detecting comprises detecting mRNA expression of said at least one stem cell cancer marker.4.权利要求1的方法，其中所述检测包括检测所述至少一种干细胞癌标记的多肽表达。4. The method of claim 1, wherein said detecting comprises detecting polypeptide expression of said at least one stem cell cancer marker.5.权利要求1的方法，其中所述受试者包含人受试者。5. The method of claim 1, wherein the subject comprises a human subject.6.权利要求1的方法，其中所述组织样品包括肿瘤组织。6. The method of claim 1, wherein said tissue sample comprises tumor tissue.7.权利要求1的方法，其进一步包括c)给所述受试者提供预后的步骤。7. The method of claim 1, further comprising the step of c) providing said subject with a prognosis.8.权利要求1的方法，其中所述至少一种干细胞癌标记来自表8。8. The method of claim 1, wherein said at least one stem cell cancer marker is from Table 8.9.权利要求1的方法，其中所述至少一种干细胞癌标记选自：Bmi-1、eed、easyh1、easyh2、rnf2、yy1、smarcA3、smarcA5、smarcD3、smarcE1、mllt3、FZD1、FZD2、FZD3、FZD4、FZD6、FZD7、FZD8、FZD9、FZD10、WNT2、WNT2B、WNT3、WNT5A、WNT10B、WNT16、AXIN1、BCL9、MYC和(TCF4)。9. The method of claim 1, wherein said at least one stem cell cancer marker is selected from the group consisting of: Bmi-1, eed, easyh1, easyh2, rnf2, yy1, smarcA3, smarcA5, smarcD3, smarcE1, mllt3, FZD1, FZD2, FZD3, FZD4, FZD6, FZD7, FZD8, FZD9, FZD10, WNT2, WNT2B, WNT3, WNT5A, WNT10B, WNT16, AXIN1, BCL9, MYC and (TCF4).10.用于减小实体瘤大小的方法，其包括将实体瘤细胞与生物学有效量的组合物接触，所述组合物包含至少一种针对显示于表4-8中的至少一种干细胞癌标记的试剂。10. A method for reducing the size of a solid tumor, comprising contacting solid tumor cells with a biologically effective amount of a composition comprising at least one cancer cell targeting at least one stem cell cancer shown in Tables 4-8 Labeled reagents.11.权利要求10的方法，其中所述生物学有效量是足以使所述实体瘤中实体瘤干细胞死亡或抑制其增殖的量。11. The method of claim 10, wherein the biologically effective amount is an amount sufficient to kill or inhibit the proliferation of solid tumor stem cells in the solid tumor.12.权利要求10的方法，其中所述至少一种试剂是抗体、肽或小分子。12. The method of claim 10, wherein said at least one agent is an antibody, peptide or small molecule.13.权利要求12的方法，其中所述抗体、肽或小分子针对所述至少一种干细胞癌标记的细胞外结构域。13. The method of claim 12, wherein said antibody, peptide or small molecule is directed against the extracellular domain of said at least one stem cell cancer marker.14.权利要求10的方法，其中所述至少一种干细胞癌标记选自：Bmi-1、eed、easyh1、easyh2、rnf2、yy1、smarcA3、smarcA5、smarcD3、smarcE1、mllt3、FZD1、FZD2、FZD3、FZD4、FZD6、FZD7、FZD8、FZD9、FZD10、WNT2、WNT2B、WNT3、WNT5A、WNT10B、WNT16、AXIN1、BCL9、MYC和(TCF4)。14. The method of claim 10, wherein said at least one stem cell cancer marker is selected from the group consisting of: Bmi-1, eed, easyh1, easyh2, rnf2, yy1, smarcA3, smarcA5, smarcD3, smarcE1, mllt3, FZD1, FZD2, FZD3, FZD4, FZD6, FZD7, FZD8, FZD9, FZD10, WNT2, WNT2B, WNT3, WNT5A, WNT10B, WNT16, AXIN1, BCL9, MYC and (TCF4).15.用于杀死或抑制实体瘤干细胞增殖的方法，其包括将所述实体瘤干细胞与生物学有效量的组合物接触，所述组合物包含至少一种靶向至少一种显示于表4-8中的干细胞癌标记的因子。15. A method for killing or inhibiting the proliferation of solid tumor stem cells, comprising contacting said solid tumor stem cells with a biologically effective amount of a composition comprising at least one targeting at least one of the compounds shown in Table 4 Factors of stem cell cancer markers in -8.16.权利要求15的方法，其进一步包括在所述接触后，鉴定所述实体瘤干细胞的死亡或生长的抑制。16. The method of claim 15, further comprising identifying, after said contacting, death or inhibition of growth of said solid tumor stem cells.17.权利要求16的方法，其中所述细胞死亡是凋亡。17. The method of claim 16, wherein said cell death is apoptosis.18.权利要求15的方法，其中所述至少一种干细胞癌标记选自：Bmi-1、eed、easyh1、easyh2、rnf2、yy1、smarcA3、smarcA5、smarcD3、smarcE1、mllt3、FZD1、FZD2、FZD3、FZD4、FZD6、FZD7、FZD8、FZD9、FZD10、WNT2、WNT2B、WNT3、WNT5A、WNT10B、WNT16、AXIN1、BCL9、MYC和(TCF4)。18. The method of claim 15, wherein said at least one stem cell cancer marker is selected from the group consisting of: Bmi-1, eed, easyh1, easyh2, rnf2, yy1, smarcA3, smarcA5, smarcD3, smarcE1, mllt3, FZD1, FZD2, FZD3, FZD4, FZD6, FZD7, FZD8, FZD9, FZD10, WNT2, WNT2B, WNT3, WNT5A, WNT10B, WNT16, AXIN1, BCL9, MYC and (TCF4).19.权利要求15的方法，其中所述实体瘤干细胞表达细胞表面标记CD44、ESA或B38.1。19. The method of claim 15, wherein said solid tumor stem cells express cell surface markers CD44, ESA, or B38.1.20.区别致瘤性和非致瘤性癌细胞的方法，其包括：检测β-连环蛋白在癌细胞中的存在，从而确定β-连环蛋白在癌细胞中的定位主要是在细胞核中还是主要在细胞质中。20. A method for distinguishing tumorigenic and non-tumorigenic cancer cells, comprising: detecting the presence of β-catenin in cancer cells, thereby determining whether the location of β-catenin in cancer cells is mainly in the nucleus or mainly in the cytoplasm.21.权利要求20的方法，其进一步包括：如果所述β-连环蛋白主要定位在细胞核中则所述癌细胞被鉴定为致瘤性的，或如果β-连环蛋白主要定位在细胞质中则所述癌细胞被鉴定为非致瘤性的。21. The method of claim 20, further comprising: identifying the cancer cell as tumorigenic if the β-catenin is predominantly localized in the nucleus, or identifying the cancer cell as tumorigenic if the β-catenin is primarily localized in the cytoplasm The cancer cells were identified as non-tumorigenic.

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