CN116298284A - Markers and system for determining tumor radiotherapy sensitivity - Google Patents
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Abstract
Description
Translated fromChinese技术领域technical field
本发明属于生物领域，具体涉及用于确定肿瘤放射治疗敏感性的标志物及系统。The invention belongs to the field of biology, and in particular relates to a marker and a system for determining tumor radiotherapy sensitivity.
背景技术Background technique
肿瘤放射治疗（简称放疗）是恶性肿瘤的一种重要治疗手段。大约50%的恶性肿瘤患者需要接受放射治疗。在头颈部鳞癌、肺癌、胶质瘤等恶性肿瘤中，放疗是手术前缩小肿瘤，手术后降低复发风险的重要辅助治疗手段；而在鼻咽癌等部分肿瘤中，由于特殊的解剖位置导致手术困难，放疗也可作为主要的肿瘤根治手段。尽管放射治疗在恶性肿瘤治疗中发挥重要作用，但不同患者肿瘤的放射敏感性存在显著差异，部分患者肿瘤的放射抗拒严重影响了放射治疗的效果，造成肿瘤放疗后的残留或复发，导致患者预后不良。因此通过寻找相关标志物预测肿瘤放射敏感性，并由此指导患者的个体化治疗具有非常重要的意义。Tumor radiation therapy (referred to as radiotherapy) is an important treatment for malignant tumors. About 50% of patients with malignant tumors require radiation therapy. In head and neck squamous cell carcinoma, lung cancer, glioma and other malignant tumors, radiotherapy is an important adjuvant treatment to shrink tumors before surgery and reduce the risk of recurrence after surgery; As a result, surgery is difficult, and radiotherapy can also be used as the main method of radical tumor treatment. Although radiotherapy plays an important role in the treatment of malignant tumors, there are significant differences in the radiosensitivity of tumors in different patients. The radioresistance of tumors in some patients seriously affects the effect of radiotherapy, resulting in residual or recurrence of tumors after radiotherapy, which leads to the prognosis of patients. bad. Therefore, it is of great significance to predict tumor radiosensitivity by finding relevant markers, and thus guide patients' individualized treatment.
HOXA1是homeobox转录因子基因家族的一个成员。其作为一种转录因子可以通过结合下游基因的启动子序列调控相关基因的表达。现有报道显示HOXA1在多种肿瘤中存在异常表达，并且可能具有促进肿瘤细胞增殖的作用。但目前尚无HOXA1参与调控肿瘤放射敏感性的报道。HOXA1 is a member of the homeobox transcription factor gene family. As a transcription factor, it can regulate the expression of related genes by binding to the promoter sequences of downstream genes. Existing reports have shown that HOXA1 is abnormally expressed in a variety of tumors, and may play a role in promoting tumor cell proliferation. However, there is no report that HOXA1 participates in the regulation of tumor radiosensitivity.
发明内容Contents of the invention
本发明的目的在于克服现有技术的至少一个不足，提供一种用于确定肿瘤放射治疗敏感性的标志物及系统。The purpose of the present invention is to overcome at least one deficiency of the prior art, and provide a marker and a system for determining tumor radiotherapy sensitivity.
本发明所采取的技术方案是：The technical scheme that the present invention takes is:
本发明的第一个方面，提供：A first aspect of the present invention provides:
定量HOXA1的试剂在制备肿瘤放射治疗敏感性判断试剂中的应用。Application of a reagent for quantifying HOXA1 in the preparation of a reagent for judging sensitivity to tumor radiotherapy.
在一些应用的实例中，所述肿瘤选自头颈部鳞癌、低级别胶质瘤或鼻咽癌。In some examples of applications, the tumor is selected from head and neck squamous cell carcinoma, low-grade glioma, or nasopharyngeal carcinoma.
在一些应用的实例中，HOXA1的表达量指HOXA1 mRNA或蛋白的表达量。In some application examples, the expression level of HOXA1 refers to the expression level of HOXA1 mRNA or protein.
在一些应用的实例中，定量HOXA1的试剂选自检测HOXA1基因mRNA水平表达的实时定量qPCR试剂盒或检测HOXA1基因表达的特异性HOXA1抗体与免疫组化试剂盒。In some application examples, the reagent for quantifying HOXA1 is selected from a real-time quantitative qPCR kit for detecting the expression of HOXA1 gene mRNA level or a specific HOXA1 antibody and immunohistochemistry kit for detecting HOXA1 gene expression.
在一些应用的实例中，定量HOXA1的试剂检测的样本为组织样本。In some application examples, the sample detected by the reagent for quantifying HOXA1 is a tissue sample.
本发明的第二个方面，提供：A second aspect of the present invention provides:
一种确定肿瘤放射治疗敏感性的系统，包括：A system for determining the sensitivity of a tumor to radiation therapy comprising:
HOXA1定量装置：用于定量样本中HOXA1的量或浓度；HOXA1 quantitative device: used to quantify the amount or concentration of HOXA1 in the sample;
判断装置：基于样本中HOXA1的量或浓度，确定肿瘤放射治疗敏感性；Judging device: based on the amount or concentration of HOXA1 in the sample, determine the sensitivity of tumor radiotherapy;
结果输出装置：输出判断装置给出的结果。Result output device: output the result given by the judging device.
在一些系统的实例中，所述样本为组织样本。In some system examples, the sample is a tissue sample.
在一些系统的实例中，所述肿瘤选自头颈部鳞癌、低级别胶质瘤或鼻咽癌。In some system examples, the tumor is selected from head and neck squamous cell carcinoma, low grade glioma, or nasopharyngeal carcinoma.
在一些系统的实例中，所述HOXA1定量装置选自mRNA定量装置或免疫组化检测装置。In some system examples, the HOXA1 quantification device is selected from an mRNA quantification device or an immunohistochemical detection device.
在一些系统的实例中，敏感性的判断标准为：免疫组化检测HOXA1蛋白表达时，强染色细胞比例大于50%时，判定HOXA1高表达，肿瘤放射治疗敏感性低；反之，则判定HOXA1低表达，肿瘤放射治疗敏感性高。In some system examples, the criterion for judging sensitivity is: when the expression of HOXA1 protein is detected by immunohistochemistry, when the proportion of strongly stained cells is greater than 50%, it is judged that HOXA1 is highly expressed and the sensitivity of tumor radiotherapy is low; otherwise, it is judged that HOXA1 is low expression, tumor radiotherapy sensitivity is high.
本发明的第三个方面，提供：A third aspect of the present invention provides:
调降HOXA1表达的试剂在制备肿瘤放射治疗增效剂中的应用。The application of the reagent for down-regulating the expression of HOXA1 in the preparation of synergists for tumor radiotherapy.
在一些应用的实例中，调降HOXA1表达的试剂选自干扰HOXA1表达的HOXA1特异性siRNA。In some application examples, the agent for down-regulating the expression of HOXA1 is selected from HOXA1-specific siRNA that interferes with the expression of HOXA1.
在一些应用的实例中，所述HOXA1特异性siRNA的核苷酸序列为GUUCCUUUCAGAUGACCUU (SEQ ID NO.：1)。In some application examples, the nucleotide sequence of the HOXA1-specific siRNA is GUUCCUUUCAGAUGACCUU (SEQ ID NO.: 1).
本发明的有益效果是：The beneficial effects of the present invention are:
发明人通过研究发现，HOXA1高表达与头颈部鳞癌、低级别胶质瘤和鼻咽癌放射抗拒密切相关。HOXA1高表达的患者放疗后复发风险升高，预后较差。通过检测HOXA1表达量，可以预测肿瘤放射治疗敏感性。The inventor found through research that the high expression of HOXA1 is closely related to the radiation resistance of head and neck squamous cell carcinoma, low-grade glioma and nasopharyngeal carcinoma. Patients with high expression of HOXA1 have an increased risk of recurrence after radiotherapy and a poorer prognosis. The sensitivity of tumor radiotherapy can be predicted by detecting the expression level of HOXA1.
发明人通过研究还发现，通过干扰RNA抑制鼻咽癌细胞HOXA1表达可以显著提高鼻咽癌细胞的放射敏感性。抑制HOXA1表达可以用于肿瘤放射增敏。The inventor also found through research that inhibiting the expression of HOXA1 in nasopharyngeal carcinoma cells by interfering RNA can significantly improve the radiosensitivity of nasopharyngeal carcinoma cells. Inhibition of HOXA1 expression can be used for tumor radiosensitization.
附图说明Description of drawings
图1是TCGA数据库数据显示HOXA1在包括头颈部鳞癌（HNSC）和低级别胶质瘤（LGG）在内的多种恶性肿瘤中表达上调。Figure 1 shows the data from the TCGA database showing that HOXA1 is upregulated in a variety of malignant tumors, including head and neck squamous cell carcinoma (HNSC) and low-grade glioma (LGG).
图2是HOXA1高表达在接受过放疗的头颈部鳞癌（A）与低级别胶质瘤（B）患者中提示肿瘤复发风险较高预后较差。Figure 2 shows that high expression of HOXA1 in patients with head and neck squamous cell carcinoma (A) and low-grade glioma (B) who have received radiotherapy indicates a higher risk of tumor recurrence and a poorer prognosis.
图3是在接受根治性放疗的鼻咽癌患者中，肿瘤高表达HOXA1提示患者放疗后复发风险较高，预后较差。Figure 3 shows that in patients with nasopharyngeal carcinoma who received radical radiotherapy, the high expression of HOXA1 in the tumor indicates that the risk of recurrence after radiotherapy is high and the prognosis is poor.
图4是干扰鼻咽癌细胞HOXA1表达可以增强相关细胞的放射敏感性。Figure 4 shows that interfering with the expression of HOXA1 in nasopharyngeal carcinoma cells can enhance the radiosensitivity of related cells.
具体实施方式Detailed ways
本发明的第一个方面，提供：A first aspect of the present invention provides:
定量HOXA1的试剂在制备肿瘤放射治疗敏感性判断试剂中的应用。Application of a reagent for quantifying HOXA1 in the preparation of a reagent for judging sensitivity to tumor radiotherapy.
在一些应用的实例中，所述肿瘤选自头颈部鳞癌、低级别胶质瘤或鼻咽癌。In some examples of applications, the tumor is selected from head and neck squamous cell carcinoma, low-grade glioma, or nasopharyngeal carcinoma.
在一些应用的实例中，HOXA1的表达量指HOXA1 mRNA或蛋白的表达量。In some application examples, the expression level of HOXA1 refers to the expression level of HOXA1 mRNA or protein.
定量HOXA1的试剂可以是已有的HOXA1 mRNA或蛋白定量试剂，试剂的类型无特殊要求。在一些应用的实例中，定量HOXA1的试剂选自检测HOXA1基因mRNA水平表达的实时定量qPCR试剂盒或检测HOXA1基因表达的特异性HOXA1抗体与免疫组化试剂盒。The reagent for quantifying HOXA1 can be an existing HOXA1 mRNA or protein quantification reagent, and there is no special requirement for the type of reagent. In some application examples, the reagent for quantifying HOXA1 is selected from a real-time quantitative qPCR kit for detecting the expression of HOXA1 gene mRNA level or a specific HOXA1 antibody and immunohistochemistry kit for detecting HOXA1 gene expression.
在一些应用的实例中，定量HOXA1的试剂检测的样本为组织样本。组织样本具体可以是肿瘤手术或活检时所获得的组织样本。In some application examples, the sample detected by the reagent for quantifying HOXA1 is a tissue sample. Specifically, the tissue sample may be a tissue sample obtained during tumor surgery or biopsy.
本发明的第二个方面，提供：A second aspect of the present invention provides:
一种确定肿瘤放射治疗敏感性的系统，包括：A system for determining the sensitivity of a tumor to radiation therapy comprising:
HOXA1定量装置：用于定量样本中HOXA1的量或浓度；HOXA1 quantitative device: used to quantify the amount or concentration of HOXA1 in the sample;
判断装置：基于样本中HOXA1的量或浓度，确定肿瘤放射治疗敏感性；Judging device: based on the amount or concentration of HOXA1 in the sample, determine the sensitivity of tumor radiotherapy;
结果输出装置：输出判断装置给出的结果。Result output device: output the result given by the judging device.
在一些系统的实例中，所述样本为组织样本。In some system examples, the sample is a tissue sample.
在一些系统的实例中，所述肿瘤选自头颈部鳞癌、低级别胶质瘤或鼻咽癌。In some system examples, the tumor is selected from head and neck squamous cell carcinoma, low grade glioma, or nasopharyngeal carcinoma.
在一些系统的实例中，所述HOXA1定量装置选自mRNA定量装置或免疫组化检测装置。In some system examples, the HOXA1 quantification device is selected from an mRNA quantification device or an immunohistochemical detection device.
敏感性的判断标准可以通过对已有病例进行回顾性研究确定，不同的肿瘤，其敏感性判断标准可能相同或不同。在一些系统的实例中，敏感性的判断标准为：免疫组化检测HOXA1蛋白表达时，强染色细胞比例大于50%时，判定HOXA1高表达，肿瘤放射治疗敏感性低；反之，则判定HOXA1低表达，肿瘤放射治疗敏感性高。Sensitivity criteria can be determined through retrospective studies on existing cases. Different tumors may have the same or different sensitivity criteria. In some system examples, the criterion for judging sensitivity is: when the expression of HOXA1 protein is detected by immunohistochemistry, when the proportion of strongly stained cells is greater than 50%, it is judged that HOXA1 is highly expressed and the sensitivity of tumor radiotherapy is low; otherwise, it is judged that HOXA1 is low expression, tumor radiotherapy sensitivity is high.
本发明的第三个方面，提供：A third aspect of the present invention provides:
调降HOXA1表达的试剂在制备肿瘤放射治疗增效剂中的应用。The application of the reagent for down-regulating the expression of HOXA1 in the preparation of synergists for tumor radiotherapy.
在一些应用的实例中，调降HOXA1表达的试剂选自干扰HOXA1表达的HOXA1特异性siRNA。In some application examples, the agent for down-regulating the expression of HOXA1 is selected from HOXA1-specific siRNA that interferes with the expression of HOXA1.
在一些应用的实例中，所述HOXA1特异性siRNA的核苷酸序列为GUUCCUUUCAGAUGACCUU。In some application examples, the nucleotide sequence of the HOXA1-specific siRNA is GUUCCUUUCAGAUGACCUU.
结合下面实验，进一步说明本实验的技术方案：Combined with the following experiment, the technical scheme of this experiment is further explained:
由The Cancer Genome Atlas (TCGA)数据库 (数据库更新截止日期为2022年5月3日)下载获得包括头颈部鳞癌 (HNSC)、低级别胶质瘤 (LGG)在内的全部33种恶性肿瘤，共11000余例癌和癌旁正常组织的转录组基因表达数据。然后通过Mann-Whitney U检验比较相对应种类的癌与癌旁组织HOXA1基因表达水平差异。结果如图1显示，HOXA1的表达水平在包括头颈部鳞癌 (HNSC)和低级别胶质瘤在内的多种恶性肿瘤中表达显著升高。Download all 33 types of malignant tumors including head and neck squamous cell carcinoma (HNSC) and low-grade glioma (LGG) from The Cancer Genome Atlas (TCGA) database (database update deadline is May 3, 2022) , a total of more than 11,000 cases of cancer and adjacent normal tissue transcriptome gene expression data. Then the Mann-Whitney U test was used to compare the differences in HOXA1 gene expression levels between the corresponding types of cancer and adjacent tissues. The results showed in Figure 1 that the expression level of HOXA1 was significantly increased in a variety of malignant tumors including head and neck squamous cell carcinoma (HNSC) and low-grade glioma.
进一步针对TCGA数据库中头颈部鳞癌与低级别胶质瘤数据，将数据库中所有具有完善临床治疗信息和随访数据的头颈部鳞癌与低级别胶质瘤样本分别按照是否接受过放射治疗各分为两组。然后按照HOXA1整体表达的中位数，将接受放射治疗组与未接受放射治疗组病例进一步分为HOXA1高表达与低表达两亚组。通过K-M生存曲线分析在接受放射治疗和未接受放射治疗的头颈部鳞癌与低级别胶质瘤中HOXA1表达水平与患者复发风险及预后的相关性。结果如图2所示，在接受放射治疗的头颈部鳞癌与低级别胶质瘤患者中，HOXA1高表达的患者相较于低表达的患者放疗后复发风险显著升高，预后较差。而在未接受放射治疗的患者中HOXA1表达水平无明显的预测价值。Further aiming at the head and neck squamous cell carcinoma and low-grade glioma data in the TCGA database, all the head and neck squamous cell carcinoma and low-grade glioma samples with complete clinical treatment information and follow-up data in the database were classified according to whether they had received radiation therapy or not. Divide each into two groups. Then according to the median of the overall expression of HOXA1, the cases of the group receiving radiation therapy and the group not receiving radiation therapy were further divided into two subgroups with high expression of HOXA1 and low expression of HOXA1. The correlation between the expression level of HOXA1 and the risk of recurrence and prognosis of patients in head and neck squamous cell carcinoma and low-grade glioma who received and did not receive radiotherapy was analyzed by K-M survival curve. The results are shown in Figure 2. Among patients with head and neck squamous cell carcinoma and low-grade glioma who received radiation therapy, patients with high expression of HOXA1 had a significantly higher risk of recurrence after radiotherapy than patients with low expression, and the prognosis was poorer. However, HOXA1 expression level had no significant predictive value in patients who did not receive radiation therapy.
在收集的50例接受根治性放疗五年后未复发鼻咽癌患者与20例放疗后五年内原位复发鼻咽癌患者活检肿瘤组织中，通过免疫组化检测HOXA1的表达情况，并进一步分析鼻咽癌组织HOXA1表达水平与患者放疗效果的相关性。结果如图3所示，HOXA1高表达的接受根治性放射治疗的鼻咽癌患者，其预后明显较差，并且HOXA1高表达提示鼻咽癌患者放疗后复发风险较高。The expression of HOXA1 was detected by immunohistochemistry in the biopsy tumor tissues of 50 patients with no recurrence of nasopharyngeal carcinoma after five years of radical radiotherapy and 20 patients with orthotopic recurrence of nasopharyngeal carcinoma within five years after radiotherapy, and further analyzed Correlation between the expression level of HOXA1 in nasopharyngeal carcinoma and the effect of radiotherapy in patients. The results are shown in Figure 3. NPC patients with high expression of HOXA1 who received radical radiotherapy had a significantly poorer prognosis, and high expression of HOXA1 suggested that NPC patients had a higher risk of recurrence after radiotherapy.
体外实验通过siRNA抑制鼻咽癌细胞CNE1和HNE1的HOXA1表达，通过实时定量qPCR验证siRNA(核苷酸序列为GUUCCUUUCAGAUGACCUU)干扰效率。在确定siRNA有效干扰了相应细胞的HOXA1表达后，分别将一定数量的对照和HOXA1表达干扰细胞接种于小培养皿，待细胞贴壁后分别以0, 0.5, 1, 2, 4, 6 和 8 Gy放射线照射相应细胞，然后培养14天以上，观察相应细胞的克隆形成情况，计算贴壁率和细胞存活分数，按照线性二次曲线 [S=e^(-αD-βD2)]拟合生成相应细胞的放射存活曲线，并比较不同处理组细胞的放射存活曲线差异，判断干扰HOXA1对细胞放射敏感性的影响。结果如图4所示，放射线照射后干扰HOXA1表达的鼻咽癌细胞的存活细胞克隆形成能力较对照细胞显著下降，放射存活曲线左移，放射敏感性增强。这一结果提示HOXA1参与引起肿瘤细胞的放射抗拒，干扰HOXA1表达可以实现鼻咽癌细胞的放射增敏。In vitro experiments used siRNA to inhibit the expression of HOXA1 in nasopharyngeal carcinoma cells CNE1 and HNE1, and verified the interference efficiency of siRNA (nucleotide sequence: GUUCCUUUCAGAUGACCUU) by real-time quantitative qPCR. After confirming that the siRNA effectively interfered with the HOXA1 expression of the corresponding cells, a certain number of control and HOXA1 expression-interfering cells were inoculated in small culture dishes, and the cells were adhered to the wall at 0, 0.5, 1, 2, 4, 6 and 8, respectively. Corresponding cells were irradiated with Gy radiation, then cultured for more than 14 days, the colony formation of the corresponding cells was observed, the adherence rate and cell survival fraction were calculated, and the corresponding cells were generated according to the linear quadratic curve [S=e^(-αD-βD2)] fitting. The radiation survival curves of the cells were compared, and the differences in the radiation survival curves of the cells in different treatment groups were compared to determine the effect of interfering with HOXA1 on the radiosensitivity of the cells. The results are shown in Figure 4. After irradiation, the ability of surviving nasopharyngeal carcinoma cells that interfered with the expression of HOXA1 to form clones was significantly lower than that of the control cells, the radiation survival curve shifted to the left, and the radiosensitivity increased. This result suggests that HOXA1 is involved in the radioresistance of tumor cells, and interfering with the expression of HOXA1 can achieve radiosensitization of nasopharyngeal carcinoma cells.
以上是对本发明所作的进一步详细说明，不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的简单推演或替换，都在本发明的保护范围之内。The above is a further detailed description of the present invention, and should not be regarded as a limitation to the specific implementation of the present invention. For those of ordinary skill in the technical field to which the present invention belongs, simple deduction or replacement without departing from the concept of the present invention is within the protection scope of the present invention.
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