Ecto-5-prime-nucleotidase (5-prime-ribonucleotide phosphohydrolase; EC 3.1.3.5) catalyzes the conversion at neutral pH of purine 5-prime mononucleotides to nucleosides, the preferred substrate beingAMP. The enzyme consists of a dimer of 2 identical 70-kD subunits bound by a glycosyl phosphatidyl inositol linkage to the external face of the plasma membrane. The enzyme is used as a marker oflymphocyte differentiation. Consequently, a deficiency of NT5 occurs in a variety of immunodeficiency diseases (e.g. see MIM 102700, MIM 300300). Other forms of 5-prime nucleotidase exist in the cytoplasm and lysosomes and can be distinguished from ecto-NT5 by their substrate affinities, requirement for divalent magnesium ion, activation by ATP, and inhibition by inorganic phosphate.[7]
NT5E (CD73) is a surfaceenzyme which is expressed on multiple cells. This enzyme mediates the gradual hydrolysis of the autocrine and paracrine danger signals ofATP andADP to anti-inflammatoryadenosine. Immune suppression mediated by adenosinergic pathways is very important for maintaining immune system homeostasis. Immune suppressive functions ofT regulatory cells (Tregs) are also dependent on CD73 expression. Tregs generally suppress the immune response. They affectproliferation and function of T cell.[8] CD73 also occurs on anergic CD4 + T cells, thereby maintaining self tolerance to healthy tissues as well as protecting the fetus from the mother's immune system during pregnancy. Also described was adenosine generated by NT5E, which limits the inflammatory immune response by negative feedback inneutrophil which express theadenosine receptor.[9]
NT5E contains binding sites fortranscription factorsAP-2,SMAD proteins,SP-1 and elements responsive tocAMP, which can be found in c-AMP promoter parts. SMADs 2, 3, 4 and 5 and SP-1 are binding to the NT5E promoter in rats, as was proven in chromatin immunoprecipitation assays. Because human and rat NT5E transcripts are 89% identical, human NT5E could be also regulated by SMAD proteins.[10]
NT5E can act as an immune inhibitory control molecule. Free adenosine generated by NT5E inhibits cellular immune responses and thereby promotes immune escape of tumor cells.[9] Due to enzymatic and non-enzymatic properties, CD73 is involved in cancer-related processes and is upregulated in many cancers such asleukemia,glioblastoma,melanoma,esophageal,prostate,ovarian andbreast cancer. It is an important key molecule in cancer regulation and development and is involved in tumor progression. In addition, NT5E functions as anadhesion andsignaling molecule and can regulate cellular signaling withextracellular matrix components such asfibronectin andlaminin. This can mediate the metastatic and invasive properties of cancer.[15] In mouse breast and prostate cancer tumor models as well as in breast cancerpatient derived xenograft models, NT5E was confirmed to support tumorangiogenesis. His expression promotes invasion and metastasis of murine and humanmelanoma cells and human breast cancer cells. Tumor infiltration by cells which express NT5E such as myeloid derived suppressor cells (MDSC), Treg's,dendritic cells (DC) leads to accumulation of adenosine. Subsequently,cAMP signaling is triggered inT cell that express the adenosineA2A receptor.[16]Adenosine receptor are also expressed onmacrophage, DCs, MDSC andnatural killer cell(NK). Thus, adenosine may inhibit the function of these immune cells. In addition, the tumor cells may also express adenosineA1 andA3 receptors associated with Gαi proteins, promoting both the migration and proliferation of tumor cells.[9][15][17] Especially due to its beneficial effects in mouse tumor models,anti-CD3 monoclonal antibody therapy is now a promising approach to cancer treatment in the future.Enzyme inhibitors of CD73 are currently being tested in clinical trials for the cancer treatment.[15]
MicroRNAs are small non-codingRNA molecules which regulategene expression at posttranscriptional level via binding to mRNA. This leads to degradation of the target mRNA molecule or translational repression. In tumor cells the miRNA expression pattern often change and therefore affect the surface NT5E, which as result interfere the anti-tumor immune response.[18][19] For example, studies confirm the role of themiR30 family in NT5E regulation. Upon miR-30a-5p expression, NT5E expression was decreased.[9]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Misumi Y, Ogata S, Ohkubo K, Hirose S, Ikehara Y (August 1990). "Primary structure of human placental 5'-nucleotidase and identification of the glycolipid anchor in the mature form".European Journal of Biochemistry.191 (3):563–9.doi:10.1111/j.1432-1033.1990.tb19158.x.PMID2129526.
^Allard B, Cousineau I, Spring K, Stagg J (January 2019). "Chapter Fifteen - Measurement of CD73 enzymatic activity using luminescence-based and colorimetric assays". In Rudqvist L, Galluzzi NP (eds.).Methods in Enzymology. Vol. 629. Academic Press. pp. 269–289.doi:10.1016/bs.mie.2019.10.007.ISBN978-0-12-818671-8.PMID31727245.S2CID208035622.
^Tripathi A, Lin E, Nussenzveig R, Yandell M, Pal SK, Agarwal N (2019-05-20). "NT5E expression and the immune landscape of prostate cancer (PC): An analysis from The Cancer Genome Atlas database".Journal of Clinical Oncology.37 (15_suppl) e16591.doi:10.1200/JCO.2019.37.15_suppl.e16591.ISSN0732-183X.S2CID190909472.
^Zhang F, Luo Y, Shao Z, Xu L, Liu X, Niu Y, et al. (April 2016). "MicroRNA-187, a downstream effector of TGFβ pathway, suppresses Smad-mediated epithelial-mesenchymal transition in colorectal cancer".Cancer Letters.373 (2):203–13.doi:10.1016/j.canlet.2016.01.037.PMID26820227.
^Ghalamfarsa G, Kazemi MH, Raoofi Mohseni S, Masjedi A, Hojjat-Farsangi M, Azizi G, et al. (February 2019). "CD73 as a potential opportunity for cancer immunotherapy".Expert Opinion on Therapeutic Targets.23 (2):127–142.doi:10.1080/14728222.2019.1559829.PMID30556751.S2CID58767911.
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