SAGE1通过调控TERT转录促进肿瘤细胞增殖的机制研究

端粒酶对于肿瘤细胞增殖至关重要，但是端粒酶活性的调控机制并不明确。SAGE1是一个肿瘤睾丸抗原（CTA）家族蛋白，在肿瘤与精子发育中特异性表达并起重要调控作用。我们的前期实验发现：SAGE1通过结合Integrator复合物中的INTS3调控转录；在SAGE1高表达的肿瘤细胞中同时有高水平的TERT（端粒酶活性亚基）表达；敲低SAGE1导致TERT明显降低，并显著抑制肿瘤细胞增殖。由此我们提出理论假说：在肿瘤细胞中，SAGE1通过INTS3调控TERT转录，影响端粒酶活性，进而调控细胞增殖。本课题将探究三个科学问题：1.SAGE1如何调控TERT转录？2.SAGE1/TERT在肿瘤生长及染色体稳定中有何作用？3.靶向SAGE1/TERT治疗肿瘤是否可行？本项目的实施将有助于阐释肿瘤细胞中端粒酶的表达调控机制，对于理解肿瘤的发生发展机理，以及靶向治疗具有重要意义。

Telomerase is essential for cancer proliferation，while the regulation mechanism of telomerase is not completely understood. SAGE1, a typical CTA (Cancer testis antigen) family protein, is highly and specifically expressed in cancer cell and testis; and plays important role in embryonic development and tumor transformation or tumor progression. In our pilot study, SAGE1 regulates TERT transcription by binding INTS3 of the Integrator complex; and the highly expression of TERT (the activity subunit of telomerase) in tumor is correlated to high level of SAGE1; knock-down of SAGE1 results in decreased expression of TERT and Inhibits tumor cell proliferation. Thus, we hypothesize that SAGE1 regulates TERT transcription and telomerase activity through INTS3 and further influences tumor cell proliferation. To address this hypothesis, we will explore the following three scientific inquiries: 1. How dose SGAE1 regulate the transcription of TERT? 2. What is the function of SAGE1/TERT in chromatin stability and cancer development? 3. Whether targeting SAGE1/TERT is feasible in tumor therapy? The implementation of this project will help to understand the regulation mechanism of telomerase expression in tumor cells, and it is of great significance for understanding the mechanism of tumor occurrence and development as well as tumor targeted therapy.