肿瘤/睾丸抗原TRIM36在前列腺癌发生发展的作用及表观遗传学调控的机制研究

Prostate cancer has become the serious influence our country men life and health of one of the malignant tumor.The discovery of cancer/testis antigen for malignant tumor relationship exists between development and germ cell development theory to provide powerful evidence.This topic early screening by proteomics and validate cancer/testis antigen TRIM36, cell and tissue level validation shows TRIM36 expression is higher than in hormone dependence prostate cancer hormone-dependent prostate cancer;In vitro experimental results hint TRIM36 can be mediated ubiquitin process promote the proliferation and metastasis of prostate cancer ability.Further through chromatin immune coprecipitation and methylation detection TRIM36 for androgen targets, and by the promoter region of DNA methylation to line their own control.On this basis, we propose a hypothesis: cancer/testis antigen TRIM36 as androgen target, through the promoter region of DNA methylation to line their own control, and can be mediated PTEN of ubiquitin PI3K/AKT/mTOR pathway, in turn, to participate in the development of prostate cancer.This project will be integrated using the latest molecular biology techniques and bioinformatics tools, to reveal TRIM36 in prostate cancer, the role and mechanism of carcinogenesis, has provided the new mentality for the prevention and treatment of prostate cancer.

前列腺癌已经成为严重影响我国男性生命健康的恶性肿瘤之一。肿瘤/睾丸抗原的发现为恶性肿瘤发生发展与生殖细胞发育间存在关联的学说提供强有力证据。本课题前期通过蛋白质组学筛选并验证肿瘤/睾丸抗原TRIM36，细胞和组织水平验证显示TRIM36在激素非依赖性前列腺癌表达高于激素依赖性前列腺癌；体外实验结果提示TRIM36可介导泛素化过程促进前列腺癌增殖和转移能力。进一步通过染色质免疫共沉淀和甲基化检测发现TRIM36可能为雄激素作用靶点，并可通过启动子区DNA甲基化来行自身调控。据此，我们提出假说：肿瘤/睾丸抗原TRIM36作为雄激素靶点，通过启动子区DNA甲基化来行自身调控，并可介导PTEN泛素化调控PI3K/AKT/mTOR通路进而参与前列腺癌的发生发展。本项目将综合运用最新分子生物学技术及生物信息学工具，以揭示TRIM36在前列腺癌发生过程中的作用及机制，为前列腺癌的预防和治疗提供新的思路。

前列腺癌已经成为严重影响我国男性生命健康的恶性肿瘤之一。肿瘤/睾丸抗原的发现为恶性肿瘤发生发展与生殖细胞发育间存在关联的学说提供强有力证据。本课题前期通过蛋白质组学筛选并验证肿瘤/睾丸抗原TRIM36在前列腺癌的发生发展中起重要作用。在这项研究中，我们发现在组织芯片中63.4％（64/95）的前列腺癌组织表达了TRIM36蛋白。通过随访，我们发现TRIM36表达阴性的患者的生化无复发生存期较短。TRIM36表达与Gleason评分（P = 0.005）、前列腺癌细胞体内外抑制均显着相关，我们发现这些作用是通过抑制MAPK / ERK磷酸化途径介导的。值得注意的是，我们发现在抗雄激素治疗期间升高TRIM36的表达可以提高药物疗效。总的来说，我们发现TRIM36是一个新的雄激素反应基因，它显着增强了抗雄激素药物对抗前列腺癌的功效。