端粒酶激活在甲状腺癌的分子机理及其临床意义

As a ribonucleoprotein enzyme, telomerase consists of two basin units including RNA template and catalytic and rate-limiting component which is referred as telomerase reverse transcriptase (TERT). TERT plays a crucial role in telomere maintenance, cell immortalization and malignant transformation. The critical role of reactivation of telomerase in cancer development and progression has been approved in different kinds of human cancer, hence, it is considered as an important molecular marker for cancer diagnosis and prognosis. Thyroid cancer is a common endocrine tumor, and the incidence increased a lot during recent years, which causes serious health problems. The applicant reported the telomerase can be used as a prognostic marker for thyroid cancer and two new point mutations on TERT promoter region in thyroid cancer. However, the molecular mechanisms underlying the activation of TERT in thyroid cancer is still unclear. This application plans to explore deeply on the mechanism of telomerase activation in thyroid based on the previous study, and plans to elucidate the crucial molecular in the regulation of TERT. This project will provide further insights into the molecular mechanism of telomerase in thyroid cancer, and will underline the clinical importance of the usage of telomerase inhibitor in thyroid cancer treatment.

端粒酶是一种核蛋白酶，其中起催化作用的酶单位被称为端粒酶逆转录酶(TERT)。 TERT 在维持端粒长度、细胞永生化和肿瘤形成中起重要作用。TERT的重新激活已被证实和多种肿瘤的发生发展密切相关，因此被认为是一种具有重要临床意义的肿瘤诊断和治疗的分子。甲状腺癌是一种常见的内分泌肿瘤，在近些年内发病率逐年升高。申请者首次发现端粒酶在甲状腺癌中是一种指示疾病预后的分子，并且发现在不同类型的甲状腺肿瘤中新的TERT基因突变及和疾病预后的关系。但是端粒酶在甲状腺癌中被重新激活的分子机理仍不清楚。本课题拟在前期工作基础上，进一步探讨端粒酶在甲状腺癌中激活的分子生物学机理并找出调控TERT的关键分子元件。这项课题的研究结果将对揭示端粒酶在甲状腺癌发病机理中的作用提供理论依据，并为利用端粒酶抑制剂在甲状腺癌的临床治疗奠定基础。

甲状腺癌是常见的内分泌系统肿瘤，近年呈现逐渐上升的趋势，甲状腺癌的分子机制还未完全明晰。端粒酶在一部分甲状腺癌中表达升高，表达升高的机制研究成为热点。课题组前期预实验发现端粒酶在甲状腺癌中被重新激活，在此基础上研究端粒酶被重新激活的机制。端粒酶起催化作用的酶单位被称为端粒酶逆转录酶(TERT)，首先从临床标本和甲状腺癌细胞株检测出TERT启动子点突变，生物信息学分析出和突变的TERT启动子结合的转录因子，从细胞水平和临床标本检测转录因子的表达情况，并从细胞水平和动物水平研究了转录因子对肿瘤发生和发展的影响，同时宏观上对TERT启动子的甲基化进行了表观遗传学的研究，并对TERT表达的相关调节蛋白进行了宏观研究，本项目有助于进一步解释甲状腺癌的分子机制，对于筛选甲状腺癌的标志分子和预后Marker奠定了基础，也为针对TERT的基因治疗甲状腺癌提供了理论依据。