TIMELESS在宫颈癌中的异常表达机制及靶向治疗研究

放化疗是晚期宫颈癌的重要治疗方案，肿瘤的DNA修复能力影响放化疗敏感性。宫颈癌中DNA修复机制的研究尚有争议。我们的生物信息学分析显示宫颈癌中存在TIMELESS等多个DNA修复基因的表达上调。文献提示TIMELESS参与DNA复制叉进展和DNA修复。前期实验证实TIMELESS在70%宫颈癌中高表达；TIMELESS基因敲减导致细胞增殖阻滞、凋亡和衰老，并增强细胞对顺铂的敏感性。TIMELESS高表达的可能机制为E2F1/4功能激活。课题拟从分子细胞水平研究TIMELESS在宫颈癌中的表达及调控机制，靶向TIMELESS对宫颈癌DNA修复、细胞增殖、衰老、放化疗敏感性的影响以及TIMELESS调控DNA修复的机制，并从临床标本和动物实验多层次验证TIMELESS在宫颈癌中的作用及靶向治疗价值，为靶向TIMELESS及DNA修复通路治疗宫颈癌提供思路。

Chemo- and radiotherapy are important therapeutic strategies for advanced cervical cancer. The sensitivity of chemo- and radiotherapy is largely dependent on DNA repair capacity in cancer. The role of DNA repair in cervical cancer is still elusive. We performed meta-analysis of gene profile database in cervical cancer, which showed upregulation of multiple genes involved in DNA repair pathway including TIMELESS. TIMELESS regulates DNA replicate fork progression and DSB repair. We demonstrated that TIMELSS was overexpressed in 70% of cervical squamous cancer by immunohistochemistry, and that TIMELESS knockdown not only resulted in cell proliferation retardation, cell apoptosis and cell senescence, but also sensitized cancer cells to cisplatin. The upregulation of TIMELESS is possibly contributed by E2F1/4 activation. Through clinical investigation, in vitro assay and animal study, we expect to determine the deregulation mechanism and functional significance of TIMELESS, illuminate the effect of targeting TIMELESS on chemo- and radiotherapy response in cervical cancer, as well as the mechanism of TIMELESS in DNA repair pathway. The expected results will provide TIMELESS as a novel molecular therapy candidate regulating DNA repair pathway in cervical cancer.