cullin 2调控环路对HPV16 E7介导的宫颈癌发生发展的促进作用及分子机制

宫颈癌是迄今严重威胁妇女的常见恶性肿瘤，高危人乳头瘤病毒（HR-HPV）感染是宫颈癌发生发展的必需因素。阐明病毒癌蛋白与宿主细胞信号通路间的相互作用对探寻宫颈癌防治新靶点有重大意义。本项目以与HPV16 E7特异性结合的宿主蛋白cullin2 (cul2)为切入点，提出在HR-HPV E7致癌促癌过程中存在"miR-424/cul2/E2F1/miR-424"反馈性调控环路（简称cul2调控环路）的假设，并拟通过细胞、动物模型和组织标本，利用免疫共沉淀、染色质免疫共沉淀和荧光素酶报告基因检测等多种分子生物学技术，依次观察miR-424对cul2、cul2对E2F1、E2F1对miR-424的调控作用、及其整个调控环路对E7功能的影响，验证由cul2调控环路引起的cul2持续过表达在HPV16介导的宫颈癌发生发展过程中的作用。旨在揭示宫颈癌发生发展的新机制和为探寻宫颈癌防治新靶点提供实验依据

Cervical cancer is a common malignancy of women worldwide. High-risk human papillomavirus (HR-HPV) infection is a necessary factor in the development of cervical cancer. Clarifing the interaction between virus oncoproteins and host cell signaling pathway promotes to explore new strategies of target therapy. In this research program, we focus on the cellular protein cul2, which is specifically binds with HPV16 E7. We propose that, in HR-HPV E7-induced carcinogenic process, there exist "miR-424/cul2/E2F1/miR-424" regulatory feedback loop(also as cul2 regulation loop), based on varoius investigations such as molecular, cellular, clinical data and animal models, and through a variety of molecular bioligy techniques,such as co-IP, pull-down, ChIP and luciferase report assay.We verify that sustained overexpression of cul2 caused by cul2 feedback loop promotes the development of HPV16-induced cervical cancer. The aim of this study is to reveal a new mechanism for the development of cervical cancer, and to provide experimental evidence for exploring new target therapy.