利用小鼠模型对ZNF496在子宫颈癌发生发展中的功能与作用机制的研究

Cervical cancer is one of the most common tumors affecting women’s health worldwide. Although human papillomavirus can be detected in nearly all cases, the mechanism of cervical carcinogenesis remains to be further addressed. KRAB-containing zinc finger protein （KZNF）family is the largest transcription factor/ cofactor family in mammals, members of which are relevant to the tumorigenesis and development of various types of human cancers. Our initial results revealed that ZNF496 expression disappeared in cervical cancer tissues, and its expression was higher in adjacent tissues. Now, the physiology and pathology function and mechanism of ZNF496 is unclear. The overexpression of ZNF496 could inhibit the colony formation of Hela cells. ZNF496 could interact with RelA, one member of NF- κB, and depress the activity of NF- κB pathway. In this program, we ought to establish the ZNF496 gene knockout and ZNF496 gene knockout HPV transgenic mice models and investigate the function ZNF496 in tumorigenesis of cervix through molecular assays, cellular assays, animal model and specimen analysis of cancer patients. We will also explore the regulatory mechanism of ZNF496 on NF- κB pathway. Taken together, this program will contribute to elucidate the function of ZNF496 and the mechanisms of cervical cancer tumorigenesis and progression.

宫颈癌是女性最常见恶性肿瘤之一，高危型HPV持续感染是其主要危险因素，但宫颈癌发生机制仍不清楚。KZNF（KRAB-containing zinc finger protein）家族是哺乳动物中最大的转录/转录调控因子家族，其成员与肿瘤发生发展关系密切。组织芯片筛选发现KZNF家族成员ZNF496未在宫颈癌中表达，ZNF496能抑制宫颈癌细胞增殖。目前，ZNF496的功能及机制均不清楚。利用酵母双杂交技术鉴定到包括RelA在内的10个与ZNF496相互作用的蛋白，还发现ZNF496能抑制NF-κB通路的活性。本项目拟通过建立ZNF496敲除小鼠模型、ZNF496敲除的HPV转基因小鼠模型，在分子、细胞、动物和临床标本等多层次研究ZNF496对宫颈癌的影响，同时探讨ZNF496对NF-κB通路的调控机制及其在宫颈癌中的作用。项目对于深入理解ZNF496的功能及宫颈癌发生发展机制具有重要意义。

宫颈癌是严重危害女性健康的最常见恶性肿瘤之一。KZNF（KRAB-containing zinc finger protein，KRAB型锌指蛋白）家族是哺乳动物中最大的转录因子/转录调控因子家族，与多种肿瘤的发生发展密切相关。其成员ZNF496的生物学功能及机制均不清楚。本研究在确证RelA与ZNF496相互作用的基础上，在分子/细胞/动物/临床多层次研究ZNF496对NF-κB信号通路的调控及其在宫颈癌发生发展中的作用。我们的工作发现ZNF496通过C2HR结构域与RelA的DBD结构域结合，依赖RelA K37位点下调RelA的甲基化水平，进而负调控NF-κB信号通路抑制宫颈癌的发生发展，增强宫颈癌对化疗药物的敏感性。同时，还发现与ZNF496相互作用的KDM2B也能够与RelA结合下调RelA的甲基化水平抑制NF-κB信号通路的活性。此项工作首次揭示了ZNF496和KDM2B作为RelA的甲基化调控分子对NF-κB通路的调控功能，及其在宫颈癌发生发展中的功能和机制，不仅扩展了对NF-κB调控通路的认识，还为宫颈癌的靶向治疗和增加宫颈癌化疗药物敏感性问题的解决提供了新的思路。