KZNF家族分子ZNF498在肝癌发生发展中功能与作用机制的研究

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers, and hepato-carcinogenesis is a multi-step process in which the activation of proto-oncogenes and inactivation of tumor suppressor genes are key molecular events. Now, its mechanism 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 ZNF498 expression evaluated in HCC. Now, the physiology and pathology function and mechanism of ZNF498 is unclear. ZNF498 could interact with p53 and suppresses p53-mediated apoptosis. The overexpression of ZNF498 could promote the growth, colony formation, migration and invasion of liver cancer cell line in a p53 dependent manner. In this program, we ought to investigate the function of ZNF498 and the regulation of ZNF498 on p53 in tumorigenesis of liver through molecular assays, cellular assays, animal model and specimen analysis of cancer patients. Taken together, this program will contribute to elucidate the function of ZNF498 and the mechanisms of HCC which will open the door towards novel and more effective targeted and personalized therapies in HCC.

原发性肝癌是常见的恶性肿瘤之一，是多因素和多基因交互作用，经过多个阶段发展而成的复杂疾病，其确切的发病机制尚未阐明。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，其成员的异变与肿瘤发生发展关系密切。组织芯片筛选和临床样本检测发现KZNF家族成员ZNF498在肝癌组织高表达。目前，ZNF498的功能及机制均不清楚。我们前期工作发现ZNF498能够与p53相互作用抑制p53的转录活性及其介导的细胞凋亡，以p53依赖的方式增强肝癌细胞的多种肿瘤相关的生物学行为。本项目拟在分子、细胞、动物和临床标本等多层次研究ZNF498对肝癌发生发展的影响，同时探讨ZNF498对p53的调控机制及其在肝癌发生发展中的作用。项目对于深入理解ZNF498的功能及肝癌发生发展的机制具有重要意义，将为肝癌的个体化诊治提供有效的靶点。

肝细胞癌（HCC）是全球最常见的肿瘤之一，其发生机制尚未完全阐释。ZNF498是KRAB型的锌指蛋白家族的成员之一，其功能和作用机制尚无任何报道。在本项研究中，我们发现ZNF498在肝癌中高表达，其高表达与HCC患者尤其是p53野生型的HCC患者的病理分级和不良的生存率呈正相关。ZNF498可以促进DEN诱导的小鼠肝癌的发生和发展。此外，ZNF498在体外和体内依赖对p53通路的调控促进HCC细胞生长。通过机制研究，我们进一步表明ZNF498能够与p53相互作用，通过抑制p53 Ser46位的磷酸化水平，负调控p53通路的活性，减少p53促凋亡靶基因的表达，进而抑制p53介导的凋亡。并且ZNF498对p53 S46位磷酸化水平的调控依赖PKCδ和p53DINP1。我们的结果表明ZNF498是p53 ser46位点磷酸化水平的负调控分子，能够参与HCC的发生和发展，此项工作能为肝癌患者的精准化诊治提供新的靶点和新的思路。