ZNF191调控Wnt信号通路促进肝癌细胞增殖分子机制研究

项目名称： ZNF191调控Wnt信号通路促进肝癌细胞增殖分子机制研究

项目编号： No.31301162

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 刘国元

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 肝癌是一种在我国人群中高发的恶性肿瘤。作为多基因病其发病的分子机制尚不明确，但已发现多条信号通路与肝癌发生相关。前期研究发现人锌指蛋白ZNF191直接靶向上调经典Wnt通路关键基因β-Catenin的转录，促进β-Catenin及下游基因Cyclin D1的mRNA及蛋白水平，促进肝癌细胞增殖。本研究中我们发现Wnt通路激活蛋白Wnt8B可能和ZNF191密切相关，且ZNF191能促进Wnt8B启动子的转录。结果提示ZNF191不仅通过调节β-Catenin，也可能通过调节上游基因Wnt8B来激活Wnt通路，从而促进肝癌细胞增殖。Wnt8B在人肝癌内的表达情况及调控尚未见报道。本课题以Wnt8B为切入点，进一步完善肝癌发生发展中ZNF191对Wnt信号通路的调控作用，回答：(1)Wnt8B在肝癌内的表达及其与ZNF191的相关性；(2)ZNF191对Wnt8B调控的分子机制。

中文关键词： 锌指蛋白191；肝细胞肝癌；增殖；转移；Wnt8B

英文摘要： Hepatocellular carcinoma (HCC) is a primary cancer of the liver and one of the most common diagnosed cancers in Chinese population. Various risk factors have been associated with HCC, The pathogenesis of the development and progression of HCC is far from being clear presently, and several cellular signal transduction pathways are involved in HCC. In our previous research, ZNF191 can directly bind to the CTNNB1 promoter and activate the expression of β-catenin and its downstream target genes such as cyclin D1 in hepatoma cell lines and we demonstrated that the key binding sequence of ZNF191 in vivo is ATTAATT. The findings suggest a possible role of ZNF191 in association with cell proliferation of HCC. In this study, we identified the expression of Wnt8B, one of Wnt family members which can activate canonical Wnt signaling cascades, maybe closely associated with ZNF191 in HCC cells, and ZNF191 can activates the 2Kbps Wnt8B promoter. The findings suggest that ZNF191 may function through up-regulating Wnt8B, in addition to β-catenin, to promote tumor cell proliferation in vivo. The expression level of Wnt8B and the molecular mechanism of transcription regulation of the Wnt8B gene remains unknown.In this research we will investigate: (1)the relationship between ZNF191 and Wnt8B mRNA and protein expression in human H

英文关键词： ZNF191；Hepatocellular carcinoma；proliferation；metastasis；Wnt8B