肿瘤细胞中坏死基因Rip3的表达调控机制

项目名称： 肿瘤细胞中坏死基因Rip3的表达调控机制

项目编号： No.31471303

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 何苏丹

作者单位： 苏州系统医学研究所

项目金额： 90万元

中文摘要： 细胞坏死参与许多重要疾病的发生，包括缺血性心脑血管疾病、急性炎症损伤和感染性疾病。我们已报道RIP3是调控TNF和TLR介导的细胞坏死的关键蛋白，并揭示其参与炎症损伤（He et al.Cell,2009；PNAS,2011）。最近的研究发现Rip3的缺陷促进NF-κB调控蛋白TAK1敲除小鼠自发的肝癌，提示RIP3可能有抑癌作用。本项目的初期研究发现多数结肠癌和肝癌细胞对TNF诱导的细胞坏死呈现抗性，进而发现这些细胞不表达Rip3且其启动子高度甲基化，利用去甲基化药物可诱导RIP3表达，还通过 RNAi等技术筛选了参与调控的转录因子，在此基础上，我们将进一步鉴定参与调控的表观遗传因子和转录因子,从机制上阐明它们调控Rip3表达的机理及在细胞坏死中的作用，并从功能上解析Rip3表达的改变对肿瘤形成的影响,从而揭示肿瘤细胞中Rip3的表达调控机制及其在抗肿瘤中的意义，为肿瘤治疗提供新的思路。

中文关键词： 基因表达调控；Rip3基因；细胞坏死；肿瘤

英文摘要： Necrosis plays a prominent role in pathological conditions including ischemia, acute inflammatory tissue injuries and microbe-associated diseases. Previously, we have demonstrated that RIP3 is a key regulator for TNF- and TLR-induced necrotic death and participates in inflammatory tissue injury（He et al.Cell,2009; PNAS,2011）.A recent work demonstrated that deficiency of Rip3 promotes hepatocarcinogenesis triggered by conditional deletion of depletion of TAK1 in liver parenchymal cells. In this proposal, we have shown that most examined colon and hepatic cancer cells are resistant to TNF-induced necrosis. These cell lines do not express Rip3 and display heavy methylation of Rip3 promoter region. A specific inhibitor of DNA methylation dramatically induced the expression of RIP3 in these cells. Moreover, we have been working on identification of transcript factors involved in the regulation of Rip3 expression by a set of approaches including RNAi. Based on above findings, we will further identify and characterize epigenetic regulators and transcript factors and demonstrate how they regulate Rip3 expression and necrosis in these cancer cells. Moreover, we will investigate the role of RIP3-dependent necrosis in carcinogenesis and provide novel opportunities to develop therapeutic strategies for cancer.

英文关键词： regulation of gene expression;Rip3 gene;necrosis;tumor