应激蛋白Gadd45g调控Stat3活化和诱导肝癌细胞衰老的研究

项目名称： 应激蛋白Gadd45g调控Stat3活化和诱导肝癌细胞衰老的研究

项目编号： No.81201542

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 杨兆娟

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 细胞衰老（Cellular Senescence）是抑制细胞恶性转化和预防肿瘤发生、维护组织稳态的重要细胞学机制。我们前期的初步工作发现，在不同癌基因转化的p53-/-鼠肝细胞和临床肝癌肿瘤样本中，应激蛋白Gadd45g(生长抑制及DNA损伤诱导蛋白45g)表达显著下调，而在肝癌细胞中过表达Gadd45g可迅速抑制重要信号蛋白Stat3的磷酸化，并可导致肿瘤细胞发生衰老。本项目将在此基础上，进一步阐明Gadd45g在诱导肝癌细胞衰老和抑制肝癌发生中的作用，着重研究Gadd45g调控Stat3活性的机制以及抑制Stat3活化在Gadd45g诱导细胞衰老过程中的作用，同时明确Gadd45g诱导细胞衰老，是否依赖衰老相关蛋白p53/p21、 p16/Rb及p27。本研究将为阐明控制肝癌发生的新的检查机制、发现诱导肝癌细胞衰老的重要分子，提供新的认识和实验依据。

中文关键词： 细胞衰老；GADD45G；肝癌；Stat3；SIP1

英文摘要： Cellular senescence, a state of irreversible growth arrest, can limit excessive or aberrant cell proliferation, so it may protects against the development of cancer. Growth arrest- and DNA damage-inducible protein 45g (Gadd45g) is a member of Gadd45 protein family, key regulators of cell cycle in response to cell stress. Our preliminary experiments revealed that the expression of Gadd45g was significantly downregulated not only in the oncogenes-transformed mouse liver cells but also in human hepatocellular carcinoma cell lines and clinic samples. Overexpression of Gadd45g in these cells directly induces cellular senescence, and represses the phorphorylation of Stat3. We will pursue the following specific aims: (1) illustrate the role the Gadd45g in the induction of cellular senescence in HCC, (2) investigate the mechanism underlying Gadd45g- mediated inhibition of Stat3 activation, and the causal role of Stat3 inactivation in Gadd45g-induced cellular senescence. (3) identify the relationship between Gadd45g and senescence-related signaling pathway, such as p53/p21, p16/Rb and p27. Thus, the study will be valuable for understanding the molecular basis for HCC development and identifying the molecules that function as key checkpoint- effectors to induce senescence of hepatocellular carcinoma cells

英文关键词： Cellular senescence；GADD45G；hepatocellular carcinoma；Stat3；SIP1