IGF-1信号通路在细胞衰老与肿瘤形成过程中的作用与分子机制研究

项目名称： IGF-1信号通路在细胞衰老与肿瘤形成过程中的作用与分子机制研究

项目编号： No.81330054

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 肖智雄

作者单位： 四川大学

项目金额： 290万元

中文摘要： 癌症是异常细胞增殖和凋亡导致的恶性疾病。细胞衰老是生命的基本现象，是机体对肿瘤发展的一种防御机制。诱导肿瘤细胞衰老成为防治肿瘤的新思路。研究表明类胰岛素生长因子-1（IGF-1）在肿瘤发生发展起重要促进作用。但阻断或削弱IGF-1信号通路则导致模式生物个体延缓衰老。目前尚无清楚的分子机理来诠释IGF-1的双重功能。我们的前期研究发现IGF-1促进细胞增殖与存活；而长期的强IGF-1信号则诱导依赖于SIRT1和p53的细胞早衰。进一步研究发现 IGF-1抑制SIRT1，导致p53 乙酰化和转录活性增加。我们的假说是：IGF-1诱导的细胞衰老是肿瘤发生发展中的重要的负调控机制，p53是监控IGF-1双功能的分子开关。本项目将阐明IGF-1抑制SIRT1的分子机制；研究IGF-1-SIRT1-p53通路在体内对肿瘤发生发展的影响；以及其与人肿瘤发生发展的相关性，为癌症检测与治疗提供新思路和方法。

中文关键词： 前列腺肿瘤;类胰岛素生长因子-1;细胞衰老;p53;SIRT1

英文摘要： Cancer is the leading cause of human mortality worldwide.Uncontrolled cell proliferation and evasion of apoptosis are hallmarks of all cancers. As a basic biological process, cellular senescence is intertwined with cell proliferation.In general, cellular senescence, which leads to irreversible growth arrest even in the presence of growth factors, can be categorized into replicative senescence caused by telomere shortening, and premature senescence caused by variety of cellular stress signals including oncogenic stress. The importance of cellular senescence is increasingly being recognized because it is prevalent in pre-malignant tumors. Given the tumor-suppressing potential of cellular senescence, it is of high interest in developing new strategies of senescence-inducing interventions for cancer treatment. Insulin-like growth factor I (IGF-1) signaling is well recognized for its role in enhancing proliferation and survival. Numerous studies have demonstrated that elevated IGF-1 signaling is closely related to tumorigenesis in animal models as well as in humans. Paradoxically, dampened IGF-1 signaling is associated with increased longevity in various model organisms. Previous studies and work-in-progress from our lab show that acute IGF-1 treatment promotes cell proliferation and survival. In sharp contrast, prolonged IGF-1 treatment leads to SIRT1- and p53-dependent premature cell senescence. We demonstrate that IGF-1 represses the deacetylase activity of SIRT1, leading to increased p53 protein acetylation and transcriptional activity. Thus, it seems that IGF-1 possesses dual function in promoting cell proliferation and in inducing premature cellular senescence, the molecular mechanisms of which, however, remain elusive. Here, we hypothesize that p53 serves as a molecular switch in modulating IGF-1 dual function. This application aims to dissect the molecular mechanisms with which IGF-1 down-regulates SIRT1 activity, to investigate the importance of IGF-1-SIRT1-p53 axis in cell senescence and tumorigenesis in vivo, and to explore its implications in human tumorigenesis. This study will not only offer new insights on cell proliferation and senescence, but also help identifying novel therapeutical targets for cancer treatment.

英文关键词： prostate cancer;IGF-1;cellular senescence;p53;SIRT1