PES1轴在细胞衰老和肿瘤中的作用及其机制

项目名称： PES1轴在细胞衰老和肿瘤中的作用及其机制

项目编号： No.81330053

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： 叶棋浓

作者单位： 中国人民解放军军事科学院军事医学研究院

项目金额： 290万元

中文摘要： 细胞衰老是防御肿瘤发生的一道重要屏障，癌基因或抑癌基因的异常可诱导细胞衰老，但调节衰老的这类基因及其作用机制还不甚清楚。我们的初步研究结果表明，具有癌基因特征的PES1能调节与衰老相关的端粒长度、β-半乳糖苷酶活性（SA-β-gal）和抑癌基因p53的表达，提示PES1是一新的衰老相关基因；另外，我们发现一条非编码RNA即miR-X能调节PES1表达和SA-β-gal活性。本研究拟在此基础上，利用细胞周期分析、SA-β-gal检测、端粒长度分析、衰老相关效应基因分析等确定miR-X/PES1轴对衰老的调节作用；利用蛋白间相互作用技术、ChIP等确定该轴对衰老的调节机制；利用基因突变分析、细胞生长分析、动物模型等探索miR-X/PES1轴调节衰老和肿瘤形成的关系；利用qPCR、免疫组化等检测该轴在肿瘤中的临床意义，为深入理解衰老和肿瘤的关系及开发新的抗肿瘤药物提供依据和靶标。

中文关键词： PES1轴;细胞衰老;肿瘤;;

英文摘要： Cellular senescence acts as a potent barrier to tumor development. Activation or inactivation of oncogenes and tumor suppressors can induce senescence. However, what kinds of these genes regulate senescence is still poorly understood. Our preliminary study indicated that PES1, a gene with oncogenic characteristics, modulated senescence-associated telomere length, β-galactosidase activity (SA-β-gal) and expression of the tumor suppressor p53, suggesting that PES1 is a new senescence-related gene. In addition, we demonstrated that the non-coding RNA miR-X could regulate PES1 expression and SA-β-gal activity. In this study, based on these observations, we will determine the role of the miR-X/PES1 axis in senescence by analyses of cell cycle, SA-β-gal, telomere length, expression of senescence-associated effector genes and so on, define the mechanisms underlying miR-X/PES1-regulated senescence using techniques such as protein-protein interaction and chromatin immunoprecipitation, explore the relationship between miR-X/PES1-modulated senescence and tumor development by use of gene mutation analysis, cell growth assay, animal models, etc., and assess clinical significance of the miR-X/PES1 axis in cancer using techniques including qPCR and immunohistochemistry. This study will further elucidate the relationship between senescence and cancer and provide candidate target for development of novel drugs against cancer.

英文关键词： PES1 axis;Cellular senescence;tumor