组蛋白甲基转移酶EZH2介导大肠癌上皮-间质转化（EMT）的发生及其调控机制

项目名称： 组蛋白甲基转移酶EZH2介导大肠癌上皮-间质转化（EMT）的发生及其调控机制

项目编号： No.31271366

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 洪洁

作者单位： 上海交通大学

项目金额： 80万元

中文摘要： 大肠肿瘤侵袭转移启动中的一个重要过程是上皮-间质转化（EMT），后者的发生机制及治疗靶点已成为近年来的研究热点。PcG蛋白在生物体生长发育和疾病中起重要调控作用，其核心亚基EZH2组蛋白甲基转移酶通过催化组蛋白甲基化而介导靶基因表型沉默。本研究发现人大肠癌中EZH2的表达显著上调，下调其表达可显著影响E-cadherin、VDR和N-cadherin 等EMT相关标志物的表达。其中EZH2介导大肠癌EMT发生及其调控的作用机制为我们感兴趣的科学问题。本研究欲从细胞实验、临床标本和动物实验等方面1.探讨进而明确EZH2响应STAT3激活后影响VDR等EMT标志物表达继而导致大肠癌EMT发生和促进肿瘤转移的机制；2.评估EZH2及VDR等EMT相关基因作为临床诊断治疗新靶点的意义。将进一步明确大肠癌浸润转移的分子机制并为今后的防治策略提供科学依据。

中文关键词： EZH2；大肠癌；上皮间质转化；STAT5；c9orf140

英文摘要： Epithelial-Mesenchymal Transition (EMT) is a major process in the initiation of tumor metastasis.The mechanism of EMT initiation and the corresponding targets of treatment have been regard as the research hotspot recently.The polycomb group proteins (PcGs) play an important role in the development and disease of organisms. As the major subunit of PcG proteins,EZH2 has histone methyltrasferase (HMT) activity,which mediates silencing expressions of target genes by alteration of the methylation level of histone in the promoter region of these target genes.In our previous research,we found that EZH2 is overexpressed in human CRC cancer.Downregulation of EZH2 significantly increased the expression of epithelial markers (E-cadherin and VDR) and decreased the expression of mesenchymal marker (N-cadherin).Downregulation of epithelial markers and upregualtion of mesenchymal markers mean the initiation of EMT in tumor development.Therefore,in this study we will focus on the mechanism by which EZH2 mediates EMT and the regulatory mechanism of EZH2.Based on our preliminary data we will 1.demonstrate the mechanism by which EZH2 induces alteration of VDR or other EMT genes expression in response to STAT3 activation in CRC EMT initiation and metastasis;2.evaluate the significance of EZH2,VDR and other EMT gene expressions in c

英文关键词： EZH2；colorectal cancer；EMT；STAT5；c9orf140