阿司匹林乙酰化修饰ALDH1选择性清除大肠癌干细胞的分子机制研究

项目名称： 阿司匹林乙酰化修饰ALDH1选择性清除大肠癌干细胞的分子机制研究

项目编号： No.31471391

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 发育生物学与生殖生物学

项目作者： 黄建

作者单位： 浙江大学

项目金额： 75万元

中文摘要： 临床上Aspirin具有明确的防治多种肿瘤尤其是结直肠癌（CRC）的作用，已证实CRC发生发展与肿瘤干细胞(CSC)密切相关，其中ALDH1酶是结直肠癌CSC（CCSC）特征性标志物之一，也是其生长、分化的必需分子，因此探讨Aspirin如何抑制ALDH1酶活性清除CCSC也是CRC防治研究的重点。我们前期研究首次发现Aspirin能选择性清除CCSC，可通过非COX2依赖途径抑制ALDH1活性，同时ALDH1发生乙酰化，但机制不清也无报道。为此，我们假设含乙酰基团的Aspirin通过乙酰化ALDH1来抑制活性进而选择清除CCSC。本课题拟在前期研究的基础上，通过免疫沉淀及乙酰化报告系统等技术筛选鉴定Aspirin介导ALDH1活性降低的乙酰化方式、位点及生物学意义；明确与乙酰化ALDH1相互作用相关HDAC及靶蛋白，为Aspirin靶向清除CCSC提供新靶点,为解析抗CRC效应提供新机制

中文关键词： 阿司匹林；乙醛脱氢酶1；乙酰化修饰；大肠癌肿瘤干细胞；分子机制

英文摘要： Clinical and epidemiological datas have revealed that Aspirin can significantly reduce the incidence and mortality of colorectal cancer(CRC),and improve the patients' prognosis. Many studies also suggest that CRC carcinigenesis and progression are closely associated with the existance of cancer stem cell (CSC). In addition,ALDH1 is one of the key CCSC markers involving tumor cell growth and differeciation. But it is still unknown whether Aspirin has effect on colorectal CSC (CCSC)as well as how it affects CCSC. Our group firstly found that Aspirin can eradicate CCSC selectively. We also found that Aspirin can restrain the enzyme activity of ALDH1 on a COX-2 independent manner, and the acetylation of ALDH1 can occur. Hence, we assume that Aspirin supresses the enzyme activity of ALDH1 through the acetylation of ALDH1,and further kills CCSC. Based on our previous results, we firstly screen and identify the mode and site of ALDH1 acetylation mediated by Aspirin ,which consequntly results in the inactivate of ALDH1 by immunoprecipitation and acetylation reporter system; Secondly, we analyze the biological significance of this modification; and then clarify the HDAC deacetylating the ALDH1 lysine residues and illuminate the target proteins interacting with acetylated ALDH1;finally verify the scientific design that Aspirin exerts its selective inhibition on CCSC through acetylated ALDH1. This study will afford a new target in CCSC interference therapy and establish a novel mechanism of Aspirin anti-CRC effect.

英文关键词： aspirin;ALDH1;acetylation;colorectal cancer stem cell;molecular mechanism