星形胶质细胞瘤IDH1基因突变导致肿瘤EMT发生的机制研究

The gene encoding isocitrate dehydrogenase 1(IDH1) is somatically mutated predominantly in glioma and was identified as a novel important genetic marker for glioma. The mutation impairs the oxidative IDH activity of the enzyme, but renders a new reduction function of converting α－keglutarate (α－KG ) to 2-hydroxyglutarate (D-2HG). High levels of D-2HG and decreased levels of α－KG are characteristics of IDH1 mutant tumors. Our previous study showed that 2-HG was a competitive inhibitor of multiple α-KG-dependent dioxygenases which led to genome-wide histone and DNA methylation alterations. Furthermore, we found IDH1 mutation correlated with epithelial mesenchymal differentiation (EMT) in astroglioma. In this study,stable IDH1 mutated astroglioma cell-line and large Chinese astroglioma samples (about 300 cases) would be used to investigate and confirm the mechanisn especially the key gene or signal transduction pathway involved in EMT occuring after IDH1 gene mutation. The study could improve current understanding the tumorigenesis of astroglioma and offer potential therapeutic implications.

异柠檬酸脱氢酶1（IDH1）基因突变现已成为胶质瘤细胞新的遗传特征。突变的IDH1可使胞内α－酮戊二酸（α－KG）含量下降，而2-羟戊二酸（2HG）累积。我们前期工作表明，升高的D-2HG可竞争抑制细胞内多种依赖α－KG双加氧酶的活性，使得细胞内组蛋白及全基因组胞嘧啶甲基化水平明显升高，产生广泛的生物学效应。我们近来又发现IDH1基因突变与星形胶质瘤上皮间质转化（EMT）发生密切相关且伴转录共激活因子TAZ（transcriptional coactivator with PDZ-binding motif）蛋白高表达。本课题将在已稳转IDH1突变基因的星形胶质瘤细胞株中研究IDH1突变诱导TAZ表达改变的调控机制，筛选IDH1突变后TAZ诱发EMT的关键基因或信号机制，并在大样本人脑星形胶质瘤标本(约300例)中加以验证。本研究将为星形胶质细胞瘤临床治疗提供新的理论指导和治疗靶点。

异柠檬酸脱氢酶1（isocitrate dehydrogenase 1, IDH1）编码基因在胶质瘤中的高突变率使之成为胶质瘤重要的分子遗传特征，也成为当前胶质瘤研究的热点之一。做为细胞内重要的代谢酶，IDH1基因突变可使细胞内α－酮戊二酸（α－keglutarate, α－KG）含量下降，而2-羟戊二酸（D-2-hydroxyglutarate，D-2HG）累积。我们前期工作表明，升高的D-2HG可竞争抑制细胞内多种依赖α－KG双加氧酶的活性，使得细胞内组蛋白及全基因组胞嘧啶甲基化水平明显升高，进而产生广泛的生物学效应。高级别星形胶质瘤细胞增殖活跃、侵袭力增加并伴有明显的血管新生是其预后差的重要原因。我们经IDH1突变与未突变的人脑胶质瘤组织及人胶质瘤细胞培养，验证了TAZ在胶质瘤中表达受到IDH1突变的影响，并与胶质瘤细胞侵袭转移能力密切相关， IDH1突变后中间代谢癌性产物2-HG水平的调节TAZ表达，同时我们发现TAZ在内皮细胞中的表达也与胶质瘤恶性程度密切相关，提示其同时参与胶质瘤的血管新生。此项研究为胶质瘤针对IDH1突变的靶向治疗提供理论依据。