EGFR野生及vIII突变共存是促进恶性胶质瘤发生的重要分子事件,但两者间相互做作用机制不明。EZH2以调控信号转导和组蛋白修饰两种方式参与胶质瘤发生。据此,我们提出"EZH2双重调节β-catenin通路介导EGFRwt/vIII型人脑胶质瘤生长"的研究假说。本次项目拟在胶质瘤标本中研究EGFRwt/vIII与EZH2表达的关系;在细胞系和动物模型中证明：EGFRvIII募集EZH2催化H3K27me3抑制NFAT5转录并活化β-catenin的机制;探讨EGFRwt活化Akt磷酸化EZH2诱发β-catenin激活的另一途径;通过质谱分析β-catenin转录产物对EGFRwt/vIII细胞的影响。预期结果将阐明EGFRvIII细胞通过β-catenin通路以旁分泌方式刺激EGFRwt胶质瘤细胞生长的分子机制,建立以EZH2为核心针对EGFRwt/vIII治疗恶性胶质瘤的新策略。

Co-expression of EGFR wide type and variation type III is the core molecular event to malignant glioma development. Yet, the mechanism of interaction between EGFRwt and EGFRvIII is still obscure. EZH2 involves in glioma growth via regulating signaling transduction and histone modification. Thus, we proposed the research hypothesis that EZH2 regulates β-catenin signaling dually to promote EGFRwt/vIII human glioblastoma growth. In the current research program, we will study as follows: the relationship between EGFRwt/vIII expression and EZH2 activation status in glioma tissue samples; the mechanism that EZH2 regulating β-catenin via H3K27me3 mediated NFAT5 transcription; and EGFRvIII dependent EZH2 phosphorylation is required to β-catenin activation. Expected research results will elucidate the mechanism that EGFRvIII triggers EGFRwt glioma cell growth via regulating β-catenin signaling through a paracrine approach and provide a novel treatment strategy targeting EGFRwt/vIII.