Pygo2/EZH2/miR-31调节回路在脑胶质瘤发展进程中的作用机制研究

迄今为止，脑胶质瘤形成的分子机制仍然不太清楚。有研究表明Pygo2、EZH2和miR-31在脑胶质瘤的发生及发展中发挥重要作用。但三者的关系及角色是什么？目前尚无报道。我们近期发现：将pHM6-miR-31质粒转入胶质瘤U251细胞中，外源表达miR-31后Pygo2及EZH2表达明显降低。而干扰EZH2后miR-31表达却升高，Pygo2表达降低。据此推测：EZH2、Pygo2及miR-31极有可能以某种调节回路的方式参与脑胶质瘤的形成及发展。本项目拟从3个方面研究: ①Pygo2调控EZH2表达的分子机制；② EZH2通过沉默miR-31促进Pygo2表达的机制；③ Pygo2/EZH2/miR-31调节回路对脑胶质瘤发展进程的作用机制。本项目的研究成果不仅有助于完善miR-31/Pygo2/EZH2调控脑胶质瘤信号网络及致病机制，更为临床脑胶质瘤的治疗及新药物的发现提供全新的思路。

So far, the molecular mechanisms of glioma formation are not fully understood. It has been reported that Pygo2, EZH2 and miR-31 plays an important role in the cause of glioma formation, recurrence and metastasis, respectively. But the relationship and regulatory network between Pygo2, EZH2 and miR-31 remain unknown. We recently found the expression level of Pygo2 and EZH2 was significant decreased after transfection with the miR-31 mimic-expressing recombinant plasmids. Further study showed miR-31 was up regulated and Pygo2 was down regulated when EZH2 knockdown by using siRNA technology. The results suggesting a regulation loop between Pygo2, EZH2 and miR-31, and further cause glioma. Based on our preliminary results, in Aim 1 we propose to investigate the regulation of EZH2 expression by Pygo2 via associates with MLL2 histone methyltransferase and GCN5 histone acetyltransferase complexes. In Aim 2 we propose to examine Pygo2 was regulated by miR-31 through the 3’-UTR, and EZH2-mediated miR-31 suppression via epigenetic silencing leads to Pygo2 activation. And in Aim 3 we propose to examine the impact of Pygo2/EZH2/miR-31 to glioma cell tumorigenesis in vitro and in vivo via Pygo2/EZH2/miR-31 over-expression or knockdown. Successful completion of experiments outlined in this proposal will enhance our current understanding of the mechanism of glioma cell tumorigenesis, and may provide novel therapeutic strategies and targets for glioma.