低氧是诱导胶质瘤上皮-间质转化（EMT）进而促其发生侵袭性生长和化疗耐药的重要微环境。我们前期芯片筛选出低氧下胶质瘤细胞中miR-26a显著上调和miR-137显著下调。同时，结合数据库分析miR-26a和miR-137启动子区分别存在HIF-1α/SP1、HIF-1α/EGR1结合位点和表观遗传修饰区域；miR-26a可能靶向APC、Bax和Bad，miR-137可能靶向LRP6、WNT5a和MDM4。因此，我们推测低氧下HIF-1α与SP1/P300和EGR1/DNMT结合通过表观遗传方式转录调控miR-26a和miR-137的异常表达，从而调控Wnt、凋亡信号通路来影响胶质瘤EMT进程和化疗耐药。本项目将从细胞、动物到临床分析全面阐明miR-26a/miR-137作为关键节点在低氧诱导胶质瘤EMT进程和化疗耐药中的作用机制。本项目的完成将为胶质瘤发生发展研究提供新的思路。

Hypoxia, an important microenvironment, induced epithelial mesenchymal transition (EMT) to promote invasion and chemo-resistance of glioma. Microarray screening revealed that miR-26a was up-regulated and miR-137 was significantly down-regulated in glioma cells after hypoxia treatment. Meanwhile, combined with bioinformatics analysis suggested that the promoter region of miR-26a and miR-137 had epigenetic modification, which may be regulated by HIF-1α/SP1 and HIF-1α/EGR1 in hypoxia. Furthermore, miR-26a may target APC, Bax and Bad. MiR-137 may target LRP6, WNT5a and MDM4. Therefore, we proposed a hypothesis that HIF-1 may recruit SP1/P300 and EGR1/DNMT to regulate the abnormal expression of miR-26a and miR-137 through transcriptional activation and epigenetic modification, and regulated the Wnt and apoptotic signaling pathways to influence EMT progression and chemo-resistance. Our project intends to use molecular biology technology to elucidate the role of miR-26a/miR-137 as a key node in hypoxia induced-glioma EMT process and TMZ resistance from cellular, animal and clinical. This project will reveal a new idea for the development of glioma.