FOXR2蛋白的SUMO化修饰对脑胶质瘤增殖的影响及机制研究

脑胶质瘤是严重威胁人类健康的疾病，其发生机制未完全阐明。转录因子FOXR2是在肿瘤发生中具有重要调控作用的新致癌基因。令人惊讶的是在正常血旺细胞系中过表达外源FOXR2，使该细胞产生了成瘤能力。我们前期证实FOXR2在脑胶质瘤中高表达，且调控其增殖和生长。但目前对FOXR2的活性调控，特别是其蛋白翻译后修饰调节机制所知甚少。SUMO化修饰可调控靶蛋白亚细胞定位、转录活性等功能，与肿瘤的发生密切相关。我们前期发现，FOXR2是SUMO化修饰的新靶蛋白，推断其SUMO化对胶质瘤增殖等方面具有重要影响。因此，本项目拟进一步明确SUMO化对FOXR2的调控及修饰位点；探明在脑胶质瘤中SUMO化修饰对FOXR2蛋白稳定性、亚细胞定位及转录活性的调控；体外和体内实验阐明FOXR2的SUMO化修饰对脑胶质瘤细胞增殖及成瘤性的影响。预期研究成果将为脑胶质瘤的分子靶向治疗提供新的有益思路及潜在靶点。

Malignant glioma is a serious threat to human health and life. However, the mechanisms of glioma oncogenesis still remain unclear. The transcription factor FOXR2, as a new oncogene, plays an important role in oncogenesis. Strikingly, unlike control cells, the Schwann cells over-expressing FOXR2 could form tumors in xenograft experiments. Our previous studies demonstrated that FOXR2 is over-expressed in glioma tissues and have important effects on the proliferation and growth of glioma cells. However, the regulation of FOXR2 activity, especially for its post-translational modification, is still poorly understood. Sumoylation could regulate the subcellular localization of target proteins and the transactivation of transcription factors, which plays important roles in tumorigenesis. We previously found that FOXR2 is modified by SUMO, suggesting that the FOXR2 sumoylation may have critical effects on the proliferation of glioma cells. In this study, we will further confirm FOXR2 is sumoylated and identify the potential sumoylation sites, elucidate the role of FOXR2 sumoylation on its protein stability, subcellular localization and transactivation in glioma, and clarify the effect of FOXR2 sumoylation on the proliferation and tumorigenesis of glioma by in vitro and in vivo experiments. Our expected results will provide valuable idea and potential targets for molecular therapy of glioma.