前凋亡因子ChaC1在人恶性胶质瘤中表达抑制的功能与分子机制

ChaC1属前凋亡因子。我们前期研究发现ChaC1在人恶性胶质瘤原神经型 (Proneural)分子亚型中异常低表达，并与肿瘤恶性程度、增殖活性密切负相关，IHC、Western Blot、qPCR显示在恶性胶质瘤中Notch1与ChaC1表达亦呈负相关。生物信息学分析提示ChaC1处于elF2α-ATF4-CHOP通路诱导的内质网应激反应的关键位置。本项目拟采用基因过表达、RNA干扰、基因转染和裸鼠原位瘤模型等技术研究ChaC1对胶质瘤增殖、侵袭和凋亡的影响；免疫共沉淀、免疫组化、蛋白相互作用分析等技术明确ChaC1调节铁死亡通路GSH/GSSH-GPX4具体环节和分子机制；反向研究Notch信号对ChaC1促细胞凋亡作用的影响。通过本研究证明ChaC1是介导触发铁死亡的ERS通路与Notch信号交互作用的关键靶点，为胶质瘤防治研究提供依据和新线索，具有重要理论和临床意义。

ChaC1 is a pro-apoptotic factor，In our previous studies, we have found that ChaC1 lowly expressed in Proneural subtypes of human malignant glioma, It is negatively related the degree of malignancy of tumor and proliferation activity. The expression of Notch1 showed the same tendency with ChaC1 by IHC, Western Blot and qPCR. Bioinformatics analysis showed ChaC1 may play a key role in the endoplasmic reticulum stress response induced by elF2α-ATF4-CHOP pathway. In view of these findings, we will focus on the influence of ChaC1 on proliferation, invasion and apoptosis of glioma through gene overexpression, RNA interference, gene transfection and nude mice tumor model technology in the next research. Further, we will elucidate the putative molecular mechanisms of ChaC1 regulate ferroptosis via GSH/GSSH-GPX4 by the co-immunoprecipitation, immunohistochemistry and protein interaction analysis technology. This will be evidenced by the present study that ChaC1 is a central regulator mediating the crosstalk of ferroptosis via ERS pathway and apoptosis via Notch signal. The study will provide a full basis and new clue for prevention and control of glioma, therefore, it has important theoretical and clinical significance.