脑胶质瘤中c-MET/E2F1/DMC1信号通路调控肿瘤同源重组及化疗耐药的机制研究

Chemoresistance is the main reason for recurrence and high mortality of gliomas. In previous studies, we found that expression of c-MET was associated with tumor grade, malignant phenotype and prognosis for gliomas. Basing on genomic data, we find c-MET may regulate DMC1 expression, which is a specific gene of homologous recombination. MAPK signaling pathway, transcription factor E2F1 and DMC1 are hyper-activated or over-expressed in c-MET high expression subtype. In this project, we focus on “mechanisms exploration of homologous recombination induced chemoresistance mediated by c-MET/E2F/DMC1 pathway in gliomas”. We will further validate the correlation and regulatory mechanism between c-MET and homologous recombination in patient tissue samples. After that, we will study the biological and potential clinical significance by ELISA, flow cytometry, western blot, target inhibition, etc. in glioma cell lines and mouse models. To prove the mechanism, we will explore the transcription regulation role of MAPK signaling pathway on DMC1 expression. This project has significant translational meanings and will lay a foundation for homologous recombination targeting treatment of gliomas.

脑胶质瘤化疗抵抗是其复发快、死亡率高的主要原因。DNA双链断裂修复主要依赖于同源重组修复的准确性，当这一通路受损时化疗药物即可有效杀伤肿瘤细胞。申请人前期研究发现c-MET表达与脑胶质瘤化疗敏感性密切相关,进一步研究发现c-MET/MAPK/E2F1/DMC1信号通路可增强同源重组，这可能是导致胶质瘤化疗耐药的关键。本项目集中在“c-MET通过MAPK/E2F1/DMC1信号通路调控脑胶质瘤同源重组导致化疗耐药的机制研究”方向，拟在大样本临床数据中，进一步验证c-MET对同源重组的调控作用；在细胞及动物模型中，通过ELISA、靶向抑制等方法，明确其调控过程及分子机制；通过ChIP等方法，研究MAPK通路对DMC1的转录调控作用；同时通过体内外实验筛选靶向上述调控通路的抑制剂。本研究预期揭示c-MET通过同源重组信号通路调控脑胶质瘤化疗抵抗的分子机制，为临床靶向治疗和化疗增敏提供新策略。

脑胶质瘤化疗抵抗是其复发快、死亡率高的主要原因。DNA损伤修复主要依赖于同源重组修复的准确性，当这一通路受损时化疗药物即可有效杀伤肿瘤细胞。课题组前期研究发现c-MET表达与胶质瘤级别、恶性表型及预后相关；c-MET表达与脑胶质瘤化疗敏感性密切相关，c-MET高表达胶质瘤对TMZ化疗不敏感，c-MET信号通路可增强同源重组。课题组利用大样本、多中心脑胶质瘤临床样本RNA测序数据、临床肿瘤组织标本、患者临床磁共振影像资料，结合细胞、动物模型，系统分析了DNA损伤反应、同源重组相关通路、c-MET抑制剂、肿瘤免疫微环境、肿瘤相关巨噬细胞、VAT1、肿瘤坏死因子超家族等指标在脑胶质瘤中的生物学及临床意义。进一步验证了前期发现的脑胶质瘤DNA损伤修复、免疫微环境在肿瘤发生、发展及治疗中的重要意义。