EGFR/ASL促进胶质母细胞瘤中启动子区突变型TERT基因表达的机制研究

胶质母细胞瘤（GBM）是中枢神经系统致死率最高的恶性肿瘤。在GBM中，常发生EGFR异常激活和端粒酶逆转录酶（TERT）基因启动子区高频突变（突变率高达83%），然而这二者之间有无互作调控以及该调控在GBM发生发展中的作用尚不清楚。我们前期研究发现，EGFR通过精氨琥珀酸裂解酶（ASL）特异性促进启动子区突变型TERT基因表达，而对野生型无影响。该项目拟从肿瘤代谢角度，借助分子生物学、细胞生物学和表观遗传学手段，深入研究EGFR/ASL及ASL代谢产物促进启动子区突变型TERT基因表达的分子机制；结合细胞、动物模型和GBM病人肿瘤组织标本探讨该分子机制对GBM肿瘤生长的影响和病人预后关联性，为鉴定GBM治疗靶点提供理论依据，为GBM病人预后和个性化精准治疗提供新思路。

Glioblastoma (GBM) is the most detrimental and malignant brain tumor in central nervous system. GBM is featured with EGFR activation and TERT promoter hotspot mutations (83%). So far, little is known about the mutual regulation and subsequent consequences between EGFR activation and TERT promoter hotspot mutations in GBM progression. Our preliminary results demonstrated that EGFR activation specifically enhanced promoter-mutant, but not -wildtype, TERT expression in an argininosuccinate lyase (ASL)-dependent manner. In this proposal, we are trying to explore the molecular mechanisms underlying EGFR/ASL- and ASL metabolic product-enhanced promoter-mutant TERT expression through cutting-edge technologies in molecular biology, cell biology and epigenetics. We will integrate data from cell culture, in vivo mice brain model and GBM patient samples to investigate how EGFR/TERT promoter mutation regulate GBM progression and patient prognosis. This study will lead to better understanding of GBM development and promise effective treatment for individual precision medicine for patients.