MTR4调控肝细胞癌糖酵解的机制研究

肿瘤细胞依赖氧化磷酸化到糖酵解的代谢转变来获得能量和生物合成所需的底物，糖酵解对建立肿瘤免疫抑制微环境也至关重要。因此，为了研发更有效的肿瘤治疗方法，阐明调控肿瘤代谢的途径至关重要。MTR4是与核外切复合体结合的RNA解旋酶，在RNA合成及质量控制中起到重要作用。申请人首次发现，MTR4在肝细胞癌中高表达，并与肝癌患者的不良预后一致，其通过促进糖酵解通路中重要基因的表达来维持肝癌的糖酵解水平，在肝癌细胞的生长中起着重要作用。本项目拟阐明MTR4调节糖酵解关键基因的表达水平的分子机制以及促癌机制，为临床肝癌的诊断及治疗提供新的生物标记物及治疗靶点。

Metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis by providing cancer cells with energy and substrates of biosynthesis, and also plays a key role in inducing immune suppressive tumor microenvironment that inhibits tumor immunotherapy. Therefore, to develop more effective cancer therapy, it is important to identify pathways that govern cancer metabolic switch. MTR4 is a RNA helicase associated with nuclear exosome that plays important roles in RNA processing and surveillance. The applicant discovered that MTR4 is overexpressed in hepatocellular carcinoma (HCC) and its overexpression predicts the poor prognosis of HCC patients. MTR4 is required for the tumorigenesis of HCC by maintaining the expression of key glycolytic genes and cancer metabolic switch. The applicant proposes to elucidate mechanisms underlying MTR4-dependent glycolytic gene expression and MTR4-driven tumorigenesis. The results will provide new candidates for biomarkers and therapeutic targets for treating HCC.