三羧酸循环通路关键基因SDHC遗传变异影响肝癌预后的作用机制

Tricarboxylic Acid Cycle (TCA) plays an important role in cellular energy metabolism, meanwhile it also mediates the occurrence of various disease, particularly in cancers. Currently several genes with mutation or abnormal expression in TCA have been identified in cancers. Furthermore, these genes were significantly associated with tumor formation and progression. Previous research of our team showed that SNP rs3935401 in SDHC (SDH subunit C), one of key genes involving TCA, has a significant association with overall survival in hepatocellular carcinoma (HCC) patients. However the molecular mechanism of SDHC and the role of rs3935401 on HCC progression are still remain poorly known. Based on this important finding and our rich experience in HCC research, we attempted to explore the underlie mechanisms of SNP rs3935401 polymorphism affected the progression of HCC. We will upregulate SDHC using plasmid transfection and downregulate SDHC by siRNA, and detect succinate concentration, ROS level and the expression of HIF-1α respectively, further examine the changes of glycolysis and oxidative phosphorylation in HCC cell lines. Therefore our project was able to understand the molecular mechanisms of disturbed SDHC expression affected HCC progress, and provide theoretical basis in establishing HCC prevention and treatment strategy.

线粒体三羧酸循环（Tricarboxylic Acid Cycle,TCA）在细胞能量代谢中发挥重要作用，并参与包括肿瘤在内的多种疾病发生。目前已在肿瘤中发现TCA关键基因存在不同程度突变及表达异常，且与肿瘤发生及进展显著相关。本项目组前期研究发现TCA关键分子琥珀酸脱氢酶基因C亚基（SDHC）SNP位点rs3935401与肝癌患者总体生存期显著相关，然而该基因及其遗传多态性影响肝癌进展的作用机制尚不明确。进而本项目拟基于这一重要发现和肝癌病理机制研究的经验，进一步探讨SNP位点rs3935401不同基因型影响SDHC表达的机制，并利用siRNA和表达质粒转染改变SDHC表达，检测琥珀酸浓度和ROS水平及其下游作用分子缺氧诱导因子1α（HIF-1α）改变，明确肝癌细胞糖酵解及氧化磷酸化功能的变化，进而深入探讨异常表达的SDHC影响肝癌恶性进展的分子机制，为建立肝癌防治策略提供理论依据。