miR-203/c-Myc调控肝细胞癌糖代谢重编程的作用及分子机制

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and its incidence is rising annually. Aberrant glucose metabolism (also named aerobic glycolysis) has been recognized as a hallmark of cancer cells, which plays important roles in tumorigenesis and progression. However, the mechanisms underlying the increasing aerobic glycolysis in HCC have not been completely understood. While most studies on aerobic glycolysis in HCC have been performed in HCC cell lines or xenograft models so far, the key questions in vivo have not been well investigated. In previous study, we have demonstrated that miR-203 is downexpressed on human HCC samples,and overexprssion of miR-203 can complelely inhibit the development of liver tumor in mice induced by oncogenes AKT and Ras, and futhure bioinformatics analysis found that the key regulator in aerobic glycolysis c-Myc is a potential target of miR-203. Our data indicates that miR-203/c-Myc involves the development of HCC via regulating aberrant glucose metabolism, and is a good target for HCC treatment. In this project, HCC cell lines, a novel mouse liver tumor model and clinical HCC samples will be used to explore the role and mechanisms of miR-203 involves the development of HCC via regulating aberrant glucose metabolism. The aim of this project is to provide new potential targets for HCC treatment based on abnomal energy metabolism.

肝细胞癌（hepatocellular carcinoma, HCC）是世界上致死率最高的恶性肿瘤之一，发病率处于上升趋势。糖代谢异常改变（即有氧糖酵解）是恶性肿瘤的标志性特征之一，在肿瘤发生进展中具有关键作用，但其在HCC失调的机制尚未阐明。既往肝癌有氧糖酵解的研究大多建立在体外细胞或移植瘤水平上，小鼠体内关键数据相对较少。我们前期研究表明：miR-203在人肝癌组织中低表达；上调miR-203的表达可抑制癌基因AKT和Ras诱导的小鼠肝癌的发生，并显著抑制糖酵解过程；生物信息学分析显示异常糖酵解的关键调控因子c-Myc是miR-203的靶点。以上提示miR-203/c-Myc可能通过调控异常糖酵解，抑制肝癌发生。本课题拟在肝癌细胞系、新型小鼠肝癌模型和人肝癌组织多个水平上，探讨miR-203分子介导肝癌细胞糖代谢重编程进而抑制肝癌发生的作用及分子机制，为肝癌的临床治疗提供靶点。

肝细胞肝癌（hepatocellular carcinoma, HCC）是世界上致死率最高的恶性肿瘤之一，治疗手段缺乏，效果有限。目前大量的研究表明，MicroRNAs在肿瘤发生中发挥重要作用，并呈现出良好的靶向治疗潜能。在本研究中，我们发现miR-203通过直接靶向调控下游基因NRas，抑制HCC的发生发展。miR-203在三种小鼠肝癌模型、多种人源肝癌细胞系和临床肝癌标本中表达下降，是肝癌不良预后的生物标志物。上调miR-203在3种不同肝癌细胞系的表达，可以抑制细胞增殖和生长，阻滞细胞周期，并显著抑制裸鼠移植瘤中HCC的生长。通过高压尾静脉注射转染方法，在小鼠肝脏过表达miR-203，可以明显抑制癌基因AKT/Ras诱导的小鼠原位HCC的发生发展，而对照组小鼠在转染AKT/Ras 6周内均发生致命性的肝脏肿瘤负担。通过基因芯片分析和western blot验证，miR-203在AKT/Ras小鼠肝脏过表达后，显著抑制了Ras/MAPK信号通路相关蛋白的表达水平。通过生物信息学分析和荧光素酶报告基因实验，证实NRas是miR-203调控HCC的直接作用靶点。总之，我们的体内和体外研究阐明miR-203在抑制HCC发生中发挥重要作用，可作为一个潜在的治疗靶点。