hsa-miR-129-5p负调节Warburg效应和抑制肝癌生长转移的分子机理研究

Liver cancer seriously does harm to people's lives and health. The c-Myc (Myc) oncogene is pathologically activated which is involved in the development of liver cancer. We have previously found that: Myc is overexpressed in hepatocellular carcinoma(HCC)tissues and is essential for the maintenance of malignant phenotypes of liver cancer; The Myc / miRNA function feedback loop regulates hepatocarcinogenesis; miRNAs directly regulated by Myc were identified and confirmed using series of technologies in the miRBase database; miR -129-5p is one of direct targets regulated by Myc; miR-129-5p and its precursors were significantly reduced in HCC tissues; The tumor suppressor functions of miR-129-5p were confirmed with gain and loss of function: it significantly inhibited transformation and Warburg effect of hepatocellular carcinoma cells; it significantly inhibited tumor growth post subcutaneous injection and intrahepatic inoculation, inhibited lung metastasis post tail vein inoculation in nude mice. Using modern experimental techniques this project continues to study the expression regulation and maturation processing of the miR-129-5p; to study the molecular mechanism of inhibition of Warburgh effect, tumor growth and metastasis; to study its targeted intervention to clarify its roles and mechanisms in the prevention and treatment of liver cancer. This will reveal the Myc/miR-129-5p signaling pathways and its mechanisms in hepatocarcinogenesis. It will also provide theoretical basis and new strategies for the prevention and treatment of liver cancer.

肝癌严重危害人民生命健康。c-Myc（Myc）癌基因病理激活参与肝癌发生发展。我们前期发现：Myc在肝癌组织过表达，对维持肝癌细胞恶性表型是必需的；Myc/miRNA功能反馈通路调节肝细胞癌变；miRBase全数据库内鉴定和证实新的Myc直接调节miRNAs;其中miR-129-5p是Myc直接调节miRNAs之一； miR-129-5p和其前体分子在肝癌组织表达显著下调；用获得和丢失性功能证实它具有抑癌功能：抑制肝癌细胞转化和Warburg效应；在裸鼠中显著抑制皮下和肝内接种的肿瘤生长，抑制尾静脉接种的肺部转移。本项目应用现代实验技术继续研究miR-129-5p的表达调控、成熟和调节靶基因，抑制Warburg效应、肿瘤生长和转移的作用分子机理；并进行靶向干预，阐明它在肝癌防治中的作用。这将揭示肝癌中Myc调控miR-129-5p信号通路和其作用机制，为防治肝癌提供理论基础和新策略。

肝癌严重危害我国人民健康，其发病率不断攀升。很多肝癌很难治愈，导致存活率相当低。因此为寻找新的有效治疗手段和提高肝癌患者的生存率，对肝癌的确切发病分子机制深入研究势在必行。肿瘤为适应微环境而进行的代谢重编程已被认为是癌症的显著特征。c-Myc癌基因和微小RNA（miRNA）在肝癌代谢重编程中起着重要作用，但其具体作用分子机制不清楚。.通过本项目的研究，我们构建了miRNA的表达文库，通过功能的miRNA表达文库筛选，鉴定到miR-129-2抑制肝癌细胞生长。发现miR-129-2是c-Myc的直接靶分子，c-Myc、HDAC3和PRC2所组成的转录复合体直接抑制miR-129-2的转录。miR-129-2表达水平与人肝癌肿瘤临床分期和分化呈负相关。发现miR-129-2抑制线粒体基质蛋白PDK4，导致PDH复合物E1α亚基磷酸化下降，而抑制Warburg效应，降低肿瘤生长和转移。 过表达PDK4能恢复miR-129-2表达所引起的表型。用shRNA或小分子抑制剂抑制PDK4，产生与miR-129-2过表达同样的表型。恢复miR-129-2的表达或抑制PDK4活性抑制二乙基亚硝胺（DEN）诱导的小鼠肝癌。这些结果揭示miR-129-2和PDK4通过改变代谢在肝癌进展中的重要作用。.还构建了miR-148a的基因敲除小鼠，发现肝癌患者中miR-148a表达下调，并与患者不良预后密切相关。在普通或高脂喂食下，miR-148a缺失显著促进DEN诱发小鼠肝癌形成。miR-148a缺失明显加重四氯化碳和DEN诱导的肝损伤和纤维化，还促进小鼠脂代谢紊乱： 促进脂类和胆固醇合成。而恢复miR-148a表达则逆转这些缺陷。发现miR-148a直接抑制脂代谢和肝癌形成中的几个重要的调控因子。这些结果揭示miR-148a缺失促进脂类代谢导致肝细胞癌变。阐明了miR-148a在肝脏生理和肝癌发生过程中的重要作用。. 本项目的研究有助于深入阐明肝癌为适应微环境而进行的代谢重编程的分子机制，诠释基因表达的精细调控分子机理，有利于阐述肝癌发病的病理机制。为肝癌的精准治疗提供理论基础和潜在的策略。在国际知名期刊共发表多篇SCI论文。

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