miR-370-LIN28A信号通路在肝癌发生发展中的作用

miR-370 is located within the DLK1/DIO3 imprinting region. Many studies have reported the aberrant expression of miR-370 in various cancers. However, the functional role of miR-370 in HCC remains elusive. Our previous study indicated that hepatocyte nuclear factor 4α up-regulated the expression of miR-370. The expression of miR-370 is significantly decreased in HCC tissues. Overexpression of miR-370 inhibited the proliferation, migration and invasion of HCC cells. Moreover, differentiation-associated gene LIN28A was firstly identified as the direct target of miR-370. Based on our previous findings, the present research aims to investigate the effects of miR-370 on human nontransformed immortalized hepatocytes (IMH) and HCC cells in vitro and in vivo as well as the prevention and treatment of experimental HCC by miR-370. We will further identify the role of LIN28A in the anti-tumore effect of miR-370 and explore the underlying molecular mechanism of miR-370-LIN28A pathway in the onset and development of HCC. In additon, we will clarify the mechanism of the down-regulation of miR-370 in HCC and the potential feedback regulatory signal pahtway. Finally, we will illuminate the impact of miR-370-LIN28A pathway on the clinical malignant phenotypes and prognosis of HCC in patients. This study will shed new light on the molecular mechanism of hepatocarcinogenesis and provide novel targets for the diagnosis and treatment of HCC.

miR-370位于DLK1-DIO3印记基因区，在多种肿瘤中表达发生改变，但其在肝癌中的作用尚不明确。我们前期研究发现肝细胞核因子4α可上调miR-370表达，miR-370在肝癌组织中表达明显下降，过表达miR-370抑制肝癌细胞增殖、迁移和侵袭，并首次确定分化相关基因LIN28A为miR-370下游靶基因。本研究将在此基础上通过体内外实验观察调控miR-370表达对永生化肝细胞和肝癌细胞的作用以及对实验性肝癌的预防和治疗效果；明确LIN28A在miR-370抑制肝癌中的作用；深入研究miR-370-LIN28A通路影响肝癌发生发展的分子机制；并进一步探讨肝癌细胞中miR-370表达下降的机制及潜在的信号反馈调节环路；明确miR-370-LIN28A通路对肝癌患者临床恶性表型和预后的影响。研究结果将有望进一步阐明肝癌发生发展的分子机制，并为肝癌的诊断和治疗提供新靶点。

miR-370位于DLK1-DIO3印记基因区，在多种肿瘤中表达发生改变。但其在肝癌中的作用有待明确。本课题研究发现miR-370在肝癌组织中表达明显下降，过表达miR-370可抑制肝癌细胞增殖、克隆形成、迁移和侵袭的能力，而抑制miR-370可促进肝癌细胞的增殖和转移的能力，并对小鼠肝癌种植瘤具有明显的治疗作用。机制研究发现分化相关基因LIN28A为miR-370下游靶基因；反之，LIN28A可调控miR-370前体成熟。进一步研究发现miR-370可通过降低LIN28A表达抑制NF-κB信号通路的重要信号分子p65的翻译，进而 降低p65表达和NF-κB信号通路的活化；而NF-κB信号通路下游细胞因子IL-6可抑制miR-370表达并间接促进了LIN28A的表达；对肝癌临床样本的分析发现miR-370与LIN28A和IL-6的表达负相关，而LIN28A和IL-6的表达正相关，同时在肝癌标本中miR-370表达下降与肝癌的恶性表型相关，miR-370表达下调的肝癌病人预后不良。我们的研究阐明了肝癌发生过程中存在miR-370/LIN28A/NF-кB/IL-6反馈环路,为肝癌的诊治提供了新靶点。