Mir-200在肝星形细胞促进肝硬化肝癌发生发展中的抑制作用和机制研究

肝炎-肝硬化-肝癌三步曲中肝硬化是其重要桥梁，但机制仍不清楚。肝星形细胞（HSC）在肝内由TGF-β、PDGF等激活并发生EMT，是细胞外基质（ECM）主要生产者，与肝硬化形成、肝癌进展密切相关，是肝炎-肝硬化-肝癌轴关键介导因素，已成为肝硬化、HCC防治靶点。miR-200靶向抑制ZEB1/2，有效抑制TGFβ、PDGF以及ECM的表达，抑制EMT，阻止纤维化、肿瘤侵袭转移发生。Mir-200能否抑制HSC活性，阻止肝纤维化向肝癌的发展，目前未见相关报道。我们发现人肝癌miR-200表达较正常肝脏明显下降，人HSC细胞株中存在miR-200低表达。本课题观察HSC的EMT过程中miR-200表达的变化，深入研究mir-200对HSC促进肝硬化、肝癌发展的抑制作用，创新性从mir-200、EMT和HSC角度探索肝炎-肝硬化-肝癌的机制，为寻找肝硬化、肝癌防治的有效靶点提供有益的实验依据。

A three-step process of hepatitis-liver fibrosis/ cirrhosis-HCC is believed to be involved in hepatocarcinogenesis. Among them, liver cirrhosis is the most important factor of HCC occurrence and progression. However, the mechanisms still remain undertermined. Hepatic Stellate cells (HSC) is known to be the major producer of extracellular matrix proteins (ECM) in the liver. Transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) are its activators. HSC plays a key role in hepatic fibrogenesis, even hepatocarcinogenesis and HCC progression, serves as an important mediator in the process of inflammation- fibrosis-carcinoma axis. At the same time, it becomes the effective target to prevent and treat liver cirrhosis and carcinoma. Mir-200 can inhibit epithelial-mesenchymal transition (EMT), fibrogenesis, tumor invasion and metastasis through inhibiting directly its target proteins (ZEB1/2), promoting E-cadherin expression, and inhibiting TGF-β, PDGF directly or indirectly. Currently it has not been reported whether mir-200 can prevent the development of liver fibrosis, hepatocarcinogenesis and HCC progression through inhibiting the activity of HSC. Our study found that mir-200 expression decreased significantly in HCC, compared with the normal liver. In addition, there was low level expression of mir-200 in cultivated human HSC cell line. The aim of this study is to deeply investigate the mechanisms of liver cirrhosis promoting HCC occurrence and progression, and to find an effctive target for the prevention and treatment of liver cirrhosis and HCC through innovatively probing the relation among miR-200, EMT and HSC.