Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
J Cell Physiol. 2019 Jun;234(6):9698-9710. doi: 10.1002/jcp.27656. Epub 2018 Oct 26.
Liver fibrosis is a wound-healing response represented by excessive extracellular matrix deposition. Activation of hepatic stellate cell (HSC) is the critical cellular basis for hepatic fibrogenesis, whereas hepatocyte undergoes epithelial-mesenchymal transition (EMT) which is also involved in chronic liver injury. Long noncoding RNA H19 has been found to be associated with cholestatic liver fibrosis lately. However, the role of H19 in liver fibrosis remains largely to be elucidated. In this study, we found that the expression of H19 was significantly upregulated in the liver tissue of CCl -induced mice, a toxicant-induced liver fibrogenesis model. Overexpression of H19 significantly aggravated activation of HSC and EMT of hepatocyte both by stimulating transforming growth factor-β (TGF-β) pathway. In terms of mechanism, H19 functioned as a competing endogenous RNA to sponge miR-148a and subsequently sustained the level of ubiquitin-specific protease 4 (USP4), which was an identified target of miR-148a and was able to stabilize TGF-β receptor I. In conclusion, our findings revealed a novel H19/miR-148a/USP4 axis which promoted liver fibrosis via TGF-β pathway in both HSC and hepatocyte, indicating that H19 could become a promising target for the treatment of liver fibrosis.
肝纤维化是一种以细胞外基质过度沉积为特征的创伤愈合反应。肝星状细胞（HSC）的激活是肝纤维化发生的关键细胞基础，而肝细胞则经历上皮-间充质转化（EMT），这也与慢性肝损伤有关。最近发现长链非编码 RNA H19 与胆汁淤积性肝纤维化有关。然而，H19 在肝纤维化中的作用仍有待阐明。在这项研究中，我们发现 CCl4 诱导的肝纤维化模型中，H19 在肝组织中的表达明显上调。H19 的过表达通过刺激转化生长因子-β（TGF-β）途径，显著加重了 HSC 的激活和肝细胞的 EMT。就机制而言，H19 作为竞争性内源性 RNA，可与 miR-148a 结合，从而维持泛素特异性蛋白酶 4（USP4）的水平，后者是 miR-148a 的一个确定靶标，能够稳定 TGF-β受体 I。总之，我们的研究结果揭示了一个新的 H19/miR-148a/USP4 轴，通过 TGF-β途径在 HSC 和肝细胞中促进肝纤维化，表明 H19 可能成为治疗肝纤维化的一个有前途的靶点。
