Participation of miR-200a in TGF-β1-mediated hepatic stellate cell activation

Hepatic stellate cell (HSC) activation is a pivotal event in the initiation and progression of hepatic fibrosis since it mediates transforming growth factor beta 1 (TGF-beta 1)-driven extracellular matrix (ECM) deposition. MicroRNAs (miRNAs), small non-coding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key factors to regulate cell proliferation, differentiation, and apoptosis. Although the function of miR-200a has been discussed in many cancers and fibrotic diseases, its role in hepatic fibrosis is still poorly understood. The aim of this study is to investigate whether miR-200a could attenuate hepatic fibrosis partly through Wnt/beta-catenin and TGF-beta-dependant mechanisms. Our study found that the expression of endogenous miR-200a was decreased in vitro in TGF-beta 1-induced HSC activation as well as in vivo in CCl4-induced rat liver fibrosis. Overexpression of miR-200a significantly inhibited alpha-SMA activity and further affected the proliferation of TGF-beta 1-dependent activation of HSC. In addition, we identified beta-catenin and TGF-beta 2 as two functional downstream targets for miR-200a. Interestingly, miR-200a specifically suppressed beta-catenin in the protein level, whereas miR-200a-mediated suppression of TGF-beta 2 was shown on both mRNA and protein levels. Our results revealed the critical regulatory role of miR-200a in HSC activation and implied miR-200a as a potential candidate for therapy by deregulation of Wnt/beta-catenin and TGF beta signaling pathways, at least in part, via decreasing the expression of beta-catenin and TGF-beta 2.