Epithelial-mesenchymal transition (EMT) has emerged as a vital process in embryogenesis, carcinogenesis, and tissue fibrosis. Transforming growth factor-beta 1 (TGF-beta 1)-mediated signaling pathways play important roles in the EMT process. MicroRNA-146a (miR-146a) has been suggested as a significant regulatory molecule in fibrogenesis. Therefore, the present study aimed to evaluate the effect of miR-146a on the EMT of hepatocytes and to investigate the role of overexpressing miR-146a on rat hepatic fibrosis. The results showed that the miR-146a level decreased during the EMT process of L02 hepatocytes induced by TGF-beta 1 in vitro. Moreover, miR-146a overexpression led to significant reduction of EMT-related markers expression in hepatocytes. Subsequent experiments revealed that miR-146a attenuated the EMT process in hepatocytes by targeting small mothers against decapentaplegic (SMAD) 4. Meanwhile, restoration of SMAD4 expression rescued the inhibitory effect of miRNA146a on EMT. Further in vivo studies revealed that intravenous injection of miR-146a-expressing adenovirus (AdmiR-146a) successfully restored the miR-146a levels and mitigated fibrogenesis in the livers of CCl4-treated rats. More importantly, after Ad-miR-146a treatment, inhibition of both EMT traits and SMAD4 expression was observed. The results of the present study showed that miR-146a/SMAD4 is a key signaling cascade that inhibits hepatocyte EMT, and the introduction of miR-146a might present a promising therapeutic option for liver fibrosis.
[1]Fudan Univ, Zhongshan Hosp, Dept Gastroenterol & Hepatol, 180 Fenglin Rd, Shanghai, Peoples R China;
[2]Shanghai Inst Liver Dis, Shanghai, Peoples R China;
[3]Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Shanghai, Peoples R China
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