miR‐181a mediates TGF‐β‐induced hepatocyte EMT and is dysregulated in cirrhosis and hepatocellular cancer

• DOI: 10.1111/liv.12517
• Publication Date: 2014-02-28T07:04:30Z
• Authors: Jennifer Brockhausen; Szun S. Tay; Candice A. Grzelak; Patrick Bertolino; David G. Bowen; William M. d'Avigdor; Narcy Teoh; Sharon Pok; Nick Shackel; Jennifer R. Gamble; Mathew Vadas; Geoff W. McCaughan
• Keywords: Liver Cirrhosis; 0301 basic medicine; Carcinoma, Hepatocellular; Epithelial-Mesenchymal Transition; Liver Neoplasms; In Vitro Techniques; Cell Line; 3. Good health; Mice; MicroRNAs; 03 medical and health sciences; Gene Expression Regulation; Transforming Growth Factor beta; Hepatocytes; Animals; Humans

AbstractBackground & AimsEpithelial–mesenchymal transition (EMT) has been implicated in the processes of embryogenesis, tissue fibrosis and carcinogenesis. Transforming growth factor‐β (TGF‐β) has been identified as a key driver of EMT and plays a key role in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC). The aim was to identify microRNA (miR) expression in TGF‐β‐induced hepatocyte EMT.MethodsWe treated a human hepatocyte cell line PH5CH8 with TGF‐β to induce an EMT‐like change in phenotype and then identified dysregulated miRs using TaqMan Low Density Arrays. MiR expression was altered using miR‐181a mimic and inhibitor in the same system and gene changes were identified using TaqMan gene arrays. MiR‐181a gene expression was measured in human and mouse cirrhotic or HCC liver tissue samples. Gene changes were identified in rAAV‐miR‐181a‐expressing mouse livers using TaqMan gene arrays.ResultsWe identified miR‐181a as a miR that was significantly up‐regulated in response to TGF‐β treatment. Over‐expression of a miR‐181a mimic induced an in vitro EMT‐like change with a phenotype similar to that seen with TGF‐β treatment alone and was reversed using a miR‐181a inhibitor. MiR‐181a was shown to be up‐regulated in experimental and human cirrhotic and HCC tissue. Mouse livers expressing rAAV‐miR‐181a showed genetic changes associated with TGF‐β signalling and EMT.ConclusionsMiR‐181a had a direct effect in inducing hepatocyte EMT and was able to replace TGF‐β‐induced effects in vitro. MiR‐181a was over‐expressed in cirrhosis and HCC and is likely to play a role in disease pathogenesis.