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

Autor: Brockhausen, Jennifer, Tay, Szun S., Grzelak, Candice A., Bertolino, Patrick, Bowen, David G., d'Avigdor, William M., Teoh, Narcy, Pok, Sharon, Shackel, Nick, Gamble, Jennifer R., Vadas, Mathew, McCaughan, Geoff W.
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Zdroj: Liver International; Jan2015, Vol. 35 Issue 1, p240-253, 14p, 4 Charts, 6 Graphs
Abstrakt: Background & Aims Epithelial-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 micro RNA (miR) expression in TGF-β-induced hepatocyte EMT. Methods We 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. Results We 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. Conclusions MiR-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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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