MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression

Jeongeun Hyun, Sihyung Wang, Jieun Kim, Kummara Madhusudana Rao, Soo Yong Park, Ildoo Chung, Chang-Sik Ha, Sang-Woo Kim, Yang H. Yun and Youngmi Jung ()
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Jeongeun Hyun: College of Natural Science, Pusan National University
Sihyung Wang: College of Natural Science, Pusan National University
Jieun Kim: College of Natural Science, Pusan National University
Kummara Madhusudana Rao: College of Engineering, Pusan National University
Soo Yong Park: College of Engineering, Pusan National University
Ildoo Chung: College of Engineering, Pusan National University
Chang-Sik Ha: College of Engineering, Pusan National University
Sang-Woo Kim: College of Natural Science, Pusan National University
Yang H. Yun: College of Engineering, The University of Akron
Youngmi Jung: College of Natural Science, Pusan National University

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl4)-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces gfap, the inactivation marker of HSCs, in CCl4-treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis.

Date: 2016
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DOI: 10.1038/ncomms10993

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