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; Youngmi Jung

doi:10.1038/ncomms10993

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

Nat Commun. 2016 Mar 22:7:10993. doi: 10.1038/ncomms10993.

Authors

Jeongeun Hyun¹, Sihyung Wang¹, Jieun Kim¹, Kummara Madhusudana Rao², Soo Yong Park², Ildoo Chung², Chang-Sik Ha², Sang-Woo Kim^{1

3}, Yang H Yun⁴, Youngmi Jung^{1

3}

Affiliations

¹ Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea.
² Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea.
³ Department of Biological Sciences, College of Natural Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 46241, Korea.
⁴ Department of Biomedical Engineering, College of Engineering, The University of Akron, Akron, Ohio 44685-0302, USA.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Base Sequence
Carbon Tetrachloride
Carcinoma, Hepatocellular / genetics
Choline
Chronic Disease
Down-Regulation
Ethionine
Gene Expression Regulation
Hepatic Stellate Cells / metabolism*
Humans
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Liver Cirrhosis / genetics*
Liver Cirrhosis / pathology
Male
Methionine
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism*
Molecular Sequence Data
Nanoparticles / chemistry
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Protein Binding / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, G-Protein-Coupled / metabolism
Smoothened Receptor
Transcription Factor RelA / metabolism
Zinc Finger Protein Gli2
Zinc Finger Protein Gli3

Substances

Gli2 protein, mouse
Gli3 protein, mouse
Kruppel-Like Transcription Factors
MIRN378 microRNA, human
MIRN378 microRNA, mouse
MicroRNAs
Nerve Tissue Proteins
RNA, Messenger
Receptors, G-Protein-Coupled
Smo protein, mouse
Smoothened Receptor
Transcription Factor RelA
Zinc Finger Protein Gli2
Zinc Finger Protein Gli3
Methionine
Carbon Tetrachloride
Choline
Ethionine