Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2019; 25(31): 4468-4480
Published online Aug 21, 2019. doi: 10.3748/wjg.v25.i31.4468
MicroRNA-194 inactivates hepatic stellate cells and alleviates liver fibrosis by inhibiting AKT2
Jun-Cheng Wu, Rong Chen, Xin Luo, Zheng-Hong Li, Sheng-Zheng Luo, Ming-Yi Xu
Jun-Cheng Wu, Rong Chen, Xin Luo, Zheng-Hong Li, Sheng-Zheng Luo, Ming-Yi Xu, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Jun-Cheng Wu, Xin Luo, Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Author contributions: Xu MY designed the research; Wu JC and Chen R performed the research; Wu JC analyzed the data; Xu MY wrote the paper; Liu T and Luo X developed software necessary for performing the study.
Supported by the National Natural Science Foundation of China, No. 81600480, No. 81570547, and No. 81770597; and the Development Program of China during the 13th Five-year Plan Period, No. 2017ZX10203202003005.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Shanghai General Hospital (No. 2016KY025).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest in this study.
ARRIVE guidelines statement: The manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ming-Yi Xu, MD, PhD, Professor of Medicine, Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100, Haining Road, Shanghai 200080, China. xumingyi2014@163.com
Telephone: +86-21-63240090 Fax: +86-21-66283869
Received: March 29, 2019
Peer-review started: March 29, 2019
First decision: June 10, 2019
Revised: June 25, 2019
Accepted: July 19, 2019
Article in press: July 19, 2019
Published online: August 21, 2019
Processing time: 145 Days and 17.4 Hours
Abstract
BACKGROUND

Activation of hepatic stellate cells (HSCs) is a pivotal event in the onset and progression of liver fibrosis. Loss of microRNA-194 (miR-194) has been reported in activated HSCs, but the actual role of miR-194 in liver fibrosis remains uncertain.

AIM

To explore the role and potential mechanism of miR-194-mediated regulation of liver fibrosis in vitro and in vivo.

METHODS

The expression of miR-194 was examined in human fibrotic liver tissues, activated HSCs, and a carbon tetrachloride (CCl4) mouse model by qPCR. The effects of AKT2 regulation by miR-194 on the activation and proliferation of HSCs were assessed in vitro. For in vivo experiments, we reintroduced miR-194 in mice using a miR-194 agomir to investigate the functions of miR-194 in liver fibrosis.

RESULTS

MiR-194 expression was notably lacking in activated HSCs from both humans and mice. Overexpression of miR-194 (OV-miR-194) inhibited α-smooth muscle actin (α-SMA) and type I collagen (Col I) expression and suppressed cell proliferation in HSCs by causing cell cycle arrest in G0/G1 phase. AKT2 was predicted to be a target of miR-194. Notably, the effects of miR-194 knockdown in HSCs were almost blocked by AKT2 deletion, indicating that miR-194 plays a role in HSCs via regulation of AKT2. Finally, miR-194 agomir treatment dramatically ameliorated liver fibrosis in CCl4-treated mice.

CONCLUSION

We revealed that miR-194 plays a protective role by inhibiting the activation and proliferation of HSCs via AKT2 suppression. Our results further propose miR-194 as a potential therapeutic target for liver fibrosis.

Keywords: Hepatic stellate cells; Liver fibrosis; MicroRNA-194; AKT2

Core tip: The expression of miR-194 was significantly downregulated in activated primary hepatic stellate cells (HSCs) from CCl4-treated mice, TGF-β1-treated LX2 cells, and the liver of advanced fibrosis patients. MiR-194 significantly inhibited the expression of α-SMA, Col I, and cyclin D1 and suppressed the activation and proliferation of HSCs in vitro by repressing AKT2 signaling. MiR-194 could attenuate liver fibrosis progression to some extent in a mouse model. Reintroduction of miR-194 offered a possible therapeutic approach for ameliorating liver fibrosis.