Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2018; 24(2): 226-236
Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.226
Hepatitis C virus core protein-induced miR-93-5p up-regulation inhibits interferon signaling pathway by targeting IFNAR1
Chang-Long He, Ming Liu, Zhao-Xia Tan, Ya-Jun Hu, Qiao-Yue Zhang, Xue-Mei Kuang, Wei-Long Kong, Qing Mao
Chang-Long He, Ming Liu, Zhao-Xia Tan, Ya-Jun Hu, Qiao-Yue Zhang, Xue-Mei Kuang, Wei-Long Kong, Qing Mao, Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
Chang-Long He, Ming Liu, Zhao-Xia Tan, Ya-Jun Hu, Qiao-Yue Zhang, Xue-Mei Kuang, Wei-Long Kong, Qing Mao, Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing 400037, China
Author contributions: All authors contributed to the manuscript.
Supported by National Natural Science Foundation of China, No. 81371849; and the TMMU Key Project for Clinical Research, No. 2012XLC05.
Institutional review board statement: This study was approved by the Ethics Committee of the First Affiliated Hospital of Third Military Medical University.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article are reported.
Data sharing statement: No additional data are available.
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/
Correspondence to: Qing Mao, MD, PhD, Doctor, Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), No. 30, Gaotanyan Street, Chongqing 400037, China. qingmao@tmmu.edu.cn
Telephone: +86-23-68754858 Fax: +86-23-68754858
Received: October 26, 2017
Peer-review started: October 27, 2017
First decision: November 21, 2017
Revised: December 5, 2017
Accepted: December 13, 2017
Article in press: December 13, 2017
Published online: January 14, 2018
Processing time: 80 Days and 2 Hours
Abstract
AIM

To investigate the mechanism by which hepatitis C virus (HCV) core protein-induced miR-93-5p up-regulation regulates the interferon (IFN) signaling pathway.

METHODS

HCV-1b core protein was exogenously expressed in Huh7 cells using pcDNA3.1 (+) vector. The expression of miR-93-5p and interferon receptor 1 (IFNAR1) was measured using quantitative reverse transcription-polymerase chain reaction and Western blot. The protein expression and phosphorylation level of STAT1 were evaluated by Western blot. The overexpression and silencing of miR-93-5p and IFNAR1 were performed using miR-93-5p agomir and antagomir, and pcDNA3.1-IFNAR1 and IFNAR1 siRNA, respectively. Luciferase assay was used to identify whether IFNAR1 is a target of miR-93-5p. Cellular experiments were also conducted.

RESULTS

Serum miR-93-5p level was increased in patients with HCV-1b infection and decreased to normal level after HCV-1b clearance, but persistently increased in those with pegylated interferon-α resistance, compared with healthy subjects. Serum miR-93-5p expression had an AUC value of 0.8359 in distinguishing patients with pegylated interferon-α resistance from those with pegylated interferon-α sensitivity. HCV-1b core protein increased miR-93-5p expression and induced inactivation of the IFN signaling pathway in Huh7 cells. Furthermore, IFNAR1 was identified as a direct target of miR-93-5p, and IFNAR1 restore could rescue miR-93-5p-reduced STAT1 phosphorylation, suggesting that the miR-93-5p-IFNAR1 axis regulates the IFN signaling pathway.

CONCLUSION

HCV-1b core protein-induced miR-93-5p up-regulation inhibits the IFN signaling pathway by directly targeting IFNAR1, and the miR-93-5p-IFNAR1 axis regulates STAT1 phosphorylation. This axis may be a potential therapeutic target for HCV-1b infection.

Keywords: Hepatitis C virus; miR-93-5p; Interferon receptor 1; IFN signaling pathway

Core tip: Hepatitis C virus-1b core protein increases miR-93-5p expression and induces inactivation of the IFN signaling pathway. MiR-93-5p expression is involved in pegylated interferon-α resistance and directly targets interferon receptor 1 (IFNAR1). The miR-93-5p-IFNAR1 axis regulates STAT1 phosphorylation.