Hepatitis C virus core protein-induced miR-93-5p up-regulation inhibits interferon signaling pathway by targeting IFNAR1

• Published in: World journal of gastroenterology : WJG Vol. 24; no. 2; pp. 226 - 236
• Main Authors: He, Chang-Long, Liu, Ming, Tan, Zhao-Xia, Hu, Ya-Jun, Zhang, Qiao-Yue, Kuang, Xue-Mei, Kong, Wei-Long, Mao, Qing
• Format: Journal Article
• Language: English
• Published: United States Baishideng Publishing Group Inc 14.01.2018
• Subjects: Adult; Antiviral Agents - therapeutic use; Basic Study; Cell Line, Tumor; Drug Resistance, Viral; Female; HEK293 Cells; Hepacivirus - drug effects; Hepacivirus - metabolism; Hepacivirus - pathogenicity; Hepatitis C - blood; Hepatitis C - drug therapy; Hepatitis C - metabolism; Hepatitis C - virology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - virology; Host-Pathogen Interactions; Humans; Interferon-alpha - therapeutic use; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Phosphorylation; Receptor, Interferon alpha-beta - drug effects; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; Signal Transduction - drug effects; STAT1 Transcription Factor - metabolism; Up-Regulation; Viral Core Proteins - genetics; Viral Core Proteins - metabolism; Hepatitis C virus; IFN signaling pathway; miR-93-5p; Interferon receptor 1
• ISSN: 1007-9327; 2219-2840; 2219-2840
• DOI: 10.3748/wjg.v24.i2.226

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