Hepatitis C virus NS5A drives a PTEN‐PI3K/Akt feedback loop to support cell survival. (4th December 2014)

• Record Type: Journal Article
• Authors: Cheng, Du; Zhang, Leiliang; Yang, Guangbo; Zhao, Lei; Peng, Feng; Tian, Yi; Xiao, Xinqiang; Chung, Raymond T.; Gong, Guozhong
• Is Part Of: Liver international. Volume 35:Number 6(2015:Jun.)
• Page Start: 1682
• Page End: 1691
• Publication Date: 2014-12-04
• Subjects: Liver -- Periodicals; Liver -- Diseases -- Periodicals; 616.362
• DOI: 10.1111/liv.12733
• Languages: English
• ISSNs: 1478-3223

Abstract

<abstract abstract-type="main" id="liv12733-abs-0001"> <title>Abstract</title> <sec id="liv12733-sec-0001" sec-type="section"> <title>Background & Aims</title> <p>Decreased levels of phosphatase and tensin homologue (PTEN) are associated with hepatocellular carcinoma (HCC) pathogenesis and poor prognosis in hepatitis C virus (HCV)‐infected HCC patients. The molecular processes governing the reduction in PTEN and outcome of PTEN dysfunction in hepatocytes are poorly understood.</p> </sec> <sec id="liv12733-sec-0002" sec-type="section"> <title>Methods</title> <p>The levels of proteins and mRNA were assessed by real time PCR and immunoblot. PTEN promoter activity was measured by reporter assay. Signalling pathways were perturbed using siRNAs or pharmacological inhibitors.</p> </sec> <sec id="liv12733-sec-0003" sec-type="section"> <title>Results</title> <p>Here, we report that HCV down‐regulates PTEN expression at the transcriptional level by decreasing its promoter activity, mRNA transcription, and protein levels. We further identify NS5A protein as a key determinant of PTEN reduction among HCV proteins. NS5A‐mediated down‐regulation of PTEN occurs through a cooperation of reactive oxygen species (ROS)‐dependent Nuclear Factor‐ kappa B (NF‐κB) and ROS‐independent phosphoinositol‐3‐kinase (PI3K) pathways. Moreover, NS5A protects cells against apoptosis. In addition, we found that down‐regulation of PTEN relieves its inhibitory effect on PI3K‐Akt pathway and triggers cumulative activation of Akt. This PTEN‐PI3K/Akt feedback network mediates the suppression of cell apoptosis caused by NS5A.</p> </sec> <sec id="liv12733-sec-0004" sec-type="section"> <title>Conclusions</title> <p>These data demonstrate that HCV NS5A down‐regulates PTEN expression through a cooperation of ROS‐dependent and ‐independent pathways that subsequently drives a PTEN‐PI3K/Akt feedback loop to support cell survival. Our findings provide new insights suggesting that NS5A contributes to HCV‐related hepatocarcinogenesis.</p> </sec> </abstract>