Premium
Hepatitis C virus NS 5A drives a PTEN ‐ PI 3K/Akt feedback loop to support cell survival
Author(s) -
Cheng Du,
Zhang Leiliang,
Yang Guangbo,
Zhao Lei,
Peng Feng,
Tian Yi,
Xiao Xinqiang,
Chung Raymond T.,
Gong Guozhong
Publication year - 2015
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12733
Subject(s) - pten , tensin , ns5a , pi3k/akt/mtor pathway , protein kinase b , cancer research , biology , phosphatase , hepatitis c virus , chemistry , microbiology and biotechnology , signal transduction , phosphorylation , immunology , virus , hepacivirus
Background & Aims 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. Methods 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. Results 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. Conclusions These data demonstrate that HCV NS 5A down‐regulates PTEN expression through a cooperation of ROS ‐dependent and ‐independent pathways that subsequently drives a PTEN ‐ PI 3K/Akt feedback loop to support cell survival. Our findings provide new insights suggesting that NS 5A contributes to HCV ‐related hepatocarcinogenesis.