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EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes
Author(s) -
Barreiros Ana Paula,
Sprinzl Martin,
Rosset Sylvia,
Höhler Thomas,
Otto Gerd,
Theobald Matthias,
Galle Peter R.,
Strand Dennis,
Strand Susanne
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23921
Subject(s) - hepatocyte growth factor , epidermal growth factor , biology , cancer research , apoptosis , extracellular matrix , immunology , hepatitis b virus , anoikis , protein kinase b , signal transduction , microbiology and biotechnology , programmed cell death , virus , cell culture , receptor , biochemistry , genetics
The hepatitis B virus (HBV) is a major causative agent of chronic liver disease and subsequent liver cirrhosis worldwide. The reduced sensitivity of virus‐infected liver cells to apoptosis may play a role in the failure to remove virus‐infected cells and eventually promote viral chronicity. The purpose of our study was to investigate whether survival factors induced during compensatory liver regeneration may protect hepatocytes against apoptosis. We evaluated the serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in HBV‐infected patients and found significant increases in HGF and EGF in patients with active virus infection. In primary human hepatocytes we show that HGF and EGF have a protective effect against CD95‐mediated apoptosis and cytotoxic T‐cell killing. Simultaneous treatment with both regeneration factors enhanced the cytoprotective effect. The PI 3‐K/Akt kinase inhibitor, wortmannin, and the STAT3 pathway inhibitor, Tyrphostin AG490, both effectively attenuated the cytoprotective effect of HGF and EGF. Furthermore, we show an EGF/HGF‐dependent upregulation of β 1 ‐integrin chains, increased adhesion to extracellular matrix and an increase in focal adhesions, suggesting outside‐in signaling from the extracellular matrix as an additional cytoprotective mechanism. Our study demonstrates that HGF and EGF can interfere with CD95‐mediated apoptosis and the action of cytotoxic T‐cells through multiple mechanisms in human hepatocytes. Together our results argue that a survival mileau generated by activation of liver regeneration factors may be a risk factor for establishing viral persistence. © 2008 Wiley‐Liss, Inc.