EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Abstract

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 b 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.

Biomarker Analyses from a Placebo-Controlled Phase II Study Evaluating Erlotinib ± Onartuzumab in Advanced Non–Small Cell Lung Cancer: MET Expression Levels Are Predictive of Patient Benefit

“…It remains to be elucidated how HGF levels in circulation relate to intratumoral levels of HGF. Although elevated circulating HGF levels have been observed in subsets of patients with cancer, elevated circulating HGF levels have additionally been described in other settings, including certain viral or bacterial infections, graft versus host disease, and surgical procedures (29–31). …”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…This enables circulating HGF to be used as a pharmacodynamic marker for these agents, but perhaps not as a catch-all predictive biomarker for selecting patients for HGF/cMET therapies. Furthermore, elevated HGF levels are observed in a number of disease settings, including virus/bacterial infections, graft-versus-host disease, and following surgical procedures, making their use as a biomarker for selection of patients less favourable [89][90][91]. It is also yet to be vigorously validated how circulating HGF levels relate to HGF levels within the tumour micro-environment [92].…”

Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells

“…IGF-I has been shown to reduce the expression of proinflammatory cytokines, to defend liver cells against oxidative stress and to stimulate liver regeneration [19,20]. On the other hand EGF has been reported to protect hepatocytes against cytotoxic attack by T cells and also to act as a hepatocyte mitogen [21,22].…”