Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways #

Abstract

Chronic hepatitis C virus (HCV) infection is associated with the production of serum cytokines, including transforming growth factor (TGF)-␤2. Despite the occurrence of hepatic angiogenesis in liver conditions, the role of HCV proteins in this context is currently unknown. We demonstrated that the development of hepatic neoangiogenesis in patients infected with HCV is associated with the expression of TGF-␤2 and vascular endothelial growth factor (VEGF) and with activation of endothelial cells, as evidenced by CD34 expression. The analysis of liver biopsies of HCV-positive and HCV-negative patients using immunostaining showed significant elevation of TGF-␤2, VEGF, and CD34 expression in patients who were HCV-positive. Using an HCV established culture system, we confirmed further the production of both TGF-␤2 and VEGF proteins, in the hepatoma cell lines HepG2 and Huh7 by transfection with full-length HCV RNA (JFH1) or by the regulated expression of core. In addition, regulated expression of core protein in HepG2 or Huh7 cells was found to induce expression and activation of the transcription factor E2F1 and apoptosis signal-regulating kinase 1 (ASK1), activation of c-jun-N-terminal kinase (JNK) and p38, and extracellular-regulated kinase (ERK), and transcription factors activator protein 1 (AP-1), activating transcription factor 2 (ATF-2), cyclic adenosine monophosphate response element binding (CREB), E2F1, hypoxia inducing factor 1 alpha (HIF-1␣), and specificity protein 1. Furthermore, data obtained from inhibitor experiments revealed the importance of E2F1 and ASK1 in the modulation of core-induced activation of JNK and p38 pathways and suggested an essential role for JNK, p38, and ERK pathways in the regulation of core-induced production of TGF-␤2 and VEGF proteins. Thus, our data provide insight into the molecular mechanisms whereby core protein mediates the development of hepatic angiogenesis in patients with chronic HCV infection.

Hepatitis C Virus (HCV) Proteins Induce NADPH Oxidase 4 Expression in a Transforming Growth Factor β-Dependent Manner: a New Contributor to HCV-Induced Oxidative Stress

“…Although the core protein does not bind directly to DNA, previous reports indicate that core-induced changes in gene expression include diverse signaling pathways and downstream transcription factors (1,26). The profibrotic cytokine TGF-␤1 is a plasma serum marker in patients with chronic HCV infection (40,61) HCV INDUCES Nox4-DEPENDENT OXIDATIVE STRESStranscription (64).…”

The Involvement of the ERK-Hypoxia-Angiogenesis Signaling Axis and HIF-1 in Hepatocellular Carcinoma

“…The genetic instability observed during the premalignant state of HCC can be caused by viral infection. HCV core protein induces HIF-1 and HIF-dependent transcriptional activation of the VEGF gene in HCC-derived cells (Hassan et al, 2009). Liver angiogenesis has been indeed observed in biopsy samples of HCV patients and is possibly an essential step for HCVrelated oncogenesis.…”

“…The most prominent pro-angiogenic signal, as revealed in a number of studies, is vascular endothelial growth factor (VEGF) (Fernandez et al, 2009;Rosmorduc & Housset, 2010). Its expression can be induced as a result of hypoxia, oncogenic signaling and viral infection, involving MAPK pathway activation and transcriptional regulation by AP1 and HIF-1 (Hassan et al, 2009). Its significant role in HCC is shown by the fact that cells isolated from human tumors are able to produce VEGF by themselves.…”

A circuit of paracrine signals between liver sinusoid endothelial cells and hepatocytes regulates hepatitis C virus replication

“…[6][7][8] However, these data were obtained with hepatocyte monocultures, and therefore a possible influence of BMP4 regulation by VEGF-A did not factor into these observations. Although both BMP4 and VEGF-A are proviral, as reported previously 6 (and by Rowe et al in this issue of HEPATOLOGY), and act on different steps of the HCV replication cycle (i.e., RNA replication and cell entry, respectively), the negative regulation of BMP4 expression by VEGF-A could profoundly influence the net outcome on HCV replication.…”

“…HCV infection induces elevated levels of VEGF-A, which facilitates HCV cell entry. [6][7][8] At the same time, VEGF-A binds VEGFR-2, triggers its phosphorylation, and activates p38 MAPK, which silences transcription of BMP4. BMP4 itself is proviral by facilitating HCV RNA replication through an unknown mechanism.…”