Hepatitis C virus-mediated angiogenesis: Molecular mechanisms and therapeutic strategies

Abstract

Angiogenesis is an essential process for organ growth and repair. Thus, an imbalance in this process can lead to several diseases including malignancy. Angiogenesis is a critical step in vascular remodeling, tissue damage and wound healing besides being required for invasive tumor growth and metastasis. Because angiogenesis sets an important point in the control of tumor progression, its inhibition is considered a valuable therapeutic approach for tumor treatment. Chronic liver disease including hepatitis C virus (HCV) infection is one of the main cause for the development of hepatic angiogenesis and thereby plays a critical role in the modulation of hepatic angiogenesis that finally leads to hepatocellular carcinoma progression and invasion. Thus, understanding of the molecular mechanisms of HCV-mediated hepatic angiogenesis will help design a therapeutic protocol for the intervention of HCV-mediated angiogenesis and subsequently its outcome. In this review, we will focus on the molecular mechanisms of HCV-mediated hepatic angiogenesis and the related signaling pathways that can be target for current and under development therapeutic approaches.

Intrahepatic angiopoietin‐2 correlates with chronic hepatitis C progression and is induced in hepatitis C virus replicon systems

“…These findings suggest that both structural and non‐structural regions of HCV genome may trigger angiogenesis by the stimulation of Ang2 synthesis. These data are consistent with earlier studies that reported the important role of Core and NS5A in stimulating the production of several key factors involved in fibrosis (TGF‐β) and angiogenesis (VEGF) through multiple signalling pathways, including PI3K, JNK/p38 and ERK . Also, other studies have described that the structural proteins E1 and E2 may be implicated in pathological regenerative angiogenesis …”

“…These pathways contribute to the stabilization and activation of HIF-1α, promoting the expression of many angiogenic factors. 38 In conclusion, this study shows a reasonable relationship between the intrahepatic levels of Ang2 and the progression of…”

“…Precisely, Core induces a notable increase in ROS (Figure ) whose main effect is the activation of important signal transduction pathways, such as STAT3 and NF‐kβ. These pathways contribute to the stabilization and activation of HIF‐1α, promoting the expression of many angiogenic factors …”

“…Signalling pathways involved in HCV ‐driven angiogenesis. Viral proteins of HCV may affect distinct signalling routes such as phosphatidylinositol 3 kinase ( PI 3K), mitogen‐activated protein ( MAP ) kinase Erk and redox balance altering multiple cellular processes such as proliferation, adhesion, and survival. As shown, the blockade of MAP kinase‐ ERK kinase signalling ( PD 98059) promoted opposite effects on angiopoietin‐2 (Ang2) synthesis with regard to the genome region of HCV .…”

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

“…167,168 HCV infection can trigger hepatic angiogenesis and HCC growth through HIF-1α and VEGF regulation. 169,170 The VEGF activation can occur through several other cell survival pathways, including PI3K/Akt, ERK1/2, NF-κB, and STAT3, which stabilize HIF-1α. It has been demonstrated that the core protein of HCV can trigger angiogenesis through a mechanism that involves cross-talk between TGF-β2, VEGF, and CD34 expression.…”