Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation

Abstract

Hepatocellular carcinoma (HCC) represents the fifth most common cancer worldwide and the third cause of cancer-related mortality. Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver fibrosis, cirrhosis, and eventually HCC. HCV is the most common risk factor for HCC in western countries and leads to a more aggressive and invasive disease with poorer patient survival rates. However, the mechanism by which the virus induces the metastatic spread of HCC tumor cells through the regulation of invadopodia, the key features of invasive cancer, is still unknown. Here, the integration of transcriptome with functional kinome screen revealed that HCV infection induced invasion and invadopodia-related gene expression combined with activation of host cell tyrosine kinases, leading to invadopodia formation and maturation and consequent cell invasiveness in vitro and in vivo. The promotion of invadopodia following HCV infection was mediated by the sustained stimulation of epidermal growth factor receptor (EGFR) via the viral NS3/4A protease that inactivates the T-cell protein tyrosine phosphatase (TC-PTP), which inhibits EGFR signaling. Characterization of an invadopodia-associated gene signature in HCV-mediated HCC tumors correlated with the invasiveness of HCC and poor patient prognosis. These findings might lead to new prognostic and therapeutic strategies for virus-mediated invasive cancer.

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

“…EGF expression is a main driver of liver fibrosis and HCC [61] and is part of a prognostic transcriptional signature associating with HCC development and patient survival [62][63][64]. Moreover, a recent study has shown that HCV infection induces the EGFR-dependent expression of invadopodia-related genes, therefore enhancing intra-and extrahepatic HCC dissemination in vivo [65].…”

Tracking Down the Epigenetic Footprint of HCV-Induced Hepatocarcinogenesis

“…First, previous reports demonstrated the activation of EGFR by HCV proteins [ 70 , 71 , 72 , 73 , 74 , 75 ]. We have recently demonstrated that HCV infection constitutively activates EGFR thus inducing invasion of HCV-infected cells [ 76 ]. Moreover, among the pathways that we have identified to be epigenetically altered, the top pathway was cytoskeleton remodeling, which is known to be induced by EGFR signaling [ 7 ].…”

The Beginning of Ending Hepatitis C Virus: A Summary of the 26th International Symposium on Hepatitis C Virus and Related Viruses

“…The majority of differentially expressed genes, as assessed by transcriptomic analysis, were not altered after eradication of the virus, suggesting a potential link between HCV-imprinted gene expression and epigenetic changes underlying HCV-related hepatocarcinogenesis. Gal-Tanamy et al performed integrated transcriptome, epigenome, and kinome screens and determined that activation of epidermal growth factor receptor (EGFR) following HCV infection upregulates the expression of invasion-related genes [3]. Regarding their results, HCV NS3 protease cleaves and inactivates T-cell protein tyrosine phosphatase (TCPTP), a phosphatase that inhibits EGFR signaling, contributing to HCV-induced invasion phenotypes.…”