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Open AccessArticle

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

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Molecular Virology Laboratory, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
2
Cell Migration and Invasion Laboratory, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
3
Drug Discovery Laboratory, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
#
Current address: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, NY 10461, USA.
Cells 2019, 8(11), 1395; https://doi.org/10.3390/cells8111395
Received: 1 September 2019 / Revised: 30 October 2019 / Accepted: 1 November 2019 / Published: 5 November 2019
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.
Keywords: hepatitis C virus; hepatocellular carcinoma (HCC); invasion; metastasis hepatitis C virus; hepatocellular carcinoma (HCC); invasion; metastasis
MDPI and ACS Style

Ninio, L.; Nissani, A.; Meirson, T.; Domovitz, T.; Genna, A.; Twafra, S.; Srikanth, K.D.; Dabour, R.; Avraham, E.; Davidovich, A.; Gil-Henn, H.; Gal-Tanamy, M. Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation. Cells 2019, 8, 1395.

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