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

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 facto...

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Autores principales: Ninio, Liat, Nissani, Abraham, Meirson, Tomer, Domovitz, Tom, Genna, Alessandro, Twafra, Shams, Srikanth, Kolluru D., Dabour, Roba, Avraham, Erez, Davidovich, Ateret, Gil-Henn, Hava, Gal-Tanamy, Meital
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912298/
https://www.ncbi.nlm.nih.gov/pubmed/31694343
http://dx.doi.org/10.3390/cells8111395
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author Ninio, Liat
Nissani, Abraham
Meirson, Tomer
Domovitz, Tom
Genna, Alessandro
Twafra, Shams
Srikanth, Kolluru D.
Dabour, Roba
Avraham, Erez
Davidovich, Ateret
Gil-Henn, Hava
Gal-Tanamy, Meital
author_facet Ninio, Liat
Nissani, Abraham
Meirson, Tomer
Domovitz, Tom
Genna, Alessandro
Twafra, Shams
Srikanth, Kolluru D.
Dabour, Roba
Avraham, Erez
Davidovich, Ateret
Gil-Henn, Hava
Gal-Tanamy, Meital
author_sort Ninio, Liat
collection PubMed
description 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.
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spelling pubmed-69122982020-01-02 Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation Ninio, Liat Nissani, Abraham Meirson, Tomer Domovitz, Tom Genna, Alessandro Twafra, Shams Srikanth, Kolluru D. Dabour, Roba Avraham, Erez Davidovich, Ateret Gil-Henn, Hava Gal-Tanamy, Meital Cells Article 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. MDPI 2019-11-05 /pmc/articles/PMC6912298/ /pubmed/31694343 http://dx.doi.org/10.3390/cells8111395 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ninio, Liat
Nissani, Abraham
Meirson, Tomer
Domovitz, Tom
Genna, Alessandro
Twafra, Shams
Srikanth, Kolluru D.
Dabour, Roba
Avraham, Erez
Davidovich, Ateret
Gil-Henn, Hava
Gal-Tanamy, Meital
Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation
title Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation
title_full Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation
title_fullStr Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation
title_full_unstemmed Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation
title_short Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation
title_sort hepatitis c virus enhances the invasiveness of hepatocellular carcinoma via egfr-mediated invadopodia formation and activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912298/
https://www.ncbi.nlm.nih.gov/pubmed/31694343
http://dx.doi.org/10.3390/cells8111395
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