title: Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus.
abstract: Hepatitis C virus (HCV) is an oncogenic virus associated with the onset of hepatocellular carcinoma (HCC). The present study investigated the possible link between HCV infection and Netrin-1, a ligand for dependence receptors that sustains tumorigenesis, in particular in inflammation-associated tumors. We show that Netrin-1 expression is significantly elevated in HCV+ liver biopsies compared to hepatitis B virus (HBV+) and uninfected samples. Furthermore, Netrin-1 was upregulated in all histological stages of HCV+ hepatic lesions, from minimal liver fibrosis to cirrhosis and HCC, compared to histologically matched HCV- tissues. Both cirrhosis and HCV contributed to the induction of Netrin-1 expression, whereas anti-HCV treatment resulted in a reduction of Netrin-1 expression. In vitro, HCV increased the level and translation of Netrin-1 in a NS5A-La-related protein 1 (LARP1)-dependent fashion. Knockdown and forced expression experiments identified the receptor uncoordinated receptor-5 (UNC5A) as an antagonist of the Netrin-1 signal, though it did not affect the death of HCV-infected cells. Netrin-1 enhanced infectivity of HCV particles and promoted viral entry by increasing the activation and decreasing the recycling of the epidermal growth factor receptor (EGFR), a protein that is dysregulated in HCC. Netrin-1 and HCV are, therefore, reciprocal inducers in vitro and in patients, as seen from the increase in viral morphogenesis and viral entry, both phenomena converging toward an increase in the level of infectivity of HCV virions. This functional association involving a cancer-related virus and Netrin-1 argues for evaluating the implication of UNC5 receptor ligands in other oncogenic microbial species.
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Plissonnier
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lahlali
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Michelet
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.|Hospices Civils de Lyon, Service d'Hépatogastroentérologie, F-69001 Lyon, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Lebossé
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cottarel
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Beer
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Grégory
authors.initials: G
authors.lastname: Neveu
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.affiliation: International Agency for Research on Cancer, F-69424 Lyon, France.
authors.forename: Rosita
authors.initials: R
authors.lastname: Accardi
authors.affiliation: Division of Clinical Pathology, University Hospital, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Clément
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69008 Lyon, France, Université de Lyon F-69003 Lyon, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Paradisi
authors.affiliation: Hospices Civils de Lyon, Service d'Anatomie Pathologique, F-69001 Lyon, France.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Devouassoux-Shisheboran
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Shirit
authors.initials: S
authors.lastname: Einav
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69008 Lyon, France, Université de Lyon F-69003 Lyon, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.|Hospices Civils de Lyon, Service d'Hépatogastroentérologie, F-69001 Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Pathogenesis of Hepatitis B and C - Equipe labellisée LabEx DEVweCAN, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France, Université de Lyon, F-69003 Lyon, Université Lyon 1, ISPB, Lyon, F-69622, France, CNRS UMR5286, F-69083 Lyon, France, Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Parent
mesh_terms: D001324:Autoantigens / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000378:metabolism*; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D012261:Ribonucleoproteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D053586:Virus Internalization; D000097585:SS-B Antigen; D012324:RNA-Dependent RNA Polymerase
chemical_list: D001324:Autoantigens; D066246:ErbB Receptors; D009414:Nerve Growth Factors; D000075388:Netrin-1; D012261:Ribonucleoproteins; D025521:Tumor Suppressor Proteins; D017361:Viral Nonstructural Proteins; D000097585:SS-B Antigen; C000617351:NTN1 protein, human; C512478:EGFR protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase