title: Lymphotoxin signaling is initiated by the viral polymerase in HCV-linked tumorigenesis.
abstract: Exposure to hepatitis C virus (HCV) typically results in chronic infection that leads to progressive liver disease ranging from mild inflammation to severe fibrosis and cirrhosis as well as primary liver cancer. HCV triggers innate immune signaling within the infected hepatocyte, a first step in mounting of the adaptive response against HCV infection. Persistent inflammation is strongly associated with liver tumorigenesis. The goal of our work was to investigate the initiation of the inflammatory processes triggered by HCV viral proteins in their host cell and their possible link with HCV-related liver cancer. We report a dramatic upregulation of the lymphotoxin signaling pathway and more specifically of lymphotoxin-β in tumors of the FL-N/35 HCV-transgenic mice. Lymphotoxin expression is accompanied by activation of NF-κB, neosynthesis of chemokines and intra-tumoral recruitment of mononuclear cells. Spectacularly, IKKβ inactivation in FL-N/35 mice drastically reduces tumor incidence. Activation of lymphotoxin-β pathway can be reproduced in several cellular models, including the full length replicon and HCV-infected primary human hepatocytes. We have identified NS5B, the HCV RNA dependent RNA polymerase, as the viral protein responsible for this phenotype and shown that pharmacological inhibition of its activity alleviates activation of the pro-inflammatory pathway. These results open new perspectives in understanding the inflammatory mechanisms linked to HCV infection and tumorigenesis.
authors.affiliation: CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France. yannick.simonin@igmm.cnrs.fr
authors.forename: Yannick
authors.initials: Y
authors.lastname: Simonin
authors.forename: Serena
authors.initials: S
authors.lastname: Vegna
authors.forename: Leila
authors.initials: L
authors.lastname: Akkari
authors.forename: Damien
authors.initials: D
authors.lastname: Grégoire
authors.forename: Etienne
authors.initials: E
authors.lastname: Antoine
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Nicolas
authors.initials: N
authors.lastname: Floc'h
authors.forename: Patrice
authors.initials: P
authors.lastname: Lassus
authors.forename: Guann-Yi
authors.initials: GY
authors.lastname: Yu
authors.forename: Arielle R
authors.initials: AR
authors.lastname: Rosenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.forename: Urszula
authors.initials: U
authors.lastname: Hibner
mesh_terms: D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D016174:Hepacivirus / Q000201:enzymology* / Q000472:pathogenicity; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology* / Q000821:virology; D053308:Lymphotoxin-beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D018925:Chemokines; D053308:Lymphotoxin-beta; D016328:NF-kappa B; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
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