Lymphotoxin Signaling Is Initiated by the Viral Polymerase in HCV-linked Tumorigenesis

PLoS Pathogens

Leila Akkari¹  Etienne Antoine¹  Yannick Simonin¹  Guann-Yi Yu¹  Michael Karin¹  Urszula Hibner¹  Nicolas Floc'h¹  David Durantel²  Serena Vegna²  Patrice Lassus²  Arielle R. Rosenberg²  Damien Grégoire²  Jacques Piette² 

[1] CNRS, UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France;Université de Montpellier 2, Place Eugène Bataillon, Université Montpellier 1, 5 Bd Henry IV, Montpellier, France

关键词: Transcription factors;    Hepatitis C virus;    Inflammation;    Cytokines;    Carcinogenesis;    Protein expression;    Hepatocellular carcinoma;    Mouse models;   

DOI  :  10.1371/journal.ppat.1003234

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY