Lymphotoxin Signaling Is Initiated by the Viral Polymerase in HCV-linked Tumorigenesis
Yannick Simonin,Yannick Simonin,Serena Vegna,Serena Vegna,Leila Akkari,Leila Akkari,Damien Grégoire,Damien Grégoire,Etienne Antoine,Etienne Antoine,Jacques Piette,Jacques Piette,Nicolas Floc'h,Nicolas Floc'h,Patrice Lassus,Patrice Lassus,Guann-Yi Yu,Arielle R. Rosenberg,Michael Karin,David Durantel,Urszula Hibner,Urszula Hibner +21 more
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TLDR
The goal of this 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 and a dramatic upregulation of the lymphotoxin signaling pathway is reported.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.read more
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Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis
Alexander V. Ivanov,Vladimir T. Valuev-Elliston,Daria A. Tyurina,Olga N. Ivanova,Sergey N. Kochetkov,Birke Bartosch,Maria G. Isaguliants +6 more
TL;DR: This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses and focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis.
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Oxidative stress and hepatic Nox proteins in chronic hepatitis C and hepatocellular carcinoma.
TL;DR: Mechanisms of oncogenesis by HCV are summarized, highlighting the roles of oxidative stress and hepatic Nox enzymes in HCC.
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Cancer cell-derived lymphotoxin mediates reciprocal tumour-stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts.
Tat-San Lau,Tony K.H. Chung,Tak Hong Cheung,Loucia K.Y. Chan,Leonard Wing-Hong Cheung,So Fan Yim,Nelson S.S. Siu,Kwok Wai Lo,May Mei-Yung Yu,Hagen Kulbe,Frances R. Balkwill,Joseph Kwong +11 more
TL;DR: It is demonstrated that cancer‐cell‐derived lymphotoxin mediates reciprocal tumour–stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts, and the findings suggest that lymphot toxin–LTBR and CxCL11–CXCR3 signalling represent therapeutic targets in ovarian cancer.
Journal ArticleDOI
Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma.
Simonetta Bandiera,C Billie Bian,Yujin Hoshida,Thomas F. Baumert,Thomas F. Baumert,Mirjam B. Zeisel,Mirjam B. Zeisel +6 more
TL;DR: A better understanding of HCV-induced HCC and more physiological liver disease models are required to prevent cancer development.
Journal ArticleDOI
Context-dependent roles for lymphotoxin-β receptor signaling in cancer development
TL;DR: The different mechanisms by which LTβR activation affects carcinogenesis are reviewed, focusing on the diverse contexts and different models assessed.
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