Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (5), p.1548-1553
Main Authors: Machida, Keigo, Tsukamoto, Hidekazu, Mkrtchyan, Hasmik, Duan, Lewei, Dynnyk, Alla, Liu, Helene Minyi, Asahina, Kinji, Govindarajan, Sugantha, Ray, Ratna, Ou, Jing-hsiung James, Seki, Ekihiro, Deshaies, Raymond, Miyake, Kensuke, Lai, Michael M.-C
Format: Article
Language:English
Subjects:
Alcohol
Alcohol related disorders
Alcoholism
Alcohols
Animals
Biological Sciences
Biomarkers
Cells
Cocarcinogenesis
Ethanol - pharmacology
Gene expression
Hepacivirus - physiology
Hepatitis
Hepatitis C virus
Hepatocellular carcinoma
Homeodomain Proteins - physiology
Humans
Lipopolysaccharides - toxicity
Liver
Liver diseases
Liver Neoplasms, Experimental - chemically induced
Liver Neoplasms, Experimental - physiopathology
Liver Neoplasms, Experimental - virology
Mice
Mice, Transgenic
Nanog Homeobox Protein
Proteins
Signal transduction
Stem cells
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - physiology
Transplantation
Tumors
Viral Nonstructural Proteins - physiology
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Summary:Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog short-hairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0807390106