Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog
Open accessAbstract
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.
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In ethanol-fed transgenic mice with global TLR4 deficiency and NS5A HCV protein expression, hepatocellular carcinoma development is reduced, suggesting TLR4 signalling synergizes with HCV to promote hepatocellular carcinoma.
“In one study, ethanol-fed transgenic mice with global TLR4 deficiency, which additionally expressed the NS5A HCV protein, were protected from HCC development, suggesting that TLR4 signalling synergizes with HCV to promote HCC49.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [49]
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- Authors
- Machida, K., Tsukamoto, H., Mkrtchyan, H., Duan, L., Dynnyk, A., Liu, H. M., Asahina, K., Govindarajan, S., Ray, R., Ou, J.-H. J., Seki, E., Deshaies, R., Miyake, K., & Lai, M. M.-C.
- Affiliations
- Bipar (FR)
- University of Southern California (US)
- Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and
- Saint Louis University (US)
- University of California San Diego (US)
- California Institute of Technology (US)
- Institute of Medical Science, The University of Tokyo (JP)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-02-03
- Volume
- 106
- Issue
- 5
- Pages
- 1548-1553
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2635765
- OpenAlex
- W1973346087
- Cited by
- 223
- References
- 36
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 9 · 2019: 10 · 2018: 14 · 2017: 17 · 2016: 16 · 2015: 13 · 2014: 20 · 2013: 29 · 2012: 20
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institutes of Health (n01ai40038-12-0-1)
- National Institute on Alcohol Abuse and Alcoholism (P50AA011999)
- National Cancer Institute (CA 108302, R01CA108302, P01CA123328, CA123328)
- National Institute of Allergy and Infectious Diseases (AI 40038, N01 AI040038)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Keywords
- TLR4, hepatitis C virus, alcohol, liver cancer, hepatocarcinogenesis, Nanog, endotoxemia, NS5A, CD133, hepatic progenitor cells, p53 deficiency, lipopolysaccharide, liver disease progression, stem cell markers
- MeSH terms
- Nanog Homeobox Protein, Ethanol, Animals, Cocarcinogenesis, Humans, Lipopolysaccharides, Liver Neoplasms, Experimental, Mice, Transgenic, RNA-Dependent RNA Polymerase, Biomarkers, Hepacivirus, Viral Nonstructural Proteins, Homeodomain Proteins, Toll-Like Receptor 4, Mice
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