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

Machida, Keigo and Tsukamoto, Hidekazu and Mkrtchyan, Hasmik and Duan, Lewei and Dynnyk, Alla and Liu, Helene Minyi and Asahina, Kinji and Govindarajan, Sugantha and Ray, Ratna and Ou, Jing-hsiung James and Seki, Ekihiro and Deshaies, Raymond and Miyake, Kensuke and Lai, Michael M.-C. (2009) Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proceedings of the National Academy of Sciences of the United States of America, 106 (5). pp. 1548-1553. ISSN 0027-8424. PMCID PMC2635765.

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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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URLURL TypeDescription CentralArticle
Deshaies, Raymond0000-0002-3671-9354
Additional Information:© 2009 by The National Academy of Sciences of the USA. Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved December 2, 2008 (received for review August 13, 2008). Published online before print January 26, 2009. We thank Qing-gao Deng, Jiaohong Wang, Sean Vorah, and Jeffrey Huang (University of Southern California) for mouse experiments; Michael Karin (University of California at San Diego) for discussions; Paul Robson (Genome Institute of Singapore, Immunos, Singapore) for Nanog-promoter luciferase construct; Steven Weinman (University of Texas) for suggestions; and Moli Chen and Alex Trana for histological service. The study was supported by pilot project funding; the Animal and Morphology Cores of the Southern California Research Center for ALPD & Cirrhosis (P50 AA011999) funded by the National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health (NIAAA/NIH); NIH Grants AI 40038, CA123328, and CA108302; and the Medical Research Service of the Veterans Administration. Author contributions: K. Machida, H.T., R.R., J.-h.J.O., R.D., and M.M.-C.L. designed research; K. Machida, H.T., H.M., L.D., A.D., H.M.L., K.A., S.G., and E.S. performed research; K. Machida, R.R., and K. Miyake contributed new reagents/analytic tools; K. Machida analyzed data; and K. Machida, H.T., J.-h.J.O., and M.M.-C.L. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Funding AgencyGrant Number
Animal and Morphology Cores of the Southern California Research Center for ALPD & CirrhosisP50 AA011999
National Institute on Alcohol Abuse and AlcoholismUNSPECIFIED
NIHAI 40038
Veterans Administration Medical Research ServiceUNSPECIFIED
Issue or Number:5
PubMed Central ID:PMC2635765
Record Number:CaltechAUTHORS:MACpnas09
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13318
Deposited By: Tony Diaz
Deposited On:11 Feb 2009 04:11
Last Modified:03 Oct 2019 00:36

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