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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.<\/jats:p>","DOI":"10.1073\/pnas.0807390106","type":"journal-article","created":{"date-parts":[[2009,1,26]],"date-time":"2009-01-26T20:45:51Z","timestamp":1233002751000},"page":"1548-1553","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":188,"title":["Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog"],"prefix":"10.1073","volume":"106","author":[{"given":"Keigo","family":"Machida","sequence":"first","affiliation":[{"name":"Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and"},{"name":"Departments of bMolecular Microbiology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekazu","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and"},{"name":"Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033;"},{"name":"VA Greater Los Angeles Healthcare System, Los Angeles, CA 90033;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasmik","family":"Mkrtchyan","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewei","family":"Duan","sequence":"additional","affiliation":[{"name":"Departments of bMolecular Microbiology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alla","family":"Dynnyk","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene Minyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of bMolecular Microbiology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinji","family":"Asahina","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sugantha","family":"Govindarajan","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and"},{"name":"Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratna","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saint Louis University, St. Louis, MO 63103;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-hsiung James","family":"Ou","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and"},{"name":"Departments of bMolecular Microbiology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekihiro","family":"Seki","sequence":"additional","affiliation":[{"name":"University of California at San Diego, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Deshaies","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, CA 91125;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Miyake","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; 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