title: Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog.
abstract: 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.
authors.affiliation: Southern California Research Center for Alcoholic, Liver, and Pancreatic Diseases and Cirrhosis, and Department of Molecular Microbiology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Hasmik
authors.initials: H
authors.lastname: Mkrtchyan
authors.forename: Lewei
authors.initials: L
authors.lastname: Duan
authors.forename: Alla
authors.initials: A
authors.lastname: Dynnyk
authors.forename: Helene Minyi
authors.initials: HM
authors.lastname: Liu
authors.forename: Kinji
authors.initials: K
authors.lastname: Asahina
authors.forename: Sugantha
authors.initials: S
authors.lastname: Govindarajan
authors.forename: Ratna
authors.initials: R
authors.lastname: Ray
authors.forename: Jing-Hsiung James
authors.initials: JH
authors.lastname: Ou
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.forename: Raymond
authors.initials: R
authors.lastname: Deshaies
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Michael M-C
authors.initials: MM
authors.lastname: Lai
mesh_terms: D000818:Animals; D015415:Biomarkers; D003043:Cocarcinogenesis; D000431:Ethanol / Q000494:pharmacology*; D016174:Hepacivirus / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000503:physiopathology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D000071317:Nanog Homeobox Protein; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000502:physiology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D015415:Biomarkers; D000431:Ethanol; D018398:Homeodomain Proteins; D008070:Lipopolysaccharides; D000071317:Nanog Homeobox Protein; D051197:Toll-Like Receptor 4; D017361:Viral Nonstructural Proteins; C475540:Nanog protein, mouse; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase