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 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.
Machida
Keigo
K
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.
Tsukamoto
Hidekazu
H
Mkrtchyan
Hasmik
H
Duan
Lewei
L
Dynnyk
Alla
A
Liu
Helene Minyi
HM
Asahina
Kinji
K
Govindarajan
Sugantha
S
Ray
Ratna
R
Ou
Jing-Hsiung James
JH
Seki
Ekihiro
E
Deshaies
Raymond
R
Miyake
Kensuke
K
Lai
Michael M-C
MM
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
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