title: TLR4-dependent tumor-initiating stem cell-like cells (TICs) in alcohol-associated hepatocellular carcinogenesis.
abstract: Alcohol abuse predisposes individuals to the development of hepatocellular carcinoma (HCC) and synergistically heightens the HCC risk in patients infected with hepatitis C virus (HCV). The mechanisms of this synergism have been elusive until our recent demonstration of the obligatory role of ectopically expressed TLR4 in liver tumorigenesis in alcohol-fed HCV Ns5a or Core transgenic mice. CD133+/CD49f+ tumor-initiating stem cell-like cells (TICs) isolated from these models are tumorigenic in a manner dependent on TLR4 and NANOG. TICs' tumor-initiating activity and chemoresistance are causally associated with inhibition of TGF-β tumor suppressor pathway due to NANOG-mediated expression of IGF2BP3 and YAP1. TLR4/NANOG activation causes p53 degradation via phosphorylation of the protective protein NUMB and its dissociation from p53 by the oncoprotein TBC1D15. Nutrient deprivation reduces overexpressed TBC1D15 in TICs via autophagy-mediated degradation, suggesting a possible role of this oncoprotein in linking metabolic reprogramming and self-renewal.
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, MMR-402, Los Angeles, CA, 90089-9141, USA, keigo.machida@med.usc.edu.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Feldman
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced*; D000431:Ethanol / Q000633:toxicity*; D020690:GTPase-Activating Proteins / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011519:Proto-Oncogenes; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D020690:GTPase-Activating Proteins; C550073:TBC1D15 protein, human; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D000431:Ethanol