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

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... anner 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.