title: Alcohol consumption, Wnt/β-catenin signaling, and hepatocarcinogenesis.
abstract: Alcohol is a well-established risk factor for hepatocellular carcinoma, and the mechanisms by which alcohol liver cancer is complex. It has been suggested that ethanol (EtOH) metabolism may enhance tumor progression by increasing hepatocyte proliferation. To test this hypothesis, ethanol (EtOH) feeding of male mice began 7 weeks post-injection of the chemical carcinogen diethylnitrosamine (DEN), and continued for 16 weeks, with a final EtOH concentration of 28% of total calories. As expected, EtOH increased the total number of cancerous foci and liver tumors identified in situ fixed livers from the EtOH+DEN group compared to corresponding pair-fed (PF)+DEN and chow+DEN control groups. In the EtOH+DEN group, tumor multiplicity corresponded to a 3- to 4-fold increase in proliferation and immunohistochemical staining of β-catenin in non-tumorigenic hepatocytes when compared to the PF+DEN and chow+DEN groups, p<0.05. Analysis of EtOH-treated livers from a previously published rat model of chronic liver disease revealed increases in hepatocyte proliferation accompanied by a hepatic depletion of retinol and retinoic acid stores (p<0.05), nuclear accumulation of β-catenin (p<0.05), increased cytosolic expression p-GSK3β (p<0.05), significant upregulation of soluble Wnts, Wnt2, and Wnt7a, and increased expression of several β-catenin targets involved in tumor promotion and progression, cyclin D1, c-myc, WISP1, and MMP7 (p<0.05). These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathway, which increases hepatocyte proliferation thus promoting tumorigenesis following an initiating insult in the liver.
authors.affiliation: Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA, kmercer@uams.edu.
authors.forename: K E
authors.initials: KE
authors.lastname: Mercer
authors.forename: L
authors.initials: L
authors.lastname: Hennings
authors.forename: M J J
authors.initials: MJ
authors.lastname: Ronis
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D004052:Diethylnitrosamine; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000032:analysis / Q000502:physiology*
chemical_list: C495267:CTNNB1 protein, mouse; D051176:beta Catenin; D004052:Diethylnitrosamine