Skip to main content
ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #307259

Title: Alcohol consumption, Wnt/ß-catenin cignaling, and hepatocarcinogenesis

item MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC)
item HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Advances in Experimental Medicine and Biology
Publication Type: Book / Chapter
Publication Acceptance Date: 5/15/2014
Publication Date: 11/10/2014
Citation: Mercer, K.E., Hennings, L., Ronis, M.J. 2014. Alcohol consumption, Wnt/ß-catenin cignaling, and hepatocarcinogenesis. Advances in Experimental Medicine and Biology. 815:185-195.

Interpretive Summary: Heavy alcohol consumption was a primary contributing factor for one-third of the hepatocellular carcionoma (HCC) cases reported in the U.S. population. In the liver, alcohol affects pathways involved in the progression of HCC to a metastatic disease. In this study, we have identified a novel pathway by which alcohol promotes tumor growth through the Wnt/beta-catenin signaling pathway. Several markers of invasive tumor growth, like c-myc, WISP-1, and MMP7, are up-regulated when the Wnt/beta-cateinin pathway is activated. Therefore, we believe these studies will reveal gene targets that may be used in therapeutic strategies designed to prevent invasive disease in alcohol populations.

Technical 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 ß-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 ß-catenin (p'<'0.05), increased cytosolic expression p-GSK3ß (p'<'0.05), significant upregulation of soluble Wnts, Wnt2, and Wnt7a, and increased expression of several ß-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/ß-catenin signaling pathway, which increases hepatocyte proliferation thus promoting tumorigenesis following an initiating insult in the liver.