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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #274831
Title: Chronic alcohol consumption promotes hepatocarcinogenesis in mice through activation of beta-catenin

Author
item MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC)
item WYNNE, REBECCA - Arkansas Children'S Nutrition Research Center (ACNC)
item CHANDLER, CHRISTOPHER - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas
item HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 10/3/2011
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Alcohol abuse is the most common cause of liver cancer in the United States, Although alcohol effects within the liver have been extensively studied, the mechanism by which alcohol causes liver cancer is complex. One mechanism involves speeding up tumor growth (promotion) by increasing the number of dividing liver cells (hepatocyte proliferation). In this study, we developed a mouse model of tumor promotion by chronic ethanol (EtOH) consumption in which EtOH feeding began 47 days post-injection of the chemical carcinogen diethylnitrosamine (DEN). After 16 weeks of EtOH at a final concentration of 28% total calories, we observed a 2 to 4-fold increase in the total number of cancerous foci and liver tumors per mouse, in livers from EtOH/DEN group compared to corresponding pair-fed/DEN and chow/DEN control groups. In addition, we also observed a 4-fold increase in hepatocyte proliferation in non-tumor liver sections from EtOH/DEN mice compared to pair-fed/DEN controls as measured by increased staining of Proliferating Cell Nuclear Antigen (PCNA). A biochemical pathway regulated though Wnt protein signaling to activate the transcription factor '-catenin has been implicated in regulation of cell division and development of some cancers. We observed an increase in cytoplasmic staining of active-'-catenin in non-tumor liver sections of EtOH/DEN mice over pair-fed/DEN controls. Using a rat model of alcoholic liver disease, we have previously demonstrated that rats receiving 36% of daily calories from EtOH for 42—150 days also have increased hepatocyte proliferation as measured by PCNA staining. Therefore, we also looked for cytoplasmic expression of active-beta-catenin and phosphorylated-GSK-3 beta'(an upstream signal connecting beta-catenin with the Wnt signaling pathway in these rat liver lysates by Western blot. Although expression between EtOH-treated animals was variable, increased beta-catenin and p-GSK-3 beta expression was observed compared isocalorically-fed controls. In addition, 2-fold increases in RNA expression of Ki67, a well known established marker for cell proliferation and of cyclin D1, a downstream target of beta-catenin were observed. Taken together, these data suggests that chronic EtOH consumption induces hepatocyte proliferation in liver through activation of beta catenin, which is a possible mechanism by which EtOH also promotes liver cancer following an initiating insult.