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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #306208
Title: Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through the activation of the Wnt/Beta-catenin signaling pathway

Author
item MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC)
item HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS)
item SHARMA, NEHA - Arkansas Children'S Nutrition Research Center (ACNC)
item LAI, KEITH - University Arkansas For Medical Sciences (UAMS)
item CLEVES, MARIO - Arkansas Children'S Nutrition Research Center (ACNC)
item WYNNE, REBECCA - University Arkansas For Medical Sciences (UAMS)
item Badger, Thomas - Arkansas Children'S Nutrition Research Center (ACNC)
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Cancer Prevention Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/20/2014
Publication Date: 7/1/2014
Citation: Mercer, K.E., Hennings, L., Sharma, N., Lai, K.K., Cleves, M.A., Wynne, R.A., Badger, T.M., Ronis, M.J. 2014. Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through the activation of the Wnt/Beta-catenin signaling pathway. Cancer Prevention Research. 7(7):675-685.

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/b-catenin signaling pathway. Several markers of invasive tumor growth, like c-myc, WISP-1 and MMP7, are up-regulated when the Wnt/Beta-catenin pathway is activated. Therefore, we believe these studies will reveal gene targets that may be used to therapeutic strategies designed to prevent invasive disease in alcohol populations.

Technical Abstract: Although alcohol effects within the liver have been extensively studied, the complex mechanisms by which alcohol causes liver cancer are not well understood. It has been suggested that ethanol (EtOH) metabolism promotes tumor growth by increasing hepatocyte proliferation. In this study, we developed a mouse model of tumor promotion by chronic EtOH consumption in which EtOH feeding began 47 days post-injection of the chemical carcinogen diethylnitrosamine (DEN) and continued for 16 weeks. With a final EtOH concentration of 28% of total calories, we observed a significant increase in the total number of cancerous foci and liver tumors per mouse in in situ fixed livers from the EtOH+DEN group compared to corresponding pair-fed (PF)+DEN and chow+DEN control groups. We also observed a 4-fold increase in hepatocyte proliferation (p<0.05) and increased cytoplasmic staining of active-Beta-catenin in non-tumor liver sections from EtOH+DEN mice compared to PF+DEN controls. In a rat model of alcohol-induced liver disease, we found increased hepatocyte proliferation (p<0.05); depletion of retinol and retinoic acid stores (p<0.05); increased expression of cytosolic and nuclear expression of b-catenin (p<0.05) and p-GSK3Beta (p<0.05); significant up-regulation in Wnt7a mRNA expression; and increased expression of several Beta-catenin targets, such as cyclinD1, c-myc, WISP1, and MMP7 (p<0.05). These data suggest that chronic EtOH consumption activates the Wnt/Beta-catenin signaling pathways which increase hepatocyte proliferation, thus promoting tumorigenesis following an initiating insult to the liver.