Author
MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC) | |
HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS) | |
SHARMA, NEHA - Arkansas Children'S Nutrition Research Center (ACNC) | |
CHANDLER, CHRISTOPHER - Arkansas Children'S Nutrition Research Center (ACNC) | |
Badger, Thomas | |
RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC) |
Submitted to: Toxicologist
Publication Type: Abstract Only Publication Acceptance Date: 2/15/2014 Publication Date: 3/15/2014 Citation: Mercer, K., Hennings, L., Sharma, N., Chandler, C., Badger, T.M., Ronis, M.J. 2014. Chronic alcohol intake promotes tumor growth in a diethylnitrosamine-induced hepatocarcinogenesis mouse model through increased Wnt/Beta-catenin signaling [abstract}. The Toxicologist. 138(1):PS254. http://www.toxicology.org/ai/pub/toxicologistDatabase.aspx. Interpretive Summary: Technical Abstract: Ethanol (EtOH) metabolism is involved in both initiating and promoting mechanisms in hepatocellular carcinoma progression in chronic alcoholics. In this study, we developed a mouse model to test the hypothesis that chronic EtOH consumption promotes tumor growth irrespective of EtOH-related initiating mechanisms. Male mice received a single dose of diethylnitrosamine (DEN) on postnatal day 13, and were assigned to either an EtOH liquid diet, a control liquid diet pair-fed (PF) to the EtOH group, or a standard chow diet 47 days post-DEN injection. After 16 wks of EtOH feeding (5.0% v/v), we observed a 2- to 4-fold increase in tumor multiplicity, but not tumor incidence in EtOH+DEN-treated livers compared to PF+DEN and chow+DEN groups, p<0.05, which corresponded to a 4-fold increase in hepatocyte proliferation in EtOH+DEN non-tumor liver tissues, p<0.05. In the EtOH+DEN non-tumor liver tissues, we also observed a significant increase in beta-catenin expression and changes in beta-catenin localization when compared to DEN-treated PF and chow controls. More importantly, in a separate rodent model of alcoholic liver disease, prolonged feeding of EtOH alone significantly reduced hepatic retinol and retinoic acid concentrations, increased cytosolic beta-catenin expression, phosphorylated (Ser 21/9) GSK3b expression, and increased nuclear accumulation of beta-catenin in rat hepatocytes, p<0.05. In addition, RNA analysis using a targeted Wnt PCR array revealed a significant up-regulation of soluble Wnts, transcription factors associated with a proliferative phenotype, and beta-catenin targets associated with disease progression, p<0.05. These findings suggest a link between alcohol-related retinoid depletion, up-regulation of Wnt/beta-catenin signaling, and tumor growth and progression in our mouse model of HCC. |