Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through activation of the Wnt/β-catenin signaling pathway.
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 46 days after 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 preneoplastic foci and liver tumors per mouse in the EtOH+DEN group compared with 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-β-catenin in nontumor liver sections from EtOH+DEN mice compared with 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 β-catenin (P < 0.05) and phosphorylated-glycogen synthase kinase 3β (p-GSK3β), P < 0.05; significant upregulation in Wnt7a mRNA expression; and increased expression of several β-catenin targets, including, glutamine synthetase (GS), cyclin D1, Wnt1 inducible signaling pathways protein (WISP1), and matrix metalloproteinase-7(MMP7), P < 0.05. These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathways to increase hepatocyte proliferation, thus promoting tumorigenesis following an initiating insult to the liver.
Authors' Affiliations: Departments of Pediatrics and Arkansas Children's Nutrition Center, Little Rock, Arkansas kmercer@uams.edu.
Kelly E
KE
Mercer
Pathology at the University of Arkansas for Medical Sciences; and.
Leah
L
Hennings
Arkansas Children's Nutrition Center, Little Rock, Arkansas.
Neha
N
Sharma
Pathology at the University of Arkansas for Medical Sciences; and.
Keith
K
Lai
Arkansas Children's Nutrition Center, Little Rock, Arkansas.
Mario A
MA
Cleves
Arkansas Children's Nutrition Center, Little Rock, Arkansas.
Rebecca A
RA
Wynne
Authors' Affiliations: Departments of Pediatrics and Arkansas Children's Nutrition Center, Little Rock, Arkansas.
Thomas M
TM
Badger
Authors' Affiliations: Departments of Pediatrics and Arkansas Children's Nutrition Center, Little Rock, Arkansas.
Martin J J
MJ
Ronis
D000428:Alcohol Drinking / Q000009:adverse effects*; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000139:chemically induced* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity*; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D060449:Wnt Signaling Pathway / Q000187:drug effects*
D000477:Alkylating Agents; D018836:Inflammation Mediators; D012333:RNA, Messenger; D004052:Diethylnitrosamine