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Title: Soy protein isolate protects against ethanol mediated tumor progression in diethylnitrosamine treated male mice

item MERCER, K - Arkansas Children'S Nutrition Research Center (ACNC)
item PULLIAM, C - Arkansas Children'S Nutrition Research Center (ACNC)
item HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS)
item LAI, KEITH - University Arkansas For Medical Sciences (UAMS)
item CLEVES, M - Arkansas Children'S Nutrition Research Center (ACNC)
item JONES, E - Medical University Of South Carolina
item DRAKE, R - Medical University Of South Carolina
item RONIS, M - Louisiana State University Medical Center

Submitted to: Cancer Prevention Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2016
Publication Date: 3/22/2016
Citation: Mercer, K.E., Pulliam, C., Hennings, L., Lai, K., Cleves, M., Jones, E., Drake, R.R., Ronis, M.J. 2016. Soy protein isolate protects against ethanol mediated tumor progression in diethylnitrosamine treated male mice. Cancer Prevention Research. 9(6):466-475. doi: 10.1158/1940-6207.CAPR-15-0417.

Interpretive Summary: Liver cancer is a leading cause of cancer mortality throughout the world, and chronic consumption of alcohol is risk factor. Even at lower consumption rates, alcohol use is synergistic with other initiating and promoting risk factors, including hepatitis infections and metabolic syndrome, increasing the overall occurrence of liver cancers in these populations worldwide. Current clinical and animal studies show that changing diets to contain more soy-based foods may prevent liver injury associated high fat diets and alcohol consumption and therefore lower cancer risk and occurrence. In this study, we tested the hypothesis that a liquid alcohol diets supplemented with soy could prevent liver injury and subsequent tumor development. Male mice treated with a liver carcinogen, diethylnitrosamine, received a high fat, EtOH containing liquid diet composed of either casein or soy protein for 16 weeks. In contrast to the EtOH/casein diet which contributed to the development of many tumors, the high fat EtOH/soy diet significantly decreased the present of tumors. Potential mechanisms underlying soy's protective effects is an anti-inflammatory response, and decreased lipid signaling associated with alcohol-related liver injury. These findings support the use of dietary intervention strategies to lower liver cancer risk in those populations having multiple risk factors.

Technical Abstract: In this study, DEN-treated male mice were assigned to 3 groups: a 35% high fat ethanol liquid diet (EtOH) with casein as the protein source, the same EtOH liquid diet with soy protein isolate as the sole protein source (EtOH/soy) and a chow group. EtOH feeding continued for 16 wks. As expected, EtOH increased the incidence and multiplicity of basophilic lesions and adenomas compared to the chow group, p<0.05. Soy protein replacement of casein in the EtOH diet significantly reduced adenoma progression when compared to the EtOH and EtOH/GEN group, p<0.05. Tumor reduction in the EtOH/soy group corresponded to lower serum ALT concentrations (p<0.05), decreased hepatic tumor necrosis factor ' and CD-14 expression and decreased nuclear accumulation of NFkB protein compared to the EtOH group (p<0.05). Detection of sphingolipids using high resolution MALDI-FTICR Imaging mass spectrometry revealed increased accumulation of long acyl chain ceramide species, sphingosine-1-phosphate, and glucosylceramide in the EtOH group that were significantly reduced in the EtOH/soy group. Chronic EtOH feeding also increased mRNA expression of beta-catenin targets, including cyclin D1, MMP7 and glutamine synthetase, which were reduced in the EtOH/soy group, p<0.05. We conclude that soy prevents tumorigenesis by reducing pro-inflammatory and oxidative environment resulting from EtOH-induced hepatic injury, and by reducing hepatocyte proliferation through inhibition beta-catenin signaling. These mechanisms may involve sphingolipid signaling.