In this study, diethylnitrosamine-treated male mice were assigned to three groups: (i) a 35% high fat ethanol liquid diet (EtOH) with casein as the protein source, (ii) the same EtOH liquid diet with soy protein isolate as the sole protein source (EtOH/SPI), (iii) and a chow group. EtOH feeding continued for 16 weeks. As expected, EtOH increased the incidence and multiplicity of basophilic lesions and adenomas compared with the chow group, P < 0.05. Soy protein replacement of casein in the EtOH diet significantly reduced adenoma progression when compared with the EtOH and EtOH/SPI group (P < 0.05). Tumor reduction in the EtOH/SPI group corresponded to reduced liver injury associated with decreased hepatic Tnfα and Cd14 antigen (Cd14) expression and decreased nuclear accumulation of NF-κB1 protein compared with the EtOH group (P < 0.05). Detection of sphingolipids using high-resolution matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR) imaging mass spectrometry revealed increased accumulation of long acyl chain ceramide species, and sphingosine-1-phosphate (S1P) in the EtOH group that were significantly reduced in the EtOH/SPI group. Chronic EtOH feeding also increased mRNA expression of β-catenin transcriptional targets, including cyclin D1 (Ccnd1), matrix metallopeptidase 7 (Mmp7), and glutamine synthetase (Glns), which were reduced in the EtOH/SPI group (P < 0.05). We conclude that soy prevents tumorigenesis by reducing proinflammatory and oxidative environment resulting from EtOH-induced hepatic injury, and by reducing hepatocyte proliferation through inhibition of β-catenin signaling. These mechanisms may involve changes in sphingolipid signaling. Cancer Prev Res; 9(6); 466-75. ©2016 AACR.
©2016 American Association for Cancer Research.