Prevention of EtOH-induced promotion of hepatocarcinogenesis by genistein/soy

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DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is now the world's third leading cause of cancer mortality. Alcohol is a well known risk factor for HCC and is suggested to account for 32-45% of all HCC cases. Since about 7% of the adult U.S. population abuses or is dependent on alcohol, alcohol-induced HCC is a serious public health problem. Despite its importance, the mechanisms whereby alcohol consumption causes HCC remain incompletely understood. The major role of ethanol (EtOH) appears to be to act as a tumor promoter, increasing the rate of development of tumors initiated as a result of exposure to dietary and environmental carcinogens such as nitrosamines found in alcoholic beverages and cigarette smoke or via hepatitis infection. Our laboratory has demonstrated liver repair (increased hepatocyte proliferation) after EtOH treatment in rats accompanied by activation of b-catenin. Moreover, our preliminary data suggest that EtOH acts as a tumor promoter in mice, also coincident with b-catenin activation. These novel data suggest that blockage of EtOH stimulation of Wnt- b-catenin signaling might be an effective prevention mechanism for alcohol related HCC. The soy product soy protein isolate (SPI) and the soy phytochemical genistein have been shown to block activation of Wnt-b-catenin signaling in several tissues including breast and colon. We will test the hypotheses that 1) The carcinogen diethylnitrosamine (DEN) and ETOH will act additively to activate b- catenin through increased transcription and via increased canonical Wnt signaling, 2) Changing the dietary protein from casein to SPI or supplementation of the diet with genistein at levels similar to those found in soy will prevent EtOH promotion of tumorigenesis by blocking EtOH activation of Wnt signaling through induction of soluble FRZ protein inhibitors. To do this we will 1) examine the ability of SPI/genistein co-administration with EtOH to reduce the number of tumors/mouse relative to EtOH treatment by itself in our mouse model of tumor promotion; 2) use a mouse reporter system (TOP-GAL) and archived samples from HCC patients to confirm EtOH induction of b-catenin and co-localization with proliferation markers in hepatocytes; and 3) determine the molecular mechanisms underlying DEN/EtOH induction of b-catenin, and interactions with dietary genistein/SPI, by analyzing gene expression using targeted microarrays, Western blotting, immunohistochemistry and immunoprecipitation.