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

金雀异黄素/大豆预防乙醇诱导的肝癌发生

• 批准号: 8354189
• 负责人: Martin J J Ronis
• 金额: $ 19.31万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354189
• 关键词: Accounting; Address; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol-Related Hepatocellular Carcinoma; Alcoholic Beverages; Alcohols; Applications Grants; Archives; Area; Arkansas; Azoxymethane; Binding; Blood; Breast; Cancer Etiology; Carcinogens; Caseins; Cell Proliferation; Cells; Child Nutrition; Clinical; Colon; Colon Carcinoma; Cyclin D1; Data; Development; Diet; Dietary Factors; Dietary Proteins; Dietary Supplementation; Diethylnitrosamine; Environmental Carcinogens; Estrogen Receptors; Ethanol; Experimental Models; Exposure to; Gene Expression; Generations; Genetic Transcription; Genistein; Hepatic; Hepatitis; Hepatocarcinogenesis; Hepatocyte; Human; Immunohistochemistry; Immunoprecipitation; Incidence; Individual; Infection; Italy; JUN gene; Laboratories; Link; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Modeling; Molecular; Molecular Target; Mus; NIH Program Announcements; National Cancer Institute; Nitrosamines; Nutritional; Oxidative Stress; Pathway interactions; Patients; Phytochemical; Population; Prevention; Primary carcinoma of the liver cells; Proliferation Marker; Prostate; Proteins; Public Health; Rattus; Recording of previous events; Relative (related person); Reporter; Risk; Risk Factors; Rodent Model; Role; Sampling; Signal Transduction; Site; Supplementation; System; Testing; Tissues; Transcription Factor AP-1; Transcriptional Activation; Tumor Promoters; Tumor Promotion; Western Blotting; animal data; bioactive food component; cancer prevention; chromatin immunoprecipitation; cigarette smoking; feeding; inhibitor/antagonist; insight; interest; liver cell proliferation; liver repair; mortality; mouse model; novel; prevent; promoter; protective effect; social; soy; soy protein isolate; tumor; tumorigenesis

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. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma is the world's third leading cause of cancer mortality and alcohol abuse now accounts for 32-45% of cases. This is a major public health issue and yet the mechanisms whereby alcohol causes HCC are incompletely understood and there are no clinical strategies to reduce risk of HCC in alcohol consumers. Our animal data link activation of Wnt-b-catenin signaling with promotion of liver cancer by ethanol and suggest that dietary factors such as soy/genistein which have been suggested to inhibit-b-catenin activation, might prevent these effects. Molecular studies of alcohol and soy/genistein actions on the liver Wnt- b-catenin signaling cascade are expected to provide fundamental insights into common pathways underlying tumor promotion.

描述(申请人提供)：肝细胞癌(肝细胞癌)现在是世界上第三大癌症死亡原因。酒精是众所周知的肝细胞癌的危险因素，建议占所有肝细胞癌病例的32-45%。由于大约7%的美国成年人口滥用或依赖酒精，酒精诱发的肝癌是一个严重的公共卫生问题。尽管饮酒很重要，但饮酒导致肝细胞癌的机制仍不完全清楚。乙醇(Etoh)的主要作用似乎是作为肿瘤促进剂，增加因接触饮食和环境致癌物质(如酒精饮料和香烟烟雾中的亚硝胺)或通过肝炎感染而引发的肿瘤的发展速度。我们的实验室已经证实，乙醇治疗后大鼠的肝脏修复(增加肝细胞增殖)伴随着b-连环蛋白的激活。此外，我们的初步数据表明，乙醇在小鼠体内起到了肿瘤促进剂的作用，这与b-连环蛋白的激活也是一致的。这些新的数据表明，阻断乙醇对Wnt-b-catenin信号的刺激可能是酒精相关性肝癌的有效预防机制。大豆产品大豆分离蛋白(SPI)和大豆植物化学物质金雀异黄素已被证明在包括乳房和结肠在内的几个组织中阻断Wnt-b-catenin信号的激活。我们将测试假设：1)致癌物二乙基亚硝胺(DEN)和乙醇将通过增加转录和通过增加典型的Wnt信号来相加地激活b-catenin，2)将饮食蛋白质从酪蛋白改变为SPI或在饮食中补充染料木素的水平与大豆中发现的水平相似，将通过诱导可溶性FRZ蛋白抑制物阻止Etoh激活Wnt信号来阻止Etoh促进肿瘤的发生。为此，我们将1)在我们的小鼠肿瘤促进模型中，检测SPI/Genistein联合应用Etoh减少肿瘤/小鼠肿瘤数量的能力；2)使用小鼠报告系统(TOP-GAL)和来自肝细胞癌患者的存档样本，以确认Etoh诱导b-catenin并且与肝细胞中的增殖标志物共存；3)通过使用靶向微阵列、Western blotting、免疫组织化学和免疫沉淀分析基因表达，确定DEN/Etoh诱导b-catenin以及与膳食Genistein/SPI相互作用的分子机制。 与公共卫生相关：肝细胞癌是世界上导致癌症死亡的第三大原因，目前酗酒占病例的32-45%。这是一个重大的公共卫生问题，但酒精导致肝癌的机制尚不完全清楚，也没有临床策略来降低酒精消费者患肝癌的风险。我们的动物数据将Wnt-b-catenin信号的激活与乙醇促进肝癌联系在一起，并表明已被认为抑制-b-catenin激活的饮食因素，如大豆/染料木素，可能会阻止这些影响。酒精和大豆/染料木素对肝脏Wnt-b-catenin信号级联反应的分子研究有望为肿瘤促进的常见途径提供基本的见解。