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

基本信息

批准号：
8547039
负责人：
Martin J J Ronis
金额：
$ 15.13万
依托单位：
ARKANSAS CHILDREN'S HOSPITAL RES INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547039
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

项目摘要

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.

描述（由申请人提供）：肝细胞癌（HCC）目前是世界上第三大癌症死亡原因。众所周知，酒精是 HCC 的危险因素，预计占所有 HCC 病例的 32-45%。由于约 7% 的美国成年人滥用或依赖酒精，因此酒精诱发的 HCC 是一个严重的公共卫生问题。尽管饮酒很重要，但其导致肝癌的机制仍不完全清楚。乙醇 (EtOH) 的主要作用似乎是充当肿瘤促进剂，增加因暴露于饮食和环境致癌物（例如酒精饮料和香烟烟雾中的亚硝胺）或肝炎感染而引发的肿瘤的发生率。我们的实验室已证明大鼠经 EtOH 治疗后可进行肝脏修复（增加肝细胞增殖）并伴有 β-连环蛋白的激活。此外，我们的初步数据表明，EtOH 在小鼠中充当肿瘤促进剂，也与 β-连环蛋白激活同时发生。这些新数据表明，阻断 EtOH 对 Wnt-b-catenin 信号传导的刺激可能是酒精相关 HCC 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染料木黄酮已被证明可以阻断包括乳房和结肠在内的多种组织中 Wnt-b-连环蛋白信号的激活。我们将测试以下假设：1) 致癌物质二乙基亚硝胺 (DEN) 和 ETOH 将通过增加转录和增加经典 Wnt 信号传导来相加地激活 β-连环蛋白，2) 将膳食蛋白质从酪蛋白改为 SPI 或在饮食中补充与大豆中发现的水平相似的金雀异黄素将通过诱导可溶性 FRZ 蛋白抑制剂来阻断 EtOH 对 Wnt 信号传导的激活，从而阻止 EtOH 促进肿瘤发生。为此，我们将 1) 在我们的肿瘤促进小鼠模型中检查 SPI/金雀异黄素与 EtOH 共同给药相对于 EtOH 单独治疗减少肿瘤/小鼠数量的能力； 2) 使用小鼠报告系统 (TOP-GAL) 和来自 HCC 患者的存档样本来确认 EtOH 诱导 b-catenin 并与肝细胞中的增殖标记物共定位； 3) 通过使用靶向微阵列、蛋白质印迹、免疫组织化学和免疫沉淀分析基因表达，确定 DEN/EtOH 诱导 b-连环蛋白以及与饮食金雀异黄素/SPI 相互作用的分子机制。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice.

大豆分离蛋白可防止二乙基亚硝胺治疗的雄性小鼠中乙醇介导的肿瘤进展。

DOI：
发表时间：
2016-06
期刊：
影响因子：
0
作者：
Mercer, Kelly E;Pulliam, Casey;Hennings, Leah;Lai, Keith;Cleves, Mario;Jones, Ellen;Drake, Richard R;Ronis, Martin
通讯作者：
Ronis, Martin

Soy protein isolate inhibits hepatic tumor promotion in mice fed a high-fat liquid diet.

大豆分离蛋白可抑制高脂流质饮食小鼠的肝肿瘤生长。