Prevention of APC-Dependent Intestinal Carcinogenesis

预防 APC 依赖性肠道癌发生

• 批准号: 8116655
• 负责人: EUGENE W GERNER
• 金额: $ 27.83万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116655
• 关键词: APC gene; Adenomatous Polyposis Coli; Affect; Alleles; Azoxymethane; Biochemical Pathway; Cancer Prevention Trial; Cell Culture Techniques; Cell model; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; DL-alpha-Difluoromethylornithine; Data; Deletion Mutation; Enzymes; Epithelial; Epithelium; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Human; Individual; Intervention; Intestines; Investigation; Knock-out; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methods; Mucous Membrane; Mus; Mutation; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Phase; Polyamine Catabolism; Polyamines; Prevention; Prevention strategy; Preventive; Process; Proteins; Role; Signal Transduction; Spermidine/Spermine N1-Acetyltransferase; Testing; Tissues; Tumor Suppressor Genes; Work; c-myc Genes; cancer chemoprevention; cancer prevention; carcinogenesis; chemical carcinogen; colon carcinogenesis; disorder risk; high risk; innovation; mouse model; novel; receptor; tumorigenesis; uptake

DESCRIPTION (provided by applicant): Mutations/deletions in the adenomatous polyposis coli (APC) gene occur in the majority of sporadic colon cancers. One mechanism by which APC mutations promote tumorigenesis is to increase transcription of ornithine decarboxylase (ODC), via a c-MYC dependent process, and polyamine synthesis. Polyamine metabolism in the intestinal and colonic mucosa is also affected by polyamine catabolism, a process regulated by the peroxisomal proliferator activated receptor 3 (PPAR3). This protein affects polyamines pools by inducing the transcription of the spermidine/spermine N1- acetyltransferase (SSAT), which encodes an enzyme initiating polyamine catabolism and export. The hypothesis to be tested in this proposal is that the APC and PPAR3 roles in intestinal and colon carcinogenesis are mediated by tissue-specific mechanisms involving polyamine metabolic genes. A corollary to this hypothesis is that targeting selected steps in polyamine metabolism will be effective means of colon cancer prevention in individuals with high risk of colon cancer. Three specific aims will test this hypothesis. First, we will use genetic methods to conditionally knockout the Apc-dependent gene c-Myc, and the c-Myc target gene Odc, in intestinal and colonic epithelial tissues in mouse models in order to determine the roles of these genes in chemical carcinogen-induced colon carcinogenesis. Second, we will determine the roles of Ppar3 and the Ppar3 target gene Ssat in intestinal and colonic tumorigenesis in mouse models. We will use genetic methods for conditional, tissue-specific knockout of Ppar3 in intestinal and colonic epithelia, in order to evaluate the role of this gene in colon carcinogenesis in azoxymethane-treated mouse models. Finally, we will evaluate novel agents that influence features of polyamine metabolism alone and in combination, as possible innovative strategies for colon cancer chemoprevention. Isogenic cell culture and mouse models will be used. The long-term goal of these studies is to develop effective chemoprevention strategies for colon, and potentially other epithelial, cancers. Tissue polyamine contents are influenced by specific synthetic, catabolic, uptake and efflux mechanisms. We have found that oncogenes and tumor suppressor genes relevant to colon carcinogenesis influence some of these processes. We will systematically evaluate agents that activate or suppress intestinal and colonic polyamine pools by mechanisms affecting polyamine uptake and metabolism, in addition to ODC inhibition, for their potential as novel colon cancer chemopreventive agents. We hope to identify interventions that can be used in combination with current strategies for which efficacy data exists (e.g., NSAIDS), or which are under current investigation in clinical cancer chemoprevention trials (e.g. DFMO). The studies proposed will investigate specific biochemical pathways involved in colon carcinogenesis, using genetically modified human cell and mouse models. The long-term goal of this work is to develop safe and effective strategies for the prevention of colon cancer in people at risk for this disease.

描述（由申请人提供）： 腺瘤性结肠息肉病 (APC) 基因的突变/缺失发生在大多数散发性结肠癌中。 APC 突变促进肿瘤发生的一种机制是通过 c-MYC 依赖性过程和多胺合成增加鸟氨酸脱羧酶 (ODC) 的转录。肠道和结肠粘膜中的多胺代谢也受到多胺分解代谢的影响，该过程受过氧化物酶体增殖物激活受体 3 (PPAR3) 调节。这种蛋白质通过诱导亚精胺/精胺 N1-乙酰转移酶 (SSAT) 的转录来影响多胺池，该酶编码一种启动多胺分解代谢和输出的酶。本提案要测试的假设是，APC 和 PPAR3 在肠道和结肠癌发生中的作用是由涉及多胺代谢基因的组织特异性机制介导的。这一假设的推论是，针对多胺代谢中的选定步骤将是预防结肠癌高风险个体结肠癌的有效手段。三个具体目标将检验这一假设。首先，我们将利用遗传学方法，条件性敲除小鼠模型肠和结肠上皮组织中的Apc依赖基因c-Myc和c-Myc靶基因Odc，以确定这些基因在化学致癌物中的作用——诱发结肠癌。其次，我们将确定 Ppar3 和 Ppar3 靶基因 Ssat 在小鼠模型肠道和结肠肿瘤发生中的作用。我们将使用遗传方法在肠和结肠上皮细胞中条件性、组织特异性敲除 Ppar3，以评估该基因在氧化偶氮处理的小鼠模型中结肠癌发生中的作用。最后，我们将评估单独和联合影响多胺代谢特征的新药物，作为结肠癌化学预防的可能创新策略。将使用同基因细胞培养和小鼠模型。这些研究的长期目标是开发针对结肠癌和其他潜在上皮癌的有效化学预防策略。组织多胺含量受特定合成、分解代谢、摄取和流出机制的影响。我们发现与结肠癌发生相关的癌基因和肿瘤抑制基因影响其中一些过程。除了 ODC 抑制之外，我们还将系统地评估通过影响多胺摄取和代谢的机制激活或抑制肠道和结肠多胺池的药物作为新型结肠癌化学预防药物的潜力。我们希望找到可以与现有策略（例如 NSAIDS）或目前正在临床癌症化学预防试验中进行研究的策略（例如 DFMO）结合使用的干预措施。拟议的研究将利用转基因人类细胞和小鼠模型来研究结肠癌发生中涉及的特定生化途径。这项工作的长期目标是制定安全有效的策略来预防结肠癌高危人群。