Prevention of APC-Dependent Intestinal Carcinogenesis

预防 APC 依赖性肠道癌发生

• 批准号: 7499523
• 负责人: EUGENE W GERNER
• 金额: $ 28.69万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499523
• 关键词: APC gene; Adenomatous Polyposis Coli; Affect; Alleles; Azoxymethane; Biochemical Pathway; Cancer Prevention Trial; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; Cultured Cells; DL-alpha-Difluoromethylornithine; Data; Deletion Mutation; Enzymes; Epithelial; Epithelium; Gene Targeting; Genes; Genetic; Genetic Transcription; Genus Cola; Goals; Human; Individual; Intervention; Intestines; Investigation; Knock-out; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methods; Mucous Membrane; Mus; Mutation; Numbers; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Phase; Polyamine Catabolism; Polyamines; Prevention; Prevention strategy; Preventive; Process; Proteins; Risk; 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; 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）： 大肠腺瘤性息肉病（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。肠和结肠粘膜中的多胺代谢也受到多胺催化剂的影响，多胺催化剂是由过氧化物酶体增殖物激活受体3（PPAR 3）调节的过程。这种蛋白质通过诱导亚精胺/精胺N1-乙酰转移酶（SSAT）的转录来影响多胺库，该酶编码启动多胺催化和输出的酶。在这个提议中要测试的假设是，APC和PPAR 3在肠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。这一假设的一个推论是，靶向多胺代谢中的选定步骤将是结肠癌高危个体预防结肠癌的有效手段。三个具体目标将检验这一假设。首先，我们将使用遗传学的方法有条件地敲除APC依赖基因c-Myc，和c-Myc的靶基因Odc，在肠道和结肠上皮组织中的小鼠模型，以确定这些基因在化学致癌物诱导的结肠癌发生中的作用。其次，我们将确定Ppar 3和Ppar 3靶基因Ssat在小鼠模型中的肠道和结肠肿瘤发生中的作用。我们将使用遗传学方法在肠道和结肠上皮中进行Ppar 3的条件性、组织特异性敲除，以评估该基因在氧化偶氮甲烷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。将使用等基因细胞培养和小鼠模型。这些研究的长期目标是为结肠癌和潜在的其他上皮癌开发有效的化学预防策略。组织多胺含量受特定的合成、分解代谢、吸收和外排机制的影响。我们发现与结肠癌发生相关的癌基因和抑癌基因影响其中的一些过程。我们将系统地评估通过影响多胺吸收和代谢的机制以及ODC抑制来激活或抑制肠道和结肠多胺库的药物，以确定其作为新型结肠癌化学预防剂的潜力。我们希望确定可以与现有有效性数据（例如，NSAIDS），或其目前正在临床癌症化学预防试验中进行研究（例如DFMO）。这项研究将使用基因修饰的人类细胞和小鼠模型，调查结肠癌发生过程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，以预防有患结肠癌风险的人患结肠癌。