IGF Signalling, Apoptosis and Adenoma Risk

IGF 信号传导、细胞凋亡和腺瘤风险

• 批准号: 7126531
• 负责人: PAULINE K LUND
• 金额: $ 7.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126531
• 关键词: adenoma; apoptosis; binding proteins; biomarker; cancer risk; clinical research; colorectal neoplasms; genetic polymorphism; genetic susceptibility; genotype; human tissue; insulin; insulin receptor; insulinlike growth factor; loss of heterozygosity; polymerase chain reaction; preneoplastic state

DESCRIPTION (provided by applicant): Defining mediators and mechanisms which favor the early stages of the colon cancer such as formation of adenoma, is integral to improved surveillance and prevention of colon cancer. Our recent studies demonstrate strong correlations between reduced apoptosis in the normal intestinal mucosa and risk of precancerous adenomatous lesions in humans. Preliminary and published evidence indicates elevated plasma insulin and increased levels or bioavailability of circulating or locally expressed insulin-like growth factors (IGF-I or IGF-II) as significant risk factors for reduced apoptosis and adenoma in the colon. Common mediators of insulin and IGF action on apoptosis or adenoma growth may represent particularly powerful biomarkers of adenoma risk. Insulin receptor substrate 1 (IRS-I) is a common mediator of the anti-apoptotic actions of IGF-I, IGF-II and insulin. Preliminary data in mouse models demonstrate that IRS-1 is required for anti-apoptotic actions of IGF-I in the normal intestine in vivo and that loss of just 1 copy of the IRS-1 gene increases apoptosis and reduces adenoma formation in the APC/Min-+model of intestinal polyposis. Recent studies link polymorphisms in the human IRS-1 gene to colon cancer risk. Together, this data supports our central hypothesis that levels of expressed IRS-1 in normal human colonic mucosa predict the levels of apoptosis and adenoma risk by mediating the anti-apoptotic actions of insulin and the IGFs. Our studies will use existing samples from a large case-control study of colorectal adenomas to test our hypothesis. Data on apoptosis, plasma insulin, IGFs and plasma or colonic levels of insulin-like growth factor binding proteins (IGFBPs) have already been collected in this same study population. Aim 1: will test the hypothesis that a Gly972Arg polymorphisms in the IRS-I gene, and/or levels of expressed IRS-1 mRNA in the normal colonic mucosa predict adenoma risk and levels of apoptosis. Genotyping will be performed by PCR based allelic discrimination and IRS-1 mRNA will be measured by real time PCR. Primary analyses will test for associations between IRS-1 genotype or expression levels and adenoma or apoptosis. Secondary analysis, we will test if there are interactions between IRS-1 genotype or IRS-1 expression with insulin/IGFs or IGFBPs in predicting apoptosis and adenoma risk. Aim 2 will test the hypothesis that loss of imprinting (LOI) for the IGF-II gene increases local IGF-II expression in colon and increases risk of adenoma or low apoptosis. Subjects heterozygous for 820G/A and 266C/T polymorphisms in the IGF-II gene will be identified. Allelic and total expression levels for IGF-II will be assessed by real time PCR. LOI for IGF-II and IGF-II expression will be tested for associations with adenoma or apoptosis and for interactions with IRS-1 genotype or expression levels in predicting adenoma risk or apoptosis.

描述（由申请人提供）：定义有利于结肠癌早期阶段（例如腺瘤形成）的介质和机制对于改善结肠癌的监测和预防是不可或缺的。我们最近的研究表明，正常肠粘膜细胞凋亡减少与人类癌前腺瘤病变的风险之间存在密切相关。初步和已发表的证据表明血浆胰岛素升高以及循环或局部表达的胰岛素样生长因子（IGF-I或IGF-II）水平或生物利用度增加是结肠细胞凋亡和腺瘤减少的重要危险因素。胰岛素和 IGF 对细胞凋亡或腺瘤生长作用的常见介质可能代表了腺瘤风险的特别强大的生物标志物。胰岛素受体底物 1 (IRS-I) 是 IGF-I、IGF-II 和胰岛素抗凋亡作用的常见介质。小鼠模型中的初步数据表明，IRS-1是体内正常肠道中IGF-I的抗凋亡作用所必需的，并且在肠息肉病的APC/Min-+模型中，仅丢失1个IRS-1基因拷贝就会增加细胞凋亡并减少腺瘤形成。最近的研究将人类 IRS-1 基因的多态性与结肠癌风险联系起来。总之，这些数据支持我们的中心假设，即正常人结肠粘膜中 IRS-1 的表达水平通过介导胰岛素和 IGF 的抗凋亡作用来预测细胞凋亡水平和腺瘤风险。我们的研究将使用来自结直肠腺瘤大型病例对照研究的现有样本来检验我们的假设。已经在同一研究人群中收集了有关细胞凋亡、血浆胰岛素、IGF 以及血浆或结肠胰岛素样生长因子结合蛋白 (IGFBP) 水平的数据。目标 1：将检验以下假设：IRS-I 基因中的 Gly972Arg 多态性和/或正常结肠粘膜中表达的 IRS-1 mRNA 水平可预测腺瘤风险和细胞凋亡水平。基因分型将通过基于 PCR 的等位基因区分进行，IRS-1 mRNA 将通过实时 PCR 进行测量。初步分析将测试 IRS-1 基因型或表达水平与腺瘤或细胞凋亡之间的关联。二次分析，我们将测试 IRS-1 基因型或 IRS-1 表达与胰岛素/IGF 或 IGFBP 之间是否存在相互作用，以预测细胞凋亡和腺瘤风险。目标 2 将检验以下假设：IGF-II 基因印记丢失 (LOI) 会增加结肠中局部 IGF-II 的表达，并增加腺瘤或低细胞凋亡的风险。将鉴定 IGF-II 基因中 820G/A 和 266C/T 多态性杂合的受试者。 IGF-II 的等位基因和总表达水平将通过实时 PCR 进行评估。将测试 IGF-II 和 IGF-II 表达的 LOI 与腺瘤或细胞凋亡的关联，以及与 IRS-1 基因型或表达水平的相互作用，以预测腺瘤风险或细胞凋亡。