Mechanisms of CDX2 regulation of the IGF axis

CDX2调节IGF轴的机制

• 批准号: 8391147
• 负责人: DUYEN DANG
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391147
• 关键词: Adult; Affect; Age; American; Apoptosis; CDX2 gene; CDX2 protein; Cancer Etiology; Carcinoma; Cell Proliferation; Cessation of life; Clinical; Colitis; Colon; Colon Adenocarcinoma; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Disease; Drosophila genus; Epithelial Cells; Goals; Growth; Homeobox; Homeobox Genes; Immunoprecipitation; In Vitro; Individual; Insulin-Like Growth Factor Binding Protein 3; Intestinal Metaplasia; Intestines; Investigation; Knockout Mice; Large Intestine Carcinoma; Lead; Link; Maintenance; Malignant Neoplasms; Mucous Membrane; Mus; Mutation; Oncogenic; Patients; Play; Population; Premalignant; Property; Protein p53; Regulation; Role; Series; Signal Pathway; Signal Transduction; Solid Neoplasm; Somatomedins; Stomach; Testing; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Veterans; adenoma; cancer prevention; cancer therapy; cell growth; colon cancer cell line; high risk; in vivo; inhibitor/antagonist; insight; intestinal epithelium; leukemia; metaplastic cell transformation; mutant; novel; promoter; protein protein interaction; public health relevance; response; transcription factor; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): PROJECT SUMMARY CDX2 is a Drosophila caudal-related homeobox transcription factor that is important for the establishment and maintenance of intestinal epithelial cells. Aberrant CDX2 expression has been linked to gastric intestinal metaplasia, leukemia, and various solid tumors, including up to 90% of colonic adenomas and adenocarcinomas. In the colon, CDX2 has been associated with both tumor suppressor and oncogenic properties. CDX2 likely functions in a context-dependent manner, yet how context affects CDX2 function remains poorly understood. The insulin-like growth factor (IGF) signaling pathway plays a central role in cellular proliferation and survival. IGF activity is inhibited by the insulin-like growth factor binding protein 3 (IGFBP3), a well- described transcriptional target of the tumor suppressor p53. Whereas wild-type p53 transcriptionally activates IGFBP3 expression; mutant p53 does not. Our preliminary data show that in a subset of colon cancers that harbor wild-type p53, CDX2 transcriptionally represses IGFBP3. This leads to the promotion of anchorage-independent colony formation, and enables cellular response to IGF. In contrast, in a subset of colon cancers that harbor mutant p53, CDX2 induces IGFBP3 and apoptosis, and blunts cellular response to IGF. The goal of this proposal is to elucidate the mechanisms whereby CDX2 regulates IGFBP3 in different p53 contexts; and the ensuing consequences on the IGF axis and growth. We hypothesize that in colon cancers with WT-p53, CDX2 transcriptionally represses IGFBP3, promotes anchorage-independent colony formation, and enables IGF signaling. Conversely, in colon cancers with MUT-p53, CDX2 has the opposite effect. Three specific aims are proposed to test the above hypotheses: Specific Aim 1: To determine the mechanisms by which CDX2 and p53 regulate IGFBP3. Specific Aim 2: To determine the effects of CDX2 and p53 on the IGF axis. Specific Aim 3: To determine the effects of CDX2 and p53 on tumor growth and response to IGF axis inhibitors. 1

描述（由申请人提供）： 项目摘要 CDX2 是一种果蝇尾部相关同源盒转录因子，对于肠上皮细胞的建立和维持非常重要。 CDX2 表达异常与胃肠化生、白血病和各种实体瘤（包括高达 90% 的结肠腺瘤和腺癌）有关。在结肠中，CDX2 与肿瘤抑制和致癌特性相关。 CDX2 可能以依赖于环境的方式发挥作用，但环境如何影响 CDX2 功能仍知之甚少。 胰岛素样生长因子（IGF）信号通路在细胞增殖和存活中发挥着核心作用。 IGF 活性受到胰岛素样生长因子结合蛋白 3 (IGFBP3) 的抑制，IGFBP3 是肿瘤抑制因子 p53 的转录靶标。而野生型 p53 转录激活 IGFBP3 表达；突变体 p53 则不然。我们的初步数据显示，在含有野生型 p53 的结肠癌亚群中，CDX2 转录抑制 IGFBP3。这导致促进不依赖贴壁的集落形成，并使细胞能够对 IGF 做出反应。相比之下，在含有突变 p53 的结肠癌亚群中，CDX2 诱导 IGFBP3 和细胞凋亡，并减弱细胞对 IGF 的反应。 该提案的目标是阐明 CDX2 在不同 p53 环境中调节 IGFBP3 的机制；以及随之而来的对 IGF 轴和生长的影响。我们假设在带有 WT-p53 的结肠癌中，CDX2 转录抑制 IGFBP3，促进贴壁独立集落形成，并启用 IGF 信号传导。相反，在具有 MUT-p53 的结肠癌中，CDX2 具有相反的作用。提出了三个具体目标来检验上述假设： 具体目标 1：确定 CDX2 和 p53 调节 IGFBP3 的机制。具体目标 2：确定 CDX2 和 p53 对 IGF 轴的影响。具体目标 3：确定 CDX2 和 p53 对肿瘤生长和对 IGF 轴抑制剂反应的影响。 1