Mechanisms of CDX2 regulation of the IGF axis

CDX2调节IGF轴的机制

• 批准号: 7688927
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688927
• 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 PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE. Colorectal cancer is the second leading cause of cancer deaths in the United States, and is one of the top ten prevalent and high-risk diseases among American veteran patients. The CDX2 protein regulates intestinal development and maintenance, and is strongly expressed in up to 90% of colorectal adenomas and carcinomas. As such, studying how CDX2 functions would provide insights into the development and progression of colonic neoplasms. This proposal advances on the concept that CDX2 regulates the IGF axis, depending on cellular p53 status. This line of investigation provides the first insights into how CDX2 can function as both a cell growth promoter and suppressor. This approach would hopefully lead to novel clinical strategies for colon cancer prevention and therapy.

描述（由申请人提供）： CDX 2是果蝇尾相关的同源盒转录因子，对肠上皮细胞的建立和维持很重要。CDX 2表达异常与胃肠道化生、白血病和各种实体瘤有关，包括高达90%的结肠腺瘤和腺癌。在结肠中，CDX 2与肿瘤抑制和致癌特性相关。CDX 2可能以上下文依赖的方式发挥作用，但上下文如何影响CDX 2功能仍然知之甚少。 胰岛素样生长因子（IGF）信号通路在细胞增殖和存活中起着核心作用。IGF活性被胰岛素样生长因子结合蛋白3（IGFBP 3）抑制，IGFBP 3是肿瘤抑制因子p53的充分描述的转录靶标。而野生型p53转录激活IGFBP 3表达;突变型p53没有。我们的初步数据显示，在一个含有野生型p53的结肠癌亚组中，CDX 2在转录上抑制IGFBP 3。这导致促进锚定非依赖性集落形成，并使细胞响应IGF。相比之下，在含有突变p53的结肠癌子集中，CDX 2诱导IGFBP 3和细胞凋亡，并减弱细胞对IGF的反应。 该提案的目标是阐明CDX 2在不同p53背景下调节IGFBP 3的机制;以及随后对IGF轴和生长的影响。我们假设在WT-p53的结肠癌中，CDX 2转录抑制IGFBP 3，促进锚定非依赖性集落形成，并使IGF信号传导成为可能。相反，在具有MUT-p53的结肠癌中，CDX 2具有相反的作用。具体目标1：确定CDX 2和p53调节IGFBP 3的机制。具体目的2：确定CDX 2和p53对IGF轴的影响。具体目的3：确定CDX 2和p53对肿瘤生长和对IGF轴抑制剂的反应的影响。1 公共卫生相关性： 项目叙述。 结直肠癌是美国癌症死亡的第二大原因，并且是美国退伍军人患者中的十大流行和高危疾病之一。CDX 2蛋白调节肠道发育和维持，并且在高达90%的结直肠腺瘤和癌中强烈表达。因此，研究CDX 2如何发挥作用将为结肠肿瘤的发展和进展提供见解。这一提议基于CDX 2调节IGF轴的概念，这取决于细胞p53状态。这一系列的研究首次揭示了CDX 2如何同时作为细胞生长促进剂和抑制剂发挥作用。这种方法有望为结肠癌的预防和治疗带来新的临床策略。