Mechanisms of CDX2 regulation of the IGF axis

描述(由申请人提供)： CDX2是一种与果蝇尾部相关的同源异型盒转录因子，对肠道上皮细胞的建立和维持具有重要作用。CDX2的异常表达与胃肠化生、白血病和各种实体肿瘤有关，包括高达90%的结肠腺瘤和腺癌。在结肠中，CDX2与肿瘤抑制和致癌特性有关。CDX2可能以一种上下文依赖的方式发挥作用，然而上下文如何影响CDX2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(IGFBP3)抑制，IGFBP3是肿瘤抑制基因P53的转录靶点。而野生型p53在转录上激活IGFBP3的表达，而突变型p53则不能。我们的初步数据显示，在携带野生型p53的结肠癌的子集中，CDX2转录抑制IGFBP3。这导致促进非锚定集落的形成，并使细胞对IGF产生反应。相反，在含有突变型p53的结肠癌中，CDX2诱导IGFBP3和细胞凋亡，并减弱细胞对IGF的反应。这项建议的目的是阐明CDX2在不同的P53环境中调节IGFBP3的机制；以及随后对IGF轴和生长的影响。我们假设，在携带WT-P53的结肠癌中，CDX2转录抑制IGFBP3，促进非锚定集落形成，并启动IGF信号转导。相反，在携带mut-p53的结肠癌中，CDX2具有相反的作用。提出了三个特定的目标来验证上述假说：特定的目标1：确定CDX2和P53调节IGFBP3的机制。特异性目的2：探讨CDX2和P53对胰岛素样生长因子轴的影响。具体目的3：探讨CDX2和P53对肿瘤生长的影响及对IGF轴抑制剂的反应。1

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