CDX2 Tumor Suppressor Pathway Defects in Colon Cancer

结肠癌中的 CDX2 肿瘤抑制通路缺陷

• 批准号: 7225518
• 负责人: Eric R. Fearon
• 金额: $ 28.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225518
• 关键词: APC gene; Accounting; Adenomatous Polyposis Coli; Adult; CDX2 gene; CDX2 protein; Cadherins; Cancer Etiology; Cancer Model; Cancer cell line; Candidate Disease Gene; Carcinogens; Carcinoma; Cells; Cessation of life; Characteristics; Colon; Colon Adenocarcinoma; Colon Carcinoma; Colon, Rectum; Colonic Neoplasms; Colonic Polyps; Colorectal; Colorectal Cancer; Constitutional; DNA; Data; Defect; Development; Diagnosis; Disruption; Doctor of Medicine; Doctor of Philosophy; Drosophila genus; E-Cadherin; Epithelial; Epithelial Cells; Epithelium; Esophagus; Estrogen Receptors; Family; Gastrointestinal Neoplasms; Gastrointestinal tract structure; Gene Expression; Gene Silencing; Genes; Genus Cola; Growth; Hamartoma; Hereditary Nonpolyposis Colorectal Neoplasms; Homeobox; Homeobox Genes; Homologous Gene; Human; Intestinal Metaplasia; Intestines; Knowledge; Lesion; Ligands; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Metaplastic; Methods; Mismatch Repair; Morbidity - disease rate; Morphogenesis; Mus; Mutation; Names; Neoplasms; Neoplastic Cell Transformation; Normal tissue morphology; Numbers; Oligonucleotide Microarrays; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; Plant Roots; Play; Polyps; Property; Proto-Oncogenes; RNA Interference; Reagent; Regulatory Element; Research; Role; Small Intestines; Squamous Differentiation; Stomach; Stomach Carcinoma; Structure; TP53 gene; Tissues; Transcription factor genes; Transgenes; Transgenic Mice; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; adenoma; base; cancer cell; chromatin immunoprecipitation; gain of function; gastrointestinal; genetic analysis; human CDX2 protein; improved; insight; interest; loss of function; malignant stomach neoplasm; man; mortality; neoplastic; novel; novel strategies; programs; protein function; recombinase; transcription factor; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Much progress has been made in defining critical mutations and gene expression changes in gastrointestinal cancer pathogenesis. In colorectal cancer, mutations in the adenomatous polyposis coli (APC), K-RAS, and p53 genes have decisive roles, and defects in other oncogenes and tumor suppressor genes contribute in a more variable fashion to cancer development and progression. The discovery of specific germline (constitutional) defects predisposing to tumor development in man and/or the mouse offers the possibility of highlighting and clarifying genes and mechanisms involved in sporadic tumor development. For instance, mice heterozygous for inactivation of the caudal-related Cdx2 homeobox transcription factor gene develop colonic polyps in which the epithelial cells lose CDX2 expression, consistent with a potential tumor suppressor function for CDX2, and loss of CDX2 expression is seen in some poorly differentiated colon carcinomas in man. Conversely, ectopic CDX2 expression in gastric epithelium of transgenic mice promotes intestinal metaplasia, and, in man, CDX2 expression is often seen in intestinal metaplasia arising in the stomach as well as gastric carcinomas. Hence, our primary hypothesis is that the CDX2 protein functions as a critical regulator of proliferation and differentiation in gastrointestinal epithelial cells and defects in its function, either loss-of-function in colonic epithelial cells or gain-of-function in gastric epithelial cells, can promote neoplastic transformation. To better understand the contribution of CDX2 defects to the pathogenesis of gastrointestinal tumors, we propose to pursue the following specific aims. In Specific Aim 1, we will define specific cellular genes that are directly regulated by CDX2. In Specific Aim 2, we will assess the role of selected CDX2-regulated genes in proliferation, differentiation, and tumorigenic growth of gastrointestinal cancer cells. In Specific Aim 3, we will explore the role of Cdx2 and a limited number of high interest CDX2-regulated genes in the pathogenesis of colon tumors, using mouse cancer models. In addition to advancing knowledge of gastrointestinal cancer pathogenesis, the results may offer insights into novel strategies for improving the diagnosis and treatment of patients with colorectal and other cancers.

描述（由申请人提供）：在定义胃肠道癌发病机理的关键突变和基因表达变化方面取得了很多进展。在结直肠癌中，腺瘤性息肉病（APC），K-RAS和p53基因的突变具有决定性的作用，并且其他癌基因和肿瘤抑制基因的缺陷以更可变的方式促进了癌症发育和进展。发现人和/或小鼠肿瘤发育的特定种系（宪法）缺陷提供了突出显示和阐明偶然肿瘤发育涉及的基因和机制的可能性。例如，小鼠杂合子因尾部相关的CDX2同源蛋白蛋白蛋白蛋白蛋白转录因子基因基因而产生结肠息肉，其中上皮细胞损失CDX2的表达，与CDX2的潜在抑制肿瘤抑制作用一致，并且在某些不良分化的结肠癌中，CDX2表达的损失在男性中被发现。相反，转基因小鼠的胃皮细胞中异位CDX2表达促进肠道上的化生，并且在人体中，CDX2表达在胃中以及胃癌产生的肠道上流化症中经常可见。因此，我们的主要假设是CDX2蛋白是胃肠道上皮细胞增殖和分化的关键调节剂，以及其功能中缺陷，即在结肠上皮细胞中的功能丧失或胃皮细胞功能的功能丧失，可以促进肿瘤转化。为了更好地了解CDX2缺陷对胃肠道肿瘤发病机理的贡献，我们建议追求以下特定目的。在特定目标1中，我们将定义由CDX2直接调节的特定细胞基因。在特定的目标2中，我们将评估所选CDX2调节基因在胃肠道癌细胞增殖，分化和致肿瘤生长中的作用。在特定目标3中，我们将使用小鼠癌模型探讨CDX2和有限数量的高兴趣CDX2调节基因在结肠肿瘤的发病机理中的作用。除了促进胃肠道癌发病机理的知识外，该结果还可以为改善结直肠癌和其他癌症患者的诊断和治疗的新型策略提供见解。