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）：在定义胃肠癌发病机制中的关键突变和基因表达变化方面已经取得了很大进展。在结直肠癌中，腺瘤性息肉病大肠杆菌 (APC)、K-RAS 和 p53 基因的突变具有决定性作用，而其他癌基因和抑癌基因的缺陷则以更加可变的方式导致癌症的发生和进展。在人类和/或小鼠中发现易导致肿瘤发生的特定种系（体质）缺陷，为强调和阐明与散发性肿瘤发生有关的基因和机制提供了可能性。例如，尾部相关的 Cdx2 同源框转录因子基因失活的杂合小鼠会形成结肠息肉，其中上皮细胞失去 CDX2 表达，这与 CDX2 的潜在肿瘤抑制功能一致，并且 CDX2 表达的丧失可见于一些低分化细胞中。男性结肠癌。相反，转基因小鼠胃上皮中的异位CDX2表达促进肠化生，而在人类中，CDX2表达常见于胃中产生的肠化生以及胃癌。因此，我们的主要假设是 CDX2 蛋白作为胃肠上皮细胞增殖和分化的关键调节因子，其功能缺陷，要么是结肠上皮细胞功能丧失，要么是胃上皮细胞功能获得。可促进肿瘤转化。为了更好地了解 CDX2 缺陷对胃肠道肿瘤发病机制的贡献，我们建议追求以下具体目标。在具体目标 1 中，我们将定义由 CDX2 直接调节的特定细胞基因。在具体目标 2 中，我们将评估选定的 CDX2 调节基因在胃肠道癌细胞增殖、分化和致瘤性生长中的作用。在具体目标 3 中，我们将使用小鼠癌症模型探讨 Cdx2 和有限数量的高度关注的 CDX2 调节基因在结肠肿瘤发病机制中的作用。除了增进对胃肠癌发病机制的了解外，这些结果还可能为改善结直肠癌和其他癌症患者的诊断和治疗的新策略提供见解。