Inactivation of the Muc2 gene and colorectal cancer

Muc2 基因失活与结直肠癌

• 批准号: 6323750
• 负责人: ANNA VELCICH
• 金额: $ 23.74万
• 依托单位: MONTEFIORE MEDICAL CENTER (BRONX, NY)
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6323750
• 关键词: apoptosis; cadherins; carcinogenesis; cell proliferation; colorectal neoplasms; gene mutation; gene targeting; genetically modified animals; goblet cells; growth factor; intestinal villi; laboratory mouse; mucins; neoplasm /cancer genetics; neoplastic process; protooncogene; wound healing

DESCRIPTION (provided by applicant): This proposal capitalizes on our development of a mouse model in which we have targeted the Muc2 gene which encodes the major colonic mucin, forinactivation. The Muc2-/- mice, which are viable and fertile, do not develop recognizable goblet cells, and the histopathology of the intestinal mucosa is distorted. By six months of age the Muc2-/-animals develop dysplasia and carcinoma in the gastrointestinal tract, including the rectum, a site at which tumors do not form in mice with Apc mutations. This is of particular importance since there exists no other rodent model of human rectal cancer, a major site of cancer that is clinically and biologically distinct from colon cancer. The development of the Muc2-/- mouse is the next step of our extensive work on the structural and functional analysis of the human and mouse MUC2 genes and on the observation that there is loss of mucin production in human, and chemically induced rodent aberrant crypt foci (ACF), early morphological lesions in the development of colon tumors, which are characterized by under-representation of goblet cells. Most important, the development of ACF precedes tumor formation in the Apc 1638 mouse, which carries a genetically inactivated Apc allele. Thus, tumor development in the Muc2-/- mouse strongly supports the hypothesis that loss of mucin production and the goblet cell phenotype is a sufficient, and perhaps a necessary early step for intestinal tumor formation and may specifically lead to rectal cancer. In this application, we will: 1) characterize the molecular biology and phenotype of the Muc2-/- mouse by determining the mechanisms contributing to the disruption of intestinal cell maturation in the Muc2-/- mouse, and whether compensatory mechanisms take place regarding levels and location of the expression of other mucin genes and intestinal trefoil factor (ITF), specifically expressed in goblet cells. 2) determine whether and how the genetic lesion in the Muc2 gene is related to the Apc pathway of tumor formation by investigating whether mutations in Apc, or alterations of the Apc pathway, are obligatory in tumor development, or whether mutations in alternative pathways (i.e. cdx2) are involved in tumor formation in the Muc2-/- mouse. 3) by utilizing mouse models already available (Apcl 638 and ITF-/- animals), we will directly test whether there is interaction between loss of Muc2 and mutation in Apc, and the role that absence of the major products of goblet cells (Muc2 and ITF) has in tumor development.

描述(由申请人提供)：这项建议充分利用了我们的 以Muc2基因为靶点的小鼠模型的建立 编码主要的结肠粘蛋白。Muc2-/-小鼠，它们是 活的和有生育能力的，不会形成可识别的杯状细胞，并且 肠粘膜的组织病理学改变。到了六个月大的时候 MUC2-/-动物在胃肠道出现不典型增生和癌症， 包括直肠，在患有APC的小鼠中，直肠是肿瘤不形成的部位 突变。这一点特别重要，因为没有其他啮齿动物 人类直肠癌的模型，是临床和临床上的主要癌症部位 在生物学上与结肠癌截然不同。 MUC2-/-鼠标的开发是我们广泛工作的下一步 人和小鼠MUC2基因的结构和功能分析 观察到人类粘蛋白产生的损失，以及化学上的 诱发鼠类迷走性隐窝病灶(ACF)，早期形态损害 结肠肿瘤的发展，其特征是表达不足 杯状细胞。最重要的是，ACF的发展先于肿瘤的形成 在携带基因失活的APC等位基因的APC 1638小鼠中。 因此，Muc2-/-小鼠体内的肿瘤发展强烈支持这一假说。 粘蛋白的产生和杯状细胞表型的丧失是足够的， 可能是肠道肿瘤形成的必要早期步骤，并可能 特别是会导致直肠癌。 在这个应用中，我们将：1)表征分子生物学和 Muc2-/-小鼠表型的研究 Muc2-/-小鼠肠道细胞成熟的破坏，以及 补偿机制发生在关于水平和位置 其他粘蛋白基因和肠道三叶因子(ITF)的表达， 在杯状细胞中特异表达。2)确定是否以及如何 Muc2基因的遗传损伤与肿瘤的APC途径有关 通过研究APC的突变或APC的改变来形成 途径，在肿瘤的发展中是必需的，或者 不同途径(如cdx2)参与Muc2-/-中肿瘤的形成 老鼠。3)利用已有的鼠标型号(APCL 638和ITF-/- 动物)，我们将直接测试损失之间是否存在交互作用 MUC2和APC中的突变，以及缺少主要产物的作用 杯状细胞(Muc2和ITF)参与肿瘤的发生发展。