A mouse model for p120 downregulation in cancer

癌症 p120 下调的小鼠模型

基本信息

批准号：
7417899
负责人：
ALBERT B REYNOLDS
金额：
$ 28.74万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7417899
关键词：
A Mouse Address Animal Model Animals Azoxymethane Biological Breast Cadherins Cancer Model Cell-Cell Adhesion Colon Colon Carcinoma Colonic Neoplasms Complex Condition Cultured Cells Data Development Disease Down-Regulation E-Cadherin Embryo Epigenetic Process Event Figs - dietary Gastrointestinal tract structure Genetic Genetic Models Genus Cola Human In Vitro Inflammatory Bowel Diseases Knock-out Knockout Mice Lead Literature Lung Malignant Neoplasms Mammary gland Mediating Modeling Molecular Mus Mutation Neoplasm Metastasis Pathology Phenocopy Phenotype Prostate Psoriasis Role Skin Small Interfering RNA Specificity Study models Syndrome Testing Time Tissues Transgenes Transgenic Mice Wild Type Mouse Work adenoma base chemical carcinogen clinically relevant gastrointestinal in vivo interest intestinal epithelium mouse model novel novel strategies research study tumor tumor progression villin

项目摘要

DESCRIPTION (provided by applicant): E-cadherin downregulation in cancer occurs frequently and is clearly a pivotal event in the transition to metastasis. Interestingly, recent studies of nearly all of the major human tumor types also reveal frequent downregulation of p120, but the mechanism and consequences of p120 downregulation are unknown. Moreover, p120 downregulation in tumors has been largely ignored because until recently there was no compelling reason to focus on the issue. This proposal is based primarily on three key observations, two of which are included as preliminary data. First, p120 is required for E-cadherin stability. Second, p120 expression is frequently downregulated or regionally absent in a significant subset of the most common human cancers (eg, colon, prostate, lung, breast, and others). Third, DN-cadherins strongly promote tumor progression and/or metastasis in animal models, and probably act via sequestering p120. The data provides compelling evidence that p120 downregulation might contribute to E-cadherin downregulation in a subset of human tumors. We have constructed a conditional p120 knockout (KO) mouse (conventional p120-KO is embryonic lethal), providing the first opportunity to examine p120 function in vivo, and the consequence(s) of p120 downregulation in disease and/or cancer. The mouse intestinal epithelium is an excellent model for studying normal p120 function, and the Min (APC mutation) and Azoxymethane (AOM) mouse models for colon cancer are ideally suited for studying p120 downregulation in cancer. However, disease and tumor modifiers also can have distinct tissue specificities that are essentially unpredictable. To address these issues, (1) We will determine the consequences or p120-loss under otherwise normal conditions using a villin-CreER transgene to control the timing and extent of p120 KO in the gastrointestinal (Gl)-tract. (2) We will directly identify the consequences of p120 downregulation in colon cancer by targeting p120-loss to the Gl-tract in the context of Min and AOM mouse cancer models. (3) We will generate a stochastic p120-deleter mouse model to induce accelerated LOH and address at the whole animal level the hypothesis that p120 is a critical disease and/or tumor modifier in susceptible tissues. Together, these experiments directly address the consequences of p120 downregulation in disease and cancer, and may lead to increased understanding of events mediating the transition to metastasis.

描述（由申请人提供）：E-钙粘蛋白下调在癌症中经常发生，并且显然是向转移转变的关键事件。有趣的是，最近对几乎所有主要人类肿瘤类型的研究也揭示了 p120 的频繁下调，但 p120 下调的机制和后果尚不清楚。此外，肿瘤中 p120 的下调在很大程度上被忽视，因为直到最近还没有令人信服的理由来关注这个问题。该提案主要基于三个关键观察结果，其中两个作为初步数据。首先，p120 是 E-钙粘蛋白稳定性所必需的。其次，在最常见的人类癌症（例如结肠癌、前列腺癌、肺癌、乳腺癌等）的一个重要亚类中，p120 表达经常下调或局部缺失。第三，DN-钙粘蛋白在动物模型中强烈促进肿瘤进展和/或转移，并且可能通过隔离 p120 发挥作用。这些数据提供了令人信服的证据，表明 p120 下调可能导致人类肿瘤子集中 E-钙粘蛋白下调。我们构建了条件性 p120 敲除 (KO) 小鼠（传统的 p120-KO 是胚胎致死的），为检查 p120 体内功能以及 p120 下调在疾病和/或癌症中的后果提供了第一个机会。小鼠肠上皮是研究正常 p120 功能的绝佳模型，而结肠癌 Min（APC 突变）和氧化偶氮甲烷 (AOM) 小鼠模型非常适合研究癌症中 p120 的下调。然而，疾病和肿瘤调节剂也可能具有本质上不可预测的独特组织特异性。为了解决这些问题，(1)我们将使用villin-CreER转基因来控制胃肠道(GI)道中p120 KO的时间和程度，以确定在其他正常条件下p120损失的后果。 (2) 我们将通过在 Min 和 AOM 小鼠癌症模型中针对胃肠道的 p120 缺失来直接确定 p120 下调在结肠癌中的后果。 (3) 我们将生成随机 p120 删除小鼠模型，以诱导加速 LOH，并在整个动物水平上解决 p120 是易感组织中的关键疾病和/或肿瘤调节剂的假设。总之，这些实验直接解决了 p120 下调在疾病和癌症中的后果，并可能导致加深对介导转移转变的事件的了解。