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：
7913602
负责人：
ALBERT B REYNOLDS
金额：
$ 26.96万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7913602
关键词：
A Mouse Address Animal Model Animals Azoxymethane Biological Breast Cadherins Cancer Model Cell-Cell Adhesion Colon Colon Carcinoma Colonic Neoplasms Complex 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）：癌症中的E-钙粘蛋白下调经常发生，显然是转移过渡的关键事件。有趣的是，最近对所有主要人类肿瘤类型的最新研究也表明P120的下调经常下调，但是P120下调的机理和后果尚不清楚。此外，肿瘤中的P120下调在很大程度上被忽略了，因为直到最近才有令人信服的理由专注于这个问题。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包括在内。首先，E-钙粘蛋白稳定性需要P120。其次，在最常见的人类癌（例如，结肠，前列腺，肺，乳房等）中，P120表达经常被下调或区域性不存在。第三，DN-辅助蛋白在动物模型中强烈促进肿瘤的进展和/或转移，并且可能通过隔离P120起作用。该数据提供了令人信服的证据，表明P120下调可能有助于人类肿瘤子集中的E-钙粘蛋白下调。我们已经构建了有条件的P120敲除（KO）小鼠（常规P120-KO是胚胎致死的），这为在体内检查P120功能提供了第一个机会，以及疾病和/或癌症中P120下调的后果。小鼠肠上皮是研究正常P120功能的绝佳模型，最小值（APC突变）和偶氮甲烷（AOM）小鼠模型用于结肠癌，非常适合研究癌症中的P120下调。但是，疾病和肿瘤修饰剂也可以具有不同的组织特异性，这些特异性基本上是不可预测的。为了解决这些问题，（1）我们将使用Villin-Creer Transgene在正常情况下确定后果或P120损失，以控制胃肠道（GL）提取中P120 KO的时间和程度。（2）我们将通过在最小小鼠和AOM小鼠癌模型的背景下将p120损失靶向GL-trains的p120下调在结肠癌中的后果。（3）我们将生成一个随机的P120小鼠模型，以诱导加速的LOH并在整个动物层面上解决P120是易感组织中P120是一种关键疾病和/或肿瘤修饰剂的假设。这些实验共同解决了疾病和癌症中P120下调的后果，并可能导致人们对介导向转移过渡的事件的了解增加。