A mouse model for p120 downregulation in cancer

癌症 p120 下调的小鼠模型

• 批准号: 7619037
• 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
• 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/7619037
• 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

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-钙粘素下调在癌症中经常发生，显然是转移到转移过程中的关键事件。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，p120在肿瘤中的下调在很大程度上被忽视了，因为直到最近，还没有令人信服的理由来关注这个问题。该提案主要基于三项关键意见，其中两项作为初步数据包括在内。首先，p120是E-钙粘附素稳定所必需的。其次，在人类最常见的癌症(如结肠癌、前列腺癌、肺癌、乳腺癌和其他癌症)中，p120的表达经常下调或区域性缺失。第三，在动物模型中，dN-钙粘附素强烈促进肿瘤进展和/或转移，并可能通过隔离p120起作用。这些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中E-钙粘附素的下调。我们构建了一个有条件的p120基因敲除(KO)小鼠(传统的p120-KO是胚胎致死的)，这为研究p120在体内的功能以及p120下调在疾病和/或癌症中的后果(S)提供了第一个机会。小鼠肠上皮细胞是研究正常p120功能的极佳模型，而Min(APC突变)和偶氮甲烷(AOM)小鼠结肠癌模型是研究癌症中p120下调的理想模型。然而，疾病和肿瘤修饰物也可能具有本质上不可预测的不同组织特异性。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(Gl)中p120 KO的时间和范围，以确定在其他正常条件下p120-KO的后果或丢失。(2)我们将在Min和AOM小鼠肿瘤模型的背景下，通过靶向Gl-道来直接确定p120下调在结肠癌中的后果。(3)我们将建立一个随机的p120缺失的小鼠模型，以诱导加速LOH，并在整个动物水平上解决p120在易感组织中是关键疾病和/或肿瘤修饰物的假设。总之，这些实验直接解决了p120下调在疾病和癌症中的后果，并可能导致对介导向转移的转变的事件的更多了解。