Regulation of p120-catenin tumor supressor activities

p120-连环蛋白肿瘤抑制活性的调节

基本信息

批准号：
8539286
负责人：
DOUGLAS B STAIRS
金额：
$ 22.48万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8539286
关键词：
Ablation Adherens Junction Binding Biological Biological Models CDKN2A gene Cancer Biology Cell Culture Techniques Cell Line Cells Cyclin D1 Cytoplasm Development Diagnosis Disease E-Cadherin Epidermal Growth Factor Receptor Epithelial Cells Esophageal Esophageal Adenocarcinoma Esophageal Neoplasms Esophageal Squamous Cell Esophagus Frequencies Genes Genetic Genetically Engineered Mouse Histocompatibility Testing Human Immune In Vitro Inflammation Intestines Lead Limited Stage Malignant Neoplasms Malignant Squamous Cell Neoplasm Malignant neoplasm of esophagus Mentors Metaplastic Metastatic Lesion Modality Molecular Mutation Neoplasm Metastasis Oncogenes Pathogenesis Pathway interactions Phenotype Proteins Regulation Research Role Squamous Epithelium Staging Survival Rate Therapeutic Intervention Tissues Translating Tumor Suppressor Genes United States base beta catenin catenin p120ctn protein cell motility combinatorial in vivo insight keratinocyte male metaplastic cell transformation mouse model novel novel diagnostics novel therapeutics outcome forecast overexpression rho therapeutic target transdifferentiation tumor tumor initiation tumor progression tumorigenesis

项目摘要

Project summary Esophageal cancer represents the 5th most frequent cancer in males worldwide. Given the poor survival rate, advanced stage of the disease at diagnosis and the increasing frequency of the disease it is increasingly important to understand the molecular mechanisms of initiation of these tumors as well as the genes involved in their metastasis. My research will focus on p120- catenin (p120ctn) and its ability to modulate tumorigenesis as well as cell migration and invasion in vitro and in vivo. P120ctn defines a subfamily of catenin proteins related to beta-catenin that also bind to E-cadherin and stabilizes E-cadherin at adherens junctions. As a result, expression of E-cadherin and p120ctn appear to be coordinately regulated in many cell lines and it is speculated that this may be another mechanism by which E-cadherin expression may be lost and lead to EMT. Functionally, we have demonstrated that successful genetic knockdown of p120ctn results in loss of the integrity of the adherens junctions with augmentation of tumor cell migration and invasion. This has been pursued as well in a genetically engineered mouse model through tissue specific ablation of p120ctn, resulting in inflammation and cancer in the esophagus. Therefore, we hypothesize that p120ctn regulates tumor cell migration and invasion by its ability to modulate effectors such as cdc42/rho/rac, and that p120ctn has a parallel and distinct role in tumorigenesis from that of other oncogenes and tumor suppressors. This hypothesis will be pursued by the following interrelated Specific Aims: Aim 1: Identify the pathways regulated by p120ctn involved in cellular transformation Aim 1a: Understand the functional role(s) of p120ctn in tumor initiation using immortalized esophageal epithelial cells (keratinocytes). Aim 1b: Determine the functional consequences of p120ctn loss in primary esophageal keratinocytes Aim2: Determine the functional interaction between p120ctn and EGFR overexpression in esophageal tumor initiation. Aim 3: Determine the functional role(s) of p120ctn in tumor progression in mouse models of esophageal cancer.

项目摘要食管癌代表了全球男性第五大频繁的癌症。鉴于存活率差，诊断时疾病的晚期阶段以及增加的频率该疾病越来越重要的是了解起始的分子机制这些肿瘤以及涉及转移的基因。我的研究将重点放在P120- Catenin（P120CTN）及其调节肿瘤发生以及细胞迁移和侵袭的能力体外和体内。 P120CTN定义了与β-catenin有关还与E-钙粘蛋白结合并稳定在粘附连接处的E-钙粘蛋白。结果，表达 E-钙黏着蛋白和P120CTN似乎在许多细胞系中进行了协调调节，它是推测这可能是另一种可能会丢失电子钙粘蛋白表达的机制并导致EMT。在功能上，我们已经证明了成功的遗传敲低 P120CTN导致粘附连接的完整性随肿瘤细胞的增强而失去迁移和入侵。这也是在基因工程的鼠标模型中进行的通过p120CTN的组织特异性消融，导致炎症和癌症食管。因此，我们假设P120CTN调节肿瘤细胞迁移，并且它通过调节效应子（例如cdc42/rho/rac）的能力进行入侵，并且P120CTN具有与其他癌基因和肿瘤抑制因子的肿瘤发生中的平行和独特作用。以下相互关联的特定目的将提出这一假设：目标1：确定由P120CTN调节的途径涉及细胞转化目标1a：了解 P120CTN的功能作用在使用永生的食管上皮细胞中（角质形成细胞）。 AIM 1B：确定初级P120CTN损失的功能后果食管角质形成细胞AIM2：确定P120CTN和食管肿瘤起始中的EGFR过表达。目标3：确定功能作用食管癌小鼠模型中肿瘤进展的P120CTN。