Regulation of p120-catenin tumor supressor activities

p120-连环蛋白肿瘤抑制活性的调节

• 批准号: 8232586
• 负责人: DOUGLAS B STAIRS
• 金额: $ 8.68万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232586
• 关键词: Regulation; p120; catenin; tumor; supressor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Over 14,000 new cases of esophageal cancer were diagnosed in the United States last year and more than 90% of those diagnosed will die of their disease, primarily from metastatic lesions. The proposed studies will provide novel insights into the biological roles of p120ctn in the development and progression of esophageal cancer. Ultimately, these studies may translate into new diagnostic and therapeutic modalities for this deadly disease.

描述（由申请人提供）：食管癌代表了全球男性中第五次最常见的癌症。鉴于存活率较差，诊断时疾病的晚期阶段以及疾病频率的增加，了解这些肿瘤起始的分子机制以及与其转移有关的基因越来越重要。我的研究将重点放在P120- catenin（P120CTN）及其调节肿瘤发生以及体外和体内细胞迁移和侵袭的能力上。 P120CTN定义了与β-catenin相关的Catenin蛋白的亚家族，该蛋白也与β-蛋白结合，并与E-钙粘蛋白结合并稳定在粘附连接处的E-钙粘着蛋白。结果，E-钙粘蛋白和P120CTN的表达似乎在许多细胞系中进行了协调调节，并且据推测，这可能是E-钙粘蛋白表达可能会丢失并导致EMT的另一种机制。从功能上讲，我们已经证明了P120CTN的成功遗传敲低导致粘附连接的完整性丧失，并增加了肿瘤细胞迁移和侵袭的增强。通过组织特异性消融P120CTN的基因工程小鼠模型也被追求，从而导致食道炎症和癌症。因此，我们假设p120CTN通过调节诸如Cdc42/rho/rac之类的效应子的能力来调节肿瘤细胞的迁移和侵袭，并且P120CTN在肿瘤发生中与其他肿瘤基因和肿瘤抑制子具有相似而独特的作用。该假设将通过以下相互关联的特定目的来提出：目标1：确定与细胞转化有关的P120CTN调节的途径AIM 1A：了解使用永生化的食管上皮细胞（角质细胞）使用永生化的食管上皮细胞中P120CTN的功能作用。 AIM 1B：确定原代食管角质形成细胞中P120CTN损失的功能后果。 AIM2：确定食管肿瘤起始中P120CTN和EGFR过表达之间的功能相互作用。 AIM 3：确定食管癌小鼠模型中P120CTN在肿瘤进展中的功能作用。 公共卫生相关性：去年在美国诊断出14,000例新的食管癌病例，其中90％以上的诊断患者将死于其疾病，主要来自转移性病变。拟议的研究将为P120CTN在食管癌的发展和发展中的生物学作用提供新的见解。最终，这些研究可能转化为这种致命疾病的新诊断和治疗方式。