Regulation of p120-catenin tumor supressor activities

描述（申请人提供）：食管癌是全球男性第五大常见癌症。由于生存率低，诊断时病情进展较晚，发病频率越来越高，因此了解这些肿瘤发生的分子机制以及参与其转移的基因变得越来越重要。我的研究将集中在p120-连环蛋白（p120ctn）及其在体外和体内调节肿瘤发生以及细胞迁移和侵袭的能力。P120ctn定义了一个与β -连环蛋白相关的连环蛋白亚家族，该亚家族也与e -钙粘蛋白结合，并在粘附连接处稳定e -钙粘蛋白。因此，E-cadherin和p120ctn的表达似乎在许多细胞系中受到协调调节，推测这可能是E-cadherin表达丢失并导致EMT的另一种机制。从功能上讲，我们已经证明p120ctn基因的成功敲除会导致粘附连接的完整性丧失，同时增强肿瘤细胞的迁移和侵袭。通过组织特异性消融p120ctn，在基因工程小鼠模型中也进行了这一研究，导致食道炎症和癌症。因此，我们假设p120ctn通过其调节cdc42/rho/rac等效应物的能力来调节肿瘤细胞的迁移和侵袭，并且p120ctn在肿瘤发生中具有与其他癌基因和肿瘤抑制因子相似且独特的作用。这一假设将通过以下相关的特定目标来实现：目标1：确定参与细胞转化的p120ctn调节的途径；目标1a：了解p120ctn在使用永生化食管上皮细胞（角化细胞）引发肿瘤中的功能作用。目的1b：确定原发性食管角化细胞中p120ctn缺失的功能后果。目的2：确定p120ctn与EGFR过表达在食管肿瘤起始中的功能相互作用。目的3：确定p120ctn在食管癌小鼠模型肿瘤进展中的功能作用。

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.