Regulation of p120-catenin tumor supressor activities

描述（由申请方提供）：食管癌是全球男性中第五常见的癌症。鉴于生存率低，诊断时疾病的晚期和疾病的频率增加，了解这些肿瘤起始的分子机制以及参与其转移的基因越来越重要。我的研究将集中在p120- catenin（p120 ctn）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。P120 ctn定义了与β-连环蛋白相关的连环蛋白质的亚家族，其也结合E-钙粘蛋白并在粘附连接处稳定E-钙粘蛋白。因此，E-cadherin和p120 ctn的表达在许多细胞系中似乎是协同调节的，并且推测这可能是E-cadherin表达丢失并导致EMT的另一种机制。在功能上，我们已经证明，成功的基因敲除p120 ctn的结果在增强肿瘤细胞迁移和侵袭的粘附连接的完整性的损失。在基因工程小鼠模型中，通过组织特异性消融p120 ctn，导致食管炎症和癌症，也一直在追求这一点。因此，我们假设p120 ctn通过其调节效应子如cdc 42/rho/rac的能力来调节肿瘤细胞的迁移和侵袭，并且p120 ctn在肿瘤发生中具有与其他癌基因和肿瘤抑制因子平行且不同的作用。这一假设将通过以下相互关联的具体目标来实现：目标1：确定参与细胞转化的p120 ctn调控的途径目标1a：使用永生化食管上皮细胞（角质形成细胞）了解p120 ctn在肿瘤发生中的功能作用。目的1b：确定原代食管角朊细胞p120 ctn缺失的功能后果。目的2：确定p120 ctn和EGFR过表达在食管肿瘤发生中的功能相互作用。目的3：在小鼠食管癌模型中确定p120 ctn在肿瘤进展中的功能作用。 公共卫生相关性：去年，美国诊断出超过14，000例新的食管癌病例，其中90%以上的诊断者将死于疾病，主要是转移性病变。这些研究将为p120 ctn在食管癌发生和发展中的生物学作用提供新的见解。最终，这些研究可能会转化为这种致命疾病的新诊断和治疗方式。

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.