Regulation of p120-catenin tumor supressor activities

描述(申请人提供)：食道癌在全球男性癌症发病率中排名第五。鉴于这些肿瘤的存活率很低，确诊时已进入晚期，而且发病率越来越高，因此了解肿瘤发生的分子机制以及参与肿瘤转移的基因变得越来越重要。我的研究将集中在p120-catenin(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-连环素相关的连环素蛋白亚家族，它也与E-钙粘附素结合，并在粘连连接处稳定E-钙粘附素。因此，E-钙粘蛋白和p120ctn的表达在许多细胞系中似乎是协同调节的，推测这可能是E-钙粘蛋白表达缺失并导致EMT的另一种机制。在功能上，我们已经证明，成功的基因敲除p120ctn会导致黏附连接的完整性丧失，从而增加肿瘤细胞的迁移和侵袭。在基因工程小鼠模型中，通过组织特异性地切除p120ctn，导致食管炎症和癌症，也追求了这一点。因此，我们假设p120ctn通过调节效应分子如CDc42/Rho/Rac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癌基因和肿瘤抑制因子具有平行和不同的作用。这一假说将通过以下相互关联的特定目标来实现：目的1：确定p120ctn参与细胞转化的调控途径目标1a：了解p120ctn在永生化食道上皮细胞(角质形成细胞)肿瘤发生中的功能作用(S)。目的1b：确定原代食道角质形成细胞中p120ctn缺失的功能后果。目的：探讨p120ctn与EGFR过表达在食道肿瘤发生中的功能相互作用。目的：探讨p120ctn在小鼠食道癌模型中的功能作用(S)。 公共卫生相关性：去年美国新诊断的食道癌病例超过1.4万例，超过90%的确诊病例将死于疾病，主要是转移性病变。这些拟议的研究将为p120ctn在食道癌的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.