Regulation of p120-catenin tumor supressor activities

项目总结 食道癌是全球第五大最常见的男性癌症。给定 存活率低，确诊时疾病已进入晚期， 这种疾病越来越重要的是了解其发病的分子机制 这些肿瘤以及与其转移有关的基因。我的研究将集中在p120上- 连环蛋白(P120ctn)及其调控肿瘤发生、细胞迁移和侵袭的能力 在体外和体内。P120ctn定义了一个与β-连环蛋白相关的连环蛋白亚家族， 还可以与E-钙粘蛋白结合，并在粘连连接处稳定E-钙粘蛋白。因此，表达 E-钙粘蛋白和p120ctn在许多细胞系中似乎是协同调节的，而且它是 推测这可能是E-钙粘蛋白表达丢失的另一种机制 通向急救中心。在功能上，我们已经证明了成功的基因敲除 P120ctn导致黏附连接的完整性丧失，使肿瘤细胞增大 移民和入侵。这一点在转基因小鼠模型中也得到了研究。 通过组织特异性消融p120ctn，导致炎症和癌症 食管。因此，我们假设p120ctn调节肿瘤细胞的迁移和 P120ctn通过其调节诸如CDC42/RHO/RAC等效应器的能力而入侵，且p120ctn具有 与其他癌基因和肿瘤抑制因子在肿瘤发生中的平行和不同的作用。 这一假设将通过下列相互关联的具体目标来实现：目标1：确定 P120ctn调控的细胞转化途径目标1a：了解 P120ctn在永生化食道上皮细胞致瘤中的作用(S) (角质形成细胞)。目标1b：确定p120ctn缺失在原发性高血压患者中的功能后果 食道角质形成细胞AIM2：确定p120ctn和p120ctn之间的功能相互作用 食管瘤发生过程中EGFR的过度表达。目标3：确定功能角色(S) P120ctn在小鼠食道癌模型肿瘤进展中的作用。

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.