Regulation of p120-catenin tumor supressor activities

项目摘要 食管癌是全球男性中第五常见的癌症。鉴于 生存率低，诊断时疾病处于晚期， 对于这种疾病，了解其启动的分子机制越来越重要。 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）及其调节肿瘤发生以及细胞迁移和侵袭的能力 在体外和体内。P120ctn定义了与β-连环蛋白相关的连环蛋白质亚家族， 也结合E-钙粘蛋白并稳定粘附连接处的E-钙粘蛋白。因此，表达式 E-cadherin和p120ctn的表达在许多细胞系中似乎是协调调节的， 推测这可能是E-cadherin表达丢失的另一种机制 然后送去急救在功能上，我们已经证明，成功的基因敲除 p120 ctn导致粘附连接的完整性丧失，肿瘤细胞增多 移民和入侵。这一点在基因工程小鼠模型中也得到了研究 通过p120ctn的组织特异性消融，导致炎症和癌症， 食道因此，我们假设p120ctn调节肿瘤细胞迁移， 通过其调节效应物如CDC42/rho/rac能力而侵袭，且p120ctn具有 与其他癌基因和肿瘤抑制因子在肿瘤发生中的作用相似且不同。 这一假设将通过以下相互关联的具体目标来实现： p120ctn调控的细胞转化途径 p120 ctn在使用永生化食管上皮细胞的肿瘤起始中的功能作用 （角质形成细胞）。目的1b：确定原发性肝癌中p120ctn缺失的功能后果。 食管角化细胞Aim 2：确定p120 ctn与 食管肿瘤发生中EGFR的过度表达目标3：确定下列机构的职能作用 p120ctn在食管癌小鼠模型中的肿瘤进展中的作用。

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.