Role of p120ctn in Esophageal Cancer

p120ctn 在食管癌中的作用

• 批准号: 7644388
• 负责人: DOUGLAS B STAIRS
• 金额: $ 1.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644388
• 关键词: Adherens Junction; Agar; American Cancer Society; Amino Acids; Binding; Biochemical; Biological; Biological Assay; Cell Line; Cells; Cessation of life; Development; Diagnosis; Disease; E-Cadherin; EGFR Protein Overexpression; Epidermal Growth Factor Receptor; Esophageal; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; Event; Family; Family member; Frequencies; Genes; Growth; Human; Human Herpesvirus 4; In Vitro; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of esophagus; Metastatic Lesion; Modality; Modeling; Molecular; Monitor; Mouse Cell Line; Mus; Mutation; Neoplasm Metastasis; Phosphorylation; Phosphorylation Site; Phosphotransferases; Protein Isoforms; Proteins; RNA Splicing; Receptor Activation; Research; Role; Serine; Signal Transduction; Site; Staging; Stimulus; Survival Rate; Therapeutic; Threonine; Translating; Tumor Cell Line; Tyrosine; United States; beta catenin; cancer cell; catenin p120ctn protein; cell motility; epithelial to mesenchymal transition; in vivo; insight; knock-down; male; matrigel; migration; monolayer; mutant; novel; novel diagnostics; overexpression; promoter; research study; small hairpin RNA; tissue culture; tumor; tumor initiation; tumorigenesis; tumorigenic

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 the catenin family member p120ctn and its ability to modulate tumorigenesis as well as cell migration and invasion in vitro and in vivo. p120ctn defines a family 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. Interestingly, p120ctn contains 16 different phosphorylation sites, 8 tyrosine and 8 serine/threonine. What kinases directly phosphorylate these sites and under what stimuli are largely unknown. However, it is clear that EGFR activation can induce phosphorylation of p120ctn at least at Y228. Additionally, many splice forms for p120ctn exist. We hypothesize that the different isoforms and phosphorylation sites of p120ctn may regulate its ability to interact with its binding partners and therefore alter its ability to promote tumorigenesis and metastasis. This hypothesis will be pursued by the following interrelated specific aims. Aim 1: To assess the effects different isoforms and phosphorylation mutants have on motility and invasiveness. Expression of p120ctn will be knocked-down in several esophageal cell lines. Various isoforms and phosphorylation-deficient mutants will be introduced and motility and invasiveness of the mutants will be determined through monolayer assays as well as three-dimensional Matrigel and organotypic culture models. Aim2: To understand the role of p120ctn in tumor initiation and progression. We will overexpress EGFR and knockdown p120ctn expressin in vivo and in vitro. We will monitor these EGFR-overexpressing, p120ctn-deleted mice and cell lines for esophageal tumorigenesis and metastasis. 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.

描述（由申请人提供）：食管癌代表了全球男性中第五次最常见的癌症。鉴于存活率较差，诊断时疾病的晚期阶段以及疾病频率的增加，了解这些肿瘤起始的分子机制以及与其转移有关的基因越来越重要。我的研究将重点放在Catenin家族成员P120CTN及其调节​​肿瘤发生的能力以及体外和体内细胞迁移和侵袭的能力。 P120CTN定义了与β-catenin相关的链氨蛋白蛋白家族，该蛋白也与E-钙粘蛋白结合并稳定在粘附连接处的E-钙粘着蛋白。结果，E-钙粘蛋白和P120CTN的表达似乎在许多细胞系中进行了协调调节，并且据推测，这可能是E-钙粘蛋白表达可能会丢失并导致EMT的另一种机制。有趣的是，P120CTN包含16个不同的磷酸化位点，8个酪氨酸和8丝氨酸/苏氨酸。什么激酶直接磷酸化了这些位点，在什么刺激下是未知的。但是，很明显，EGFR激活至少在Y228时诱导P120CTN的磷酸化。此外，存在许多P120CTN的剪接形式。我们假设P120CTN的不同同工型和磷酸化位点可能调节其与其结合伴侣相互作用的能力，从而改变其促进肿瘤发生和转移的能力。以下相互关联的特定目的将提出这一假设。目标1：评估不同的同工型的影响，磷酸化突变体对运动性和侵入性具有。 P120CTN的表达将在几种食管细胞系中被击倒。将引入各种同工型和磷酸化缺陷的突变体，突变体的运动和侵入性将通过单层测定法以及三维母质和器官型培养模型确定。 AIM2：了解p120CTN在肿瘤开始和进展中的作用。我们将在体内和体外过度表达EGFR和敲除P120CTN表达素。我们将监测这些过表达EGFR的P120CTN缺失小鼠和细胞系，用于食管肿瘤发生和转移。去年在美国诊断出了14,000例新的食管癌病例，其中90％以上的诊断患者将死于其疾病，主要来自转移性病变。拟议的研究将为P120CTN在食管癌的发展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。