Role of N-cadherin in Urothelial Neoplastic Progression

N-钙粘蛋白在尿路上皮肿瘤进展中的作用

• 批准号: 6318149
• 负责人: IAN CHARLES SUMMERHAYES
• 金额: $ 18.36万
• 依托单位: LAHEY CLINIC
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6318149
• 关键词: athymic mouse; biological signal transduction; bladder neoplasm; cadherins; cell cell interaction; fibroblasts; fusion gene; molecular oncology; neoplasm /cancer transplantation; neoplastic process; tissue /cell culture; transfection; vascular endothelium

DESCRIPTION (Adapted from the Applicant's Abstract): The long-term objectives of this project are to understand the role and mechanism of action of N-cadherin in the invasive process related to bladder carcinomas. Preliminary work has identified decreased invasive potential associated with the down regulation of N-cadherin in bladder carcinoma cells. We hypothesize that N-cadherin is a positive mediation in this model. To identify the molecular domain(s) of N-cadherin responsible for eliciting the invasive phenotype we will create chimeras between E- and N-cadherinn genes assaying for in vitro invasive capacity in appropriate transfected cells. We propose that the juxtamembrane domain (JMD) of N-cadherin is critical in generating the invasive behavior and this will be tested directly using a construct where the JMD of N-cadherin is deleted. The P120 protein is associated with the JMD of cadherins and is likely an important regulator of cadherin function. Distinct p120 isoforms have been identified in bladder carcinoma cells expressing different cadherins where p120-1A is the predominant isoform found in invasive, N-cadherin expressing bladder cells. To investigate the importance of this association for invasion, we will isolate clones of p120 isoforms and introduce p120-1A into bladder cell lines expressing E- or E-/N-cadherin lacking p1201A. We further propose to identify the signaling pathway(s) linked to N-cadherin and invasion, initially evaluating established signaling events implicated in this process. Since the goals of this proposal focus upon the role of N-cadherin in invasion of bladder carcinoma cells, we propose to develop new in vitro models representing different states of the metastatic process in which we can investigate the role(s) of N-cadherin. Validation of N-cadherin in bladder tumor metastasis would identify it as a potential marker of invasion and a possible therapeutic target for the future.

描述（改编自申请人的摘要）：长期目标 该项目的目的是了解 N-钙粘蛋白在与膀胱癌相关的侵袭过程中。初步的 工作已确定与羽绒相关的侵入潜力降低 N-钙粘蛋白在膀胱癌细胞中的调节。我们假设 N-钙粘蛋白在此模型中起到正向调节作用。鉴定分子 N-钙粘蛋白的结构域负责引发我们的侵袭表型 将在 E- 和 N-cadherinn 基因之间创建嵌合体，用于体外检测 适当转染细胞的侵袭能力。我们建议 N-钙粘蛋白的近膜结构域 (JMD) 对于产生侵入性至关重要 行为，这将使用 JMD 的构造直接进行测试 N-钙粘蛋白被删除。 P120 蛋白与钙粘蛋白的 JMD 相关 并且可能是钙粘蛋白功能的重要调节剂。独特的p120 已在表达不同的膀胱癌细胞中鉴定出亚型 钙粘蛋白，其中 p120-1A 是侵入性、 表达 N-钙粘蛋白的膀胱细胞。为了调查这一点的重要性 入侵关联，我们将分离 p120 亚型的克隆并引入 p120-1A 进入表达缺乏 p1201A 的 E- 或 E-/N-钙粘蛋白的膀胱细胞系。 我们进一步建议鉴定与 N-钙粘蛋白相关的信号通路 和入侵，最初评估涉及的已建立的信号事件 这个过程。由于该提案的目标侧重于 N-钙粘蛋白在膀胱癌细胞侵袭中的作用，我们建议开发新的 代表转移过程不同状态的体外模型，其中 我们可以研究 N-钙粘蛋白的作用。 N-钙粘蛋白的验证 膀胱肿瘤转移将其识别为潜在的侵袭标志物 以及未来可能的治疗目标。