The Role of p73 in Upper Gastrointestinal Carcinomas

p73 在上消化道癌中的作用

• 批准号: 6921826
• 负责人: ALEXANDER I. ZAIKA
• 金额: $ 27.08万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921826
• 关键词: SCID mouse; adenocarcinoma; athymic mouse; biological signal transduction; biomarker; cadherins; cell line; clinical research; esophagus neoplasm; gene expression; human subject; immunocytochemistry; neoplasm /cancer genetics; neoplastic process; oncogenes; p53 gene /protein; polymerase chain reaction; protein isoforms; protein protein interaction; statistics /biometry; stomach neoplasms; transcription factor

DESCRIPTION (provided by applicant): Upper gastrointestinal carcinomas (UGC) are a leading cause of cancer-related morbidity and mortality worldwide. Moreover, the incidences of proximal stomach, gastroesophageal junctional and esophageal adenocarcinomas are the fastest rising of any tumors in the United States and Western World. These tumors are characterized by a poor response to the present chemotherapeutic regiments and an overall low survival rate. The mechanisms of tumorigenesis in upper gastrointestinal tumors are unclear. p73, a new p53 family member, and its isoform deltaNp73 are increasingly recognized as key players in tumorigenesis, as well as in chemotherapeutic drug sensitivity. Upregulation of these p73 isoforms correlates with poor clinicopathological outcome in several types of tumors. However, in gastrointestinal tumors the role of the p73 gene remains unknown. Our preliminary results indicate that p73 and deltaNp73 transcripts and proteins are frequently overexpressed in UGC. At same time, these proteins have strong oncogenic effects in gastrointestinal cells, as has been demonstrated in our preliminary studies. Taken altogether, these data suggest that p73 and deltaNp73 may be involved in development or progression of UGC. We propose to delineate the role of p73 isoforms in upper gastrointestinal tumorigenesis. In addition, we aim to evaluate their clinical significance. Using a number of cellular and molecular biology techniques, we will characterize the interaction of p73 isoforms with other signaling pathways and investigate the mechanisms that regulate p73 gene expression. For the expression analysis of p73 isoforms in upper gastrointestinal carcinomas, we will employ a real-time RT-PCR analysis and immunohistochemical staining of tumor tissue arrays from our gastrointestinal cancer tissue bank. This information may provide new avenues for the development of novel prognostic and therapeutic targets. Our specific aims are: Aim 1: Characterize the clinical significance of p73 isoforms in upper gastrointestinal carcinomas. Aim 2: Characterize the biological functions of p73 isoforms in upper gastrointestinal adenocarcinomas. Aim 3: Investigate the regulation of p73 gene expression in upper gastrointestinal carcinomas.

描述（由申请人提供）：上消化道癌（UGC）是全世界癌症相关发病率和死亡率的主要原因。此外，在美国和西方世界，近端胃、胃食管交界处和食管腺癌的发病率是所有肿瘤中增长最快的。这些肿瘤的特点是对现有化疗方案反应较差且总体存活率较低。上消化道肿瘤的肿瘤发生机制尚不清楚。 p73 是 p53 家族的新成员，其亚型 deltaNp73 越来越被认为是肿瘤发生以及化疗药物敏感性中的关键参与者。这些 p73 亚型的上调与多种类型肿瘤的不良临床病理结果相关。然而，p73 基因在胃肠道肿瘤中的作用仍然未知。我们的初步结果表明，p73 和 deltaNp73 转录本和蛋白质在 UGC 中经常过度表达。同时，正如我们的初步研究所证明的那样，这些蛋白质对胃肠道细胞具有强烈的致癌作用。总而言之，这些数据表明 p73 和 deltaNp73 可能参与 UGC 的发生或进展。我们建议描述 p73 亚型在上消化道肿瘤发生中的作用。此外，我们的目的是评估它们的临床意义。使用多种细胞和分子生物学技术，我们将表征 p73 亚型与其他信号通路的相互作用，并研究调节 p73 基因表达的机制。为了对上消化道癌中 p73 亚型的表达进行分析，我们将对消化道癌组织库中的肿瘤组织阵列进行实时 RT-PCR 分析和免疫组织化学染色。这些信息可能为开发新的预后和治疗靶点提供新途径。 我们的具体目标是： 目标 1：表征 p73 亚型在上消化道癌中的临床意义。 目标 2：表征 p73 亚型在上消化道腺癌中的生物学功能。目标 3：研究上消化道癌中 p73 基因表达的调控。