The Role of p73 in Upper Gastrointestinal Carcinomas

p73 在上消化道癌中的作用

• 批准号: 7046787
• 负责人: ALEXANDER I. ZAIKA
• 金额: $ 27.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-28 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046787
• 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）：上胃肠道癌（UGC）是全球与癌症有关的发病率和死亡率的主要原因。此外，胃部近端，胃食管和食管腺癌的发病率是美国和西方世界的任何肿瘤中最快的升高。这些肿瘤的特征是对当前化学治疗方案的反应不佳和总体低存活率。上胃肠道肿瘤中肿瘤发生的机制尚不清楚。 P73是新的P53家庭成员及其同工型Deltanp73越来越多地被认为是肿瘤发生的关键参与者以及化学治疗药物敏感性。这些p73同工型的上调与几种类型的肿瘤中的临床病理结果差相关。但是，在胃肠道肿瘤中，p73基因的作用仍然未知。我们的初步结果表明，P73和Deltanp73转录本和蛋白质在UGC中经常过表达。同时，这些蛋白质在胃肠道细胞中具有强大的致癌作用，正如我们的初步研究所证明的那样。完全采用这些数据，这些数据表明p73和deltanp73可能参与了UGC的发展或发展。我们建议描述p73同工型在上胃肠道肿瘤发生中的作用。此外，我们旨在评估它们的临床意义。使用许多细胞和分子生物学技术，我们将表征p73同工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。为了表达上胃肠道癌中p73同工型的表达分析，我们将对我们胃肠道癌组织库的肿瘤组织阵列进行实时RT-PCR分析和免疫组织化学染色。该信息可能为开发新的预后和治疗靶标提供了新的途径。 我们的具体目的是： AIM 1：表征上胃肠道癌中p73同工型的临床意义。 AIM 2：表征上胃肠道腺癌中p73同工型的生物学功能。目标3：研究上胃肠道癌中p73基因表达的调节。