The Role of p73 in Upper Gastrointestinal Carcinomas

描述(由申请人提供)：上消化道肿瘤(UGC)是全球癌症相关发病率和死亡率的主要原因。此外，近端胃、胃食道交界处和食管腺癌的发病率是美国和西方世界所有肿瘤中上升最快的。这些肿瘤的特点是对目前的化疗方案反应差，总体存活率低。上消化道肿瘤的发生机制尚不清楚。 P73是一种新的P53家族成员，其异构体DeltaNp73在肿瘤发生和化疗药物敏感性中的作用日益受到重视。在几种类型的肿瘤中，这些p73亚型的上调与不良的临床病理结果相关。然而，在胃肠道肿瘤中，p73基因的作用仍不清楚。我们的初步结果表明，p73和deltaNp73转录本和蛋白在UGC中经常过表达。同时，我们的初步研究表明，这些蛋白质在胃肠道细胞中具有很强的致癌作用。综上所述，这些数据提示p73和deltaNp73可能参与了UGC的发生发展。我们建议描述p73亚型在上消化道肿瘤发生中的作用。此外，我们的目标是评估它们的临床意义。利用一些细胞和分子生物学技术，我们将描述p73亚型与其他信号通路的相互作用，并探讨调控p73基因表达的机制。为了分析p73亚型在上消化道癌中的表达，我们将采用实时RT-PCR分析和免疫组织化学染色的方法从我们的胃肠道癌组织库中提取肿瘤组织阵列。这些信息可能为开发新的预后和治疗靶点提供新的途径。 我们的具体目标是： 目的1：探讨p73亚型在上消化道肿瘤中的临床意义。 目的2：研究p73亚型在上消化道腺癌中的生物学功能。目的：探讨p73基因在上消化道肿瘤中的表达调控。

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.