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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA108956-02
Application #
7046787
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Thurin, Magdalena
Project Start
2006-04-28
Project End
2010-03-31
Budget Start
2006-04-28
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$271,513
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Zaika, Elena; Wei, Jinxiong; Yin, Dengping et al. (2011) p73 protein regulates DNA damage repair. FASEB J 25:4406-14
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Vilgelm, Anna; El-Rifai, Wael; Zaika, Alexander (2008) Therapeutic prospects for p73 and p63: rising from the shadow of p53. Drug Resist Updat 11:152-63
Wei, Jinxiong; O'Brien, Daniel; Vilgelm, Anna et al. (2008) Interaction of Helicobacter pylori with gastric epithelial cells is mediated by the p53 protein family. Gastroenterology 134:1412-23
Hong, Seung-Mo; Cho, Hyungjun; Moskaluk, Christopher A et al. (2007) p63 and p73 expression in extrahepatic bile duct carcinoma and their clinical significance. J Mol Histol 38:167-75
Zaika, A I; El-Rifai, W (2006) The role of p53 protein family in gastrointestinal malignancies. Cell Death Differ 13:935-40

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