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.
| Horvat, Andela; Zaika, Alexander I (2017) How does bacterial pathogen Helicobacter pylori control responses to cellular stress? Future Microbiol 12:105-108 |
| Wei, Jinxiong; Zaika, Elena; Zaika, Alexander (2012) p53 Family: Role of Protein Isoforms in Human Cancer. J Nucleic Acids 2012:687359 |
| Zaika, Elena; Wei, Jinxiong; Yin, Dengping et al. (2011) p73 protein regulates DNA damage repair. FASEB J 25:4406-14 |
| Vilgelm, Anna E; Washington, Mary K; Wei, Jinxiong et al. (2010) Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors. Mol Cancer Ther 9:693-705 |
| Wei, Jinxiong; Nagy, Toni A; Vilgelm, Anna et al. (2010) Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells. Gastroenterology 139:1333-43 |
| Vilgelm, A E; Hong, S-M; Washington, M K et al. (2010) Characterization of ?Np73 expression and regulation in gastric and esophageal tumors. Oncogene 29:5861-8 |
| 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 |
Showing the most recent 10 out of 11 publications
