Gastric carcinoma (GC) is the second most common cause of cancer-related death worldwide. Moreover, a sharp increase in incidence of proximal Gastroesophageal Junctional (GEJ) and esophageal adenocarcinomas was recently noted in the United States as well as many other Western populations. The critical molecular alterations that drive gastric tumorigenesis remain largely uncharacterized. Overall relative 5- year survival rates are currently less than 20%. Improvement in our presently limited diagnostic, preventive, and therapeutic approach to gastric cancer is currently a pressing issue. During the previous funding period, we have successfully completed all original aims and systematically characterized the chromosome 17q amplicon in gastric cancer. We have cloned and identified, for the first time, Dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32) and a novel transcriptional splice variant that encodes a truncated protein isoform that we named t-DARPP as novel cancer genes with potent anti-apoptotic and drug resistance properties. DARPP-32 and t-DARPP mRNAs and proteins are overexpressed in more than two- thirds of GCs, thus becoming prevalent molecular changes in these tumors. In this proposal, we plan to continue our work and characterize the in vitro and in vivo role(s) of DARPP-32 and t-DARPP proteins in modulation of gastric tumorigenesis and pro-survival pathways. We hypothesize, based on our preliminary data, that over-expression of DARPP-32 proteins is an important molecular mechanism during gastric tumorigenesis. In this proposal, we will investigate the clinical, molecular, and pathobiological roles of DARPP-32 and t-DARPP in GCs. In this proposal, we will analyze, on tissue microarrays that contain more than 300 tumor samples, the expression of DARPP-32 proteins with other proteins (pAkt and PTEN) that regulate cancer cell survival. We will investigate the mechanism(s) by which DARPP-32 and t-DARPP regulate the PTEN-PI3K/AKT signaling pathway. The role of DARPP-32/t-DARPP in modulation of PI3K survival pathway is a novel and a previously unexplored mechanism in GCs. We will also explore the role of DARPP-32/t-DARPP in regulating the balance between the pro-apoptotic and pro-survival members of the BCL-2 family proteins. Using advanced proteomic approaches, we plan to identify downstream signaling targets of DARPP-32 and t-DARPP proteins in cancer. This step is expected to reveal novel molecular signaling pathways that are regulated by these proteins in GC. In order to study the role of t-DARPP in gastric tumorigeneses in vivo, we will develop a transgenic mouse model using the TFF1 promoter to drive the t-DARPP expression in the glandular stomach. We expect that completion of this proposal will provide important clinical, molecular, and pathobiological information that have significant impact on the clinical management of patients with adenocarcinomas of the stomach.

Public Health Relevance

This proposal connects in vitro and in vivo experiments in order to characterize the role(s) of Darpp-32 proteins in gastric carcinogenesis. We plan to investigate the contribution of Darpp-32 proteins to PI3K/Akt survival pathway. Using state-of-the-art proteomics approaches, we expect to reveal novel signaling molecules and pathways for these proteins in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093999-11
Application #
8252216
Study Section
Special Emphasis Panel (ZRG1-DIG-C (04))
Program Officer
Yassin, Rihab R,
Project Start
2001-07-01
Project End
2013-09-25
Budget Start
2012-05-01
Budget End
2013-09-25
Support Year
11
Fiscal Year
2012
Total Cost
$299,889
Indirect Cost
$104,521
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Soutto, Mohammed; Peng, DunFa; Katsha, Ahmed et al. (2015) Activation of ?-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Gut 64:1028-39
Belkhiri, Abbes; El-Rifai, Wael (2014) 5-Methylcytosine hydroxylation-mediated LINE-1 hypomethylation: a novel mechanism of proto-oncogenes activation in colorectal cancer? Gut 63:538-9
Chen, Zheng; Saad, Rama; Jia, Peilin et al. (2013) Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma. Cancer 119:1985-93
Zhu, Shoumin; Hong, Jun; Tripathi, Manish K et al. (2013) Regulation of CXCR4-mediated invasion by DARPP-32 in gastric cancer cells. Mol Cancer Res 11:86-94
Zhu, Shoumin; Belkhiri, Abbes; El-Rifai, Wael (2011) DARPP-32 increases interactions between epidermal growth factor receptor and ERBB3 to promote tumor resistance to gefitinib. Gastroenterology 141:1738-48.e1-2
Jackson, Kaya; Soutto, Mohammed; Peng, DunFa et al. (2011) Epigenetic silencing of somatostatin in gastric cancer. Dig Dis Sci 56:125-30
Vangamudi, Bhavatarini; Zhu, Shoumin; Soutto, Mohammed et al. (2011) Regulation of ?-catenin by t-DARPP in upper gastrointestinal cancer cells. Mol Cancer 10:32
Soutto, Mohammed; Belkhiri, Abbes; Piazuelo, M Blanca et al. (2011) Loss of TFF1 is associated with activation of NF-ýýB-mediated inflammation and gastric neoplasia in mice and humans. J Clin Invest 121:1753-67
Schneider, Barbara G; Peng, Dun-Fa; Camargo, M Constanza et al. (2010) Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer. Int J Cancer 127:2588-97
Mukherjee, Kaushik; Peng, Dunfa; Brifkani, Zaid et al. (2010) Dopamine and cAMP regulated phosphoprotein MW 32 kDa is overexpressed in early stages of gastric tumorigenesis. Surgery 148:354-63

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