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.
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.
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