Dopamine and cAMP regulated phosphoprotein MW 32 kDa is overexpressed in early stages of gastric tumorigenesis

Kaushik Mukherjee, Dunfa Peng, Zaid Brifkani, Abbes Belkhiri, Manuel Pera, Tatsuki Koyama, Elizabeth A.S. Koehler, Frank L. Revetta, Mary K. Washington, Wael El-Rifai

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17 Scopus citations

Abstract

Background: Gastric adenocarcinoma is a leading cause of cancer mortality. The role of dopamine and cAMP regulated phosphoprotein MW 32 kDa (DARPP-32) overexpression in the gastric tumorigenesis cascade remains unclear. Methods: The expression of DARPP-32 in the multistep carcinogenesis cascade was examined using immunohistochemistry analysis on 533 samples. The contribution of DARPP-32 in cellular transformation and molecular signaling was investigated using NIH3T3, AGS, and SNU16 cells. Results: The composite expression score (CES), calculated from immunostaining patterns, increased significantly from normal or gastritis to metaplasia, dysplasia, and adenocarcinoma (P < .001). In patients with normal stomach or gastritis and tumor samples, a 76% and 77% chance, respectively, was found (P < .001) that CES was higher in the tumor. High median CES correlated with well- or moderately differentiated (P = .03) gastric adenocarcinomas. NIH3T3 cells transfected with DARPP-32 demonstrated increased levels of phospho-AKT and a 5-fold increase in the number of foci as compared with the control (P = .02). DARPP-32 expression in AGS cells led to increased protein levels of phospho-AKT and BCL-2. For validation, the knockdown of endogenous DARPP-32 expression in SNU16 cells using shRNA resulted in decreased levels of phospho-AKT phosphorylation and BCL-2. Conclusion: Our results suggest that DARPP-32 overexpression may participate in the transition to intestinal metaplasia and in the progression to neoplasia. The ability of DARPP-32 to transform NIH3T3 cells and to regulate AKT and BCL-2 underscores its possible oncogenic potential.

Original languageEnglish (US)
Pages (from-to)354-363
Number of pages10
JournalSurgery
Volume148
Issue number2
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Surgery

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    Mukherjee, K., Peng, D., Brifkani, Z., Belkhiri, A., Pera, M., Koyama, T., Koehler, E. A. S., Revetta, F. L., Washington, M. K., & El-Rifai, W. (2010). Dopamine and cAMP regulated phosphoprotein MW 32 kDa is overexpressed in early stages of gastric tumorigenesis. Surgery, 148(2), 354-363. https://doi.org/10.1016/j.surg.2010.05.011