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


CONCLUSIONS
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.
Mukherjee
Kaushik
K
Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Peng
Dunfa
D
Brifkani
Zaid
Z
Belkhiri
Abbes
A
Pera
Manuel
M
Koyama
Tatsuki
T
Koehler
Elizabeth A S
EA
Revetta
Frank L
FL
Washington
Mary K
MK
El-Rifai
Wael
W
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005756:Gastritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008679:Metaplasia; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497928:PPP1R1B protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt