PGE2 up-regulates vascular endothelial growth factor expression in MKN28 gastric cancer cells via epidermal growth factor receptor signaling system.
OBJECTIVE
1) To evaluate the effect of prostaglandin E2 (PGE2) on the regulation of vascular endothelial growth factor (VEGF) expression in gastric MKN28 cells, and 2) to investigate the role of the epidermal growth factor receptor (EGFR) signal transduction pathway in any effect exerted by PGE2 on VEGF expression.


METHODS
MKN28 cells were incubated with the vehicle (control) or with PGE2 in the presence or absence of AG1478, a selective inhibitor of EGFR tyrosine kinase, or PD098059, a selective inhibitor of the kinase responsible for ERK2 phosphorylation (mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK)). Real-time quantitative polymerase chain reaction and Western blot analysis were used to evaluate VEGF mRNA and protein expression. The activity of EGFR and ERK2 was measured by Western blot analysis.


RESULTS
PGE2 significantly up-regulated VEGF mRNA and protein expression and increased the activation of EGFR and ERK2. Incubation of MKN28 cells with AG1478 significantly reduced PGE2-induced EGFR activity, ERK2 activity, and VEGF mRNA and protein expression. Meanwhile, incubation of MKN28 with PD098059 reduced PGE2-induced ERK2 activity and VEGF mRNA and protein expression, but had no effect on EGFR activity.


CONCLUSIONS
Our data suggested that PGE2 up-regulates VEGF expression in gastric cancer cells via transactivation of EGFR-MAPK signaling pathways, which may be mechanisms underlying the contribution of COX-2 to tumor angiogenesis in gastric cancer.
Ding
Yan-Bing
YB
Department of Gastroenterology and Oncology, Yangzhou First Municipal Hospital, Yangzhou University, Yangzhou 225001, Jiangsu Province, China. chinadyb@hotmail.com
Shi
Rui-Hua
RH
Tong
Jian-Dong
JD
Li
Xiao-Yu
XY
Zhang
Guo-Xin
GX
Xiao
Wei-Ming
WM
Yang
Jian-Guo
JG
Bao
Yun
Y
Wu
Jian
J
Yan
Zhi-Gang
ZG
Wang
Xue-Hao
XH
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D015232:Dinoprostone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010120:Oxytocics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010120:Oxytocics; D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C101044:RTKI cpd; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one