Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma

Shih-Pei Huang, Ming-Shiang Wu, Chia-Tung Shun, Hsiu-Po Wang, Chang-Yao Hsieh, Min-Liang Kuo, Jaw-Town Lin
Journal of Biomedical Science 2005, 12 (1): 229-41
Cyclooxygenase-2 (COX-2) is an inducible enzyme important in inflammation and which is overexpressed in a variety of cancers. This study investigated its role in angiogenesis of gastric carcinoma (GC). Immunohistochemical examination of surgical specimens showed a positive correlation among COX-2, vascular endothelial growth factor (VEGF), and vasculature in GC. After transfection with a COX-2-expressing vector, the AGS GC cell line showed increases in both proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). These in vitro angiogenic effects on HUVECs were reduced either by blocking VEGF or NS-398, a COX-2 inhibitor. To elucidate the mechanism by which COX-2 increases angiogenesis, we established a COX-2-expressing clone, AGS/COX-2, and its vector control clone, AGS/pcDNA3, and verified their functions by determining prostaglandin E2 (PGE2). Among 6 angiogenesis-associated factors, VEGF was considerably expressed in AGS/COX-2. After reducing hypoxia-inducible factor-1alpha (HIF-1alpha) protein by antisense HIF-1alpha transfection, VEGF production was reduced in AGS/COX-2 cells in a dose-dependent manner. We found that HIF-1alpha increased concomitantly with VEGF after exogenous PGE2 stimulation to wild-type AGS cells, but this effect was blocked by SC19220, a PGE2 receptor antagonist. In addition, pretreatment with NS-398 to reduce PGE2 also effectively suppressed HIF-1alpha protein accumulation and achieved a similar inhibitory effect on VEGF production as did antisense HIF-1alpha transfection. Our work supports the COX-2/PGE2/HIF-1alpha/VEGF pathway possibly contributing to tumor angiogenesis in GC.

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