- 作者: Shih-Pei Huang; Ming-Shiang Wu; Chia-Tung Shun; Hsiu-Po Wang; Chang-Yao Hsieh; Min-Liang Kuo; Jaw-Town Lin
- 作者服務機構: 1 Department of Internal Medicine. ; 2 Department of Forensic Medicine and Pathology, ; 3 Department of Emergency Medicine, ; 4 Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, and ; 5 Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, National Taiwan University College of Medicine, No. 7, Chung-Shan S. Road, Taipei 100, Taiwan
- 中文摘要: --
- 英文摘要: 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). Immu-nohistochemical 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-la (HIF-1α) protein by antisense HIF-1α transfection, VEGF production was reduced in AGS/ COX-2 cells in a dose-dependent manner. We found that HIF-1α 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-1α protein accumulation and achieved a similar inhibitory effect on VEGF production as did antisense HIF-lα transfection. Our work supports the COX-2/PGE2/HIF-1α/VEGF pathway possibly contributing to tumor angiogenesis in GC.
- 中文關鍵字: --
- 英文關鍵字: angiogenesis, cyclooxygenase-2, gastric carcinoma