Abstract
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-1α (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-1α transfection. Our work supports the COX-2/PGE2/HIF-1α/VEGF pathway possibly contributing to tumor angiogenesis in GC.
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References
D. Hanahan R.A. Weinberg (2000) ArticleTitleThe hallmarks of cancer Cell 100 57–70 Occurrence Handle10.1016/S0092-8674(00)81683-9 Occurrence Handle1:CAS:528:DC%2BD3cXks1CktA%3D%3D Occurrence Handle10647931
L.M. Coussens Z. Werb (2002) ArticleTitleInflammation and cancer Nature 420 860–867 Occurrence Handle10.1038/nature01322 Occurrence Handle1:CAS:528:DC%2BD38XpsFygtb4%3D Occurrence Handle12490959
P.A. Janne R.J. Mayer (2000) ArticleTitleChemoprevention of colorectal cancer New Engl. J. Med. 342 1960–1968
G.A. FitzGerald C. Patrono (2001) ArticleTitleThe coxibs, selective inhibitors of cyclooxygenase-2 New Engl. J. Med. 345 433–442
P. Carmeliet R.K. Jain (2000) ArticleTitleAngiogenesis in cancer and other diseases Nature 407 249–257 Occurrence Handle10.1038/35025220
J. Folkman (1995) ArticleTitleSeminars in Medicine of the Beth Israel Hospital, Boston Clinical applications of research on angiogenesis. New Engl. J. Med. 333 1757–1763
N. Ferrara H.P. Gerber J. LeCouter (2003) ArticleTitleThe biology of VEGF and its receptors Nat. Med. 9 669–676
P. Carmeliet Y. Dor J.M. Herbert D. Fukumura K. Brusselmans M. Dewerchin M. Neeman F. Bono R. Abramovitch P. Maxwell C.J. Koch P. Ratcliffe L. Moons R.K. Jain D. Collen E. Keshert E. Keshet (1998) ArticleTitleRole of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis Nature 394 485–490
A. Giaccia B.G. Siim R.S. Johnson (2003) ArticleTitleHIF-1 as a target for drug development Nat. Rev. Drug Discov. 2 803–811
G.L. Semenza (2003) ArticleTitleTargeting HIF-1 for cancer therapy Nat. Rev. Cancer 3 721–732
J.W. Lee S.H. Bae J.W. Jeong S.H. Kim K.W. Kim (2004) ArticleTitleHypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions Exp. Mol. Med. 36 1–12
K. Subbaramaiah A.J. Dannenberg (2003) ArticleTitleCyclooxygenase 2: a molecular target for cancer prevention and treatment Trends Pharmacol. Sci. 24 96–102
K. Saukkonen J. Rintahaka A. Sivula C.J. Buskens ParticleVan B.P. Rees M.C. Rio C. Haglund ParticleVan J.J. Lanschot G.J. Offerhaus A. Ristimaki (2003) ArticleTitleCyclooxygenase-2 and gastric carcinogenesis Apmis. 111 915–925
P.J. Hu J. Yu Z.R. Zeng W.K. Leung H.L. Lin B.D. Tang A.H. Bai J.J. Sung (2004) ArticleTitleChemoprevention of gastric cancer by celecoxib in rats Gut 53 195–200
A.J. Dannenberg N.K. Altorki J.O. Boyle C. Dang L.R. Howe B.B. Weksler K. Subbaramaiah (2001) ArticleTitleCyclo-oxygenase 2: a pharmacological target for the prevention of cancer Lancet Oncol. 2 544–551
M.A. Iniguez A. Rodriguez O.V. Volpert M. Fresno J.M. Redondo (2003) ArticleTitleCyclooxygenase-2: a therapeutic target in angiogenesis Trends Mol. Med. 9 73–78
T. Kajitani (1981) ArticleTitleThe general rules for the gastric cancer study in surgery and pathology Part I. Clinical classification. Jpn. J. Surg. 11 127–139
D.R. Lauren D.J. Jensen J.A. Douglas J.M. Follett (2001) ArticleTitleEfficient method for determining the glycyrrhizin content of fresh and dried roots, and root extracts, of Glycyrrhiza species Phytochem. Anal. 12 332–335
K.S. Chapple E.J. Cartwright G. Hawcroft A. Tisbury C. Bonifer N. Scott A.C. Windsor P.J. Guillou A.F. Markham P.L. Coletta M.A. Hull (2000) ArticleTitleLocalization of cyclooxygenase-2 in human sporadic colorectal adenomas Am. J. Pathol. 156 545–553
R. Yamaguchi H. Yano A. Iemura S. Ogasawara M. Haramaki M. Kojiro (1998) ArticleTitleExpression of vascular endothelial growth factor in human hepatocellular carcinoma Hepatology 28 68–77
S.P. Huang M.S. Wu C.T. Shun H.P. Wang J.T. Lin (2002) ArticleTitleTumor angiogenesis increases with nuclear p53 accumulation in gastric carcinoma Hepatogastroenterology 49 1453–1456
M.J. Fackler C.I. Civin D.R. Sutherland M.A. Baker W.S. May (1990) ArticleTitleActivated protein kinase C directly phosphorylates the CD34 antigen on hematopoietic cells J. Biol. Chem. 265 11056–11061
Y. Kubota H.K. Kleinman G.R. Martin T.J. Lawley (1988) ArticleTitleRole of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures J. Cell. Biol. 107 1589–1598
J.C. Juarez X. Guan N.V. Shipulina M.L. Plunkett G.C. Parry D.E. Shaw J.C. Zhang S.A. Rabbani K.R. McCrae A.P. Mazar W.T. Morgan F. Donate (2002) ArticleTitleHistidine-proline-rich glycoprotein has potent antiangiogenic activity mediated through the histidine-proline-rich domain Cancer Res. 62 5344–5350
K.M. Comerford T.J. Wallace J. Karhausen N.A. Louis M.C. Montalto S.P. Colgan (2002) ArticleTitleHypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene Cancer Res. 62 3387–3394
I. Caniggia H. Mostachfi J. Winter M. Gassmann S.J. Lye M. Kuliszewski M. Post (2000) ArticleTitleHypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3) J. Clin. Invest. 105 577–587
Y.E. Joo J.S. Rew Y.H. Seo S.K. Choi Y.J. Kim C.S. Park S.J. Kim (2003) ArticleTitleCyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer J. Clin. Gastroenterol. 37 28–33
W.K. Leung K.F. To M.Y. Go K.K. Chan F.K. Chan E.K. Ng S.C. Chung J.J. Sung (2003) ArticleTitleCyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma Int. J. Oncol. 23 1317–1322
H.X. Li X.M. Chang Z.J. Song S.X. He (2003) ArticleTitleCorrelation between expression of cyclooxygenase-2 and angiogenesis in human gastric adenocarcinoma World J. Gastroenterol. 9 674–677
H.G. Yu J.Y. Li Y.N. Yang H.S. Luo J.P. Yu J.J. Meier H. Schrader A. Bastian W.E. Schmidt F. Schmitz (2003) ArticleTitleIncreased abundance of cyclooxygenase-2 correlates with vascular endothelial growth factor-A abundance and tumor angiogenesis in gastric cancer Cancer Lett. 195 43–51
P.J. Keck S.D. Hauser G. Krivi K. Sanzo T. Warren J. Feder D.T. Connolly (1989) ArticleTitleVascular permeability factor, an endothelial cell mitogen related to PDGF Science 246 1309–1312
D.W. Leung G. Cachianes W.J. Kuang D.V. Goeddel N. Ferrara (1989) ArticleTitleVascular endothelial growth factor is a secreted angiogenic mitogen Science 246 1306–1309 Occurrence Handle1:CAS:528:DyaK3cXls1GltLo%3D Occurrence Handle2479986
P.H. Maxwell P.J. Ratcliffe (2002) ArticleTitleOxygen sensors and angiogenesis Semin. Cell Dev. Biol. 13 29–37
G.L. Semenza (2002) ArticleTitleHIF-1 and tumor progression: pathophysiology and therapeutics Trends Mol. Med. 8 S62–67
Y.S. Chun M.S. Kim J.W. Park (2002) ArticleTitleOxygen-dependent and -independent regulation of HIF-1alpha J. Korean Med. Sci. 17 581–588
M.K. Jones I.L. Szabo H. Kawanaka S.S. Husain A.S. Tarnawski (2002) ArticleTitlevon Hippel Lindau tumor suppressor and HIF-1alpha: new targets of NSAIDs inhibition of hypoxia-induced angiogenesis Faseb J. 16 264–266
N. Futaki S. Takahashi M. Yokoyama I. Arai S. Higuchi S. Otomo (1994) ArticleTitleNS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro Prostaglandins 47 55–59
N. Futaki I. Arai Y. Hamasaka S. Takahashi S. Higuchi S. Otomo (1993) ArticleTitleSelective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation J. Pharm. Pharmacol. 45 753–755
S.T. Palayoor P.J. Tofilon C.N. Coleman (2003) ArticleTitleIbuprofen-mediated reduction of hypoxia-inducible factors HIF-1alpha and HIF-2alpha in prostate cancer cells Clin. Cancer Res. 9 3150–3157
A. Rapisarda B. Uranchimeg D.A. Scudiero M. Selby E.A. Sausville R.H. Shoemaker G. Melillo (2002) ArticleTitleIdentification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway Cancer Res. 62 4316–4324
Y.J. Jung J.S. Isaacs S. Lee J. Trepel L. Neckers (2003) ArticleTitleIL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis Faseb J. 17 2115–2117
W.J. Lukiw A. Ottlecz G. Lambrou M. Grueninger J. Finley H.W. Thompson N.G. Bazan (2003) ArticleTitleCoordinate activation of HIF-1 and NF-kappaB DNA binding and COX-2 and VEGF expression in retinal cells by hypoxia Invest. Ophthalmol. Vis. Sci. 44 4163–4170
Y.Q. Wang J.M. Luk K. Ikeda K. Man A.C. Chu K. Kaneda S.T. Fan (2004) ArticleTitleRegulatory role of vHL/HIF-1alpha in hypoxia-induced VEGF production in hepatic stellate cells Biochem. Biophys. Res. Commun. 317 358–362
M.J. Thun S.J. Henley C. Patrono (2002) ArticleTitleNonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues J. Natl. Cancer Inst. 94 252–266
B.S. Reddy H. Maruyama G. Kelloff (1987) ArticleTitleDose-related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteroidal antiinflammatory drug, during different stages of rat colon tumor development Cancer Res. 47 5340–5346
S.P. Huang M.S. Wu C.T. Shun H.P. Wang M.T. Lin M.L. Kuo J.T. Lin (2004) ArticleTitleInterleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma J. Biomed. Sci. 11 517–527
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Huang, SP., Wu, MS., Shun, CT. et al. Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma. J Biomed Sci 12, 229–241 (2005). https://doi.org/10.1007/s11373-004-8177-5
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DOI: https://doi.org/10.1007/s11373-004-8177-5