title: In vitro evidence of the role of COX-2 in attenuating gastric inflammation and promoting gastric carcinogenesis.
abstract: Although gastric adenocarcinoma is one of the most common malignancies in the world, little is known about its exact molecular processes in development and progression. Recent studies suggest that COX-2 is important in carcinogenesis of gastrointestinal cancers, and is especially involved in carcinogenesis in a mouse model of familial adenomatosis polyposis. To understand the role of COX-2 in gastric carcinogenesis and Helicobacter pylori-associated gastritis, we measured COX-2 expression in 170 human gastric carcinoma tissues byimmunohistochemical analysis and compared the expression of COX-2 in paired tissues obtained from normal-looking and cancer-bearing mucosa. Further evidence of the involvement of COX-2 in gastritis and gastric carcinogenesis was obtained by establishing stable cell lines overexpressing COX-2. After subcloning of COX-2 into pCB7 mammalian expression vector, two stable cell lines named MKN-28-COX-2 and MKN-45-COX-2 were generated by transfection of COX-2 cDNA. To understand the effect of COX-2 on gastritis, we performed an electrophoretic mobility shift assay of NF-kappaB (inflammation-associated transcription factor), and measured malondialdehyde levels and chemiluminescence activities in both mock-transfected MKN and MKN-COX-2 cells after stimulation of H. pylori (1 x 10(6) CFU/mL) and neutrophils (10(2) cells/mL). A marked attenuation of NF-kappaB bindings and generation of free radicals was observed in COX-2 overexpressed cells. Another set of experiments, including the growth inhibition by TGF-beta treatment, Matrigel invasion assay, and apoptosis assay, was done. COX-2 showed the advantage of the escape from the growth inhibition by TGF-beta through decreasing TGF-beta RII expression and increased cell invasiveness. In conclusion, COX-2 expression seems to be induced to attenuate the degree of atrophic gastritis, the initial event in gastric carcinogenesis, and promote gastric carcinogenesis.
authors.affiliation: Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea. hahmkb@hotmail.com
authors.forename: Ki-Baik
authors.initials: KB
authors.lastname: Hahm
authors.forename: Ho-Yeong
authors.initials: HY
authors.lastname: Lim
authors.forename: Seongbyang
authors.initials: S
authors.lastname: Sohn
authors.forename: Hyuk-Jae
authors.initials: HJ
authors.lastname: Kwon
authors.forename: K-Myung
authors.initials: KM
authors.lastname: Lee
authors.forename: Jeong-Sang
authors.initials: JS
authors.lastname: Lee
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Hee-Jae
authors.initials: HJ
authors.lastname: Joo
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Kim
authors.forename: Seung-Won
authors.initials: SW
authors.lastname: Cho
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology*; D017209:Apoptosis; D001284:Atrophy; D051546:Cyclooxygenase 2; D005756:Gastritis / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D016481:Helicobacter Infections / Q000150:complications*; D006801:Humans; D007249:Inflammation; D007527:Isoenzymes / Q000494:pharmacology*; D008565:Membrane Proteins; D016328:NF-kappa B / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000503:physiopathology*
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases