title: Roles of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression and beta-catenin activation in gastric carcinogenesis in N-methyl-N-nitrosourea-treated K19-C2mE transgenic mice.
abstract: K19-C2mE transgenic (Tg) mice, simultaneously expressing cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) in the gastric mucosa under the cytokeratin 19 gene promoter, were here treated with N-methyl-N-nitrosourea (MNU) and inoculated with Helicobacter pylori (H. pylori) to investigate gastric carcinogenesis. Wild-type (WT) and Tg mice undergoing MNU treatment frequently developed tumors in the pyloric region (100% and 94.7%, respectively); multiplicity in Tg was higher than that in WT (P < 0.05) with H. pylori infection. Larger pyloric tumors were more frequently observed in Tg than in WT (P < 0.05). In addition, Tg developed fundic tumors, where WT did not. No gastric tumors were observed without MNU treatment. Transcripts of TNF-alpha, iNOS, IL-1beta, and CXCL14 were up-regulated with H. pylori infection in both genotypes and were also increased more in Tg than in WT within H. pylori-inoculated animals. Immunohistochemical analysis demonstrated significantly greater beta-catenin accumulation in pyloric tumors, compared with those in the fundus (P < 0.01) with mutations of exon 3; 18.2% and 31.6% in MNU-alone and MNU + H. pylori-treated WT, whereas 21.4% and 62.5% was observed in the Tg, respectively; the latter significantly higher (P < 0.05), suggesting the role of H. pylori in Wnt activation. In conclusion, K19-C2mE mice promoted gastric cancer in both fundic and pyloric regions. Furthermore beta-catenin activation may play the important role of pyloric carcinogenesis especially in H. pylori-infected Tg. Induction of various inflammatory cytokines in addition to overexpression of COX-2/mPGES-1 could be risk factors of gastric carcinogenesis and may serve as a better gastric carcinogenesis model.
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takasu
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Cao
authors.forename: Takeshi
authors.initials: T
authors.lastname: Toyoda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirata
authors.forename: Hisayo
authors.initials: H
authors.lastname: Ban
authors.forename: Masami
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.forename: Tokuma
authors.initials: T
authors.lastname: Yanai
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Masegi
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori / Q000472:pathogenicity; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008770:Methylnitrosourea / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008861:Microsomes; D000071876:Prostaglandin-E Synthases; D011897:Random Allocation; D013274:Stomach Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D051176:beta Catenin; D008770:Methylnitrosourea; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse