• Open Access

Roles of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression and β-catenin activation in gastric carcinogenesis in N-methyl-N-nitrosourea-treated K19-C2mE transgenic mice

Authors

  • Shinji Takasu,

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
    2. Department of Veterinary Pathology, Gifu University, Yanagido, 1-1, Gifu 501-1193, Japan;
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  • Tetsuya Tsukamoto,

    Corresponding author
    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
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  • Xue-Yuan Cao,

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
    2. Department of General Surgery, the First Clinical Hospital of Jilin University, Changchun 130021, China;
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  • Takeshi Toyoda,

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
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  • Akihiro Hirata,

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
    2. Division of Animal Experiment, Life Science Research Center, Gifu University, 1-1 Yanangido, Gifu 501-1194, Japan;
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  • Hisayo Ban,

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
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  • Masami Yamamoto,

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
    2. Nippon Veterinary and Life Science University, School of Veterinary Nursing and Technology, 1-7-1 Sakaiminamimachi, Musashino, Tokyo 180-8602;
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  • Hiroki Sakai,

    1. Department of Veterinary Pathology, Gifu University, Yanagido, 1-1, Gifu 501-1193, Japan;
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  • Tokuma Yanai,

    1. Department of Veterinary Pathology, Gifu University, Yanagido, 1-1, Gifu 501-1193, Japan;
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  • Toshiaki Masegi,

    1. Department of Veterinary Pathology, Gifu University, Yanagido, 1-1, Gifu 501-1193, Japan;
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  • Masanobu Oshima,

    1. Division of Genetics, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
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  • Masae Tatematsu

    1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681;
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To whom correspondence should be addressed. E-mail: ttsukamt@aichi-cc.jp

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-α, iNOS, IL-1β, 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 β-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 β-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. (Cancer Sci 2008; 99: 2356–2364)

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