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Chemopreventive Effect of Peroxisome Proliferator–Activated Receptor on Gastric Carcinogenesis in Mice

Departments of ¹ Gastrointestinal Surgery and ² Internal Medicine, Faculty of Medicine; ³ Department of Metabolic Diseases, Graduate School of Medicine; and ⁴ Department of Hematopoietic Factors, Institute of Medical Science, University of Tokyo, Tokyo, Japan; ⁵ Investigative Treatment Division and ⁶ Pathology Division, National Cancer Center Research Institute East, Kashiwa, Chiba, Japan; and ⁷ Gastroenterology Division, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Requests for reprints: Jie Lu, Investigative Treatment Division, National Cancer Center Research Institute East, 6-5-1, Kashiwa, Chiba 277-8577, Japan. Phone: 81-471-34-6859; Fax: 81-471-34-6866; E-mail: jlu{at}east.ncc.go.jp.

Peroxisome proliferator–activated receptor (PPAR) is known to be expressed in several cancers, and the treatment of these cancer cells with PPAR ligands often induces cell differentiation and apoptosis. Recently, the chemopreventive potential of PPAR ligands on colon carcinogenesis was reported, although the effect of PPAR on colon carcinogenesis and the mechanism of the effect remain controversial. In this study, we attempted to elucidate the role of PPAR in gastric carcinogenesis and explored the possible use of PPAR ligand as a chemopreventive agent for gastric cancer. N-methyl-N-nitrosourea (MNU, 240 ppm) was given in drinking water for 10 weeks to induce gastric cancer in PPAR wild-type (+/+) and heterozygous-deficient (+/–) mice, followed by treatment with PPAR ligand [troglitazone, 0.15% (w/w) in powder food] or the vehicle alone for 42 weeks. At the end of the experiment, PPAR (+/–) mice were more susceptible to MNU-induced gastric cancer than wild-type (+/+) mice (89.5%/55.5%), and troglitazone significantly reduced the incidence of gastric cancer in PPAR (+/+) mice (treatment 55.5%/vehicle 9%) but not in PPAR (+/–) mice. The present study showed that (a) PPAR suppresses gastric carcinogenesis, (b) the PPAR ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and (c) troglitazone's chemopreventative effect is dependent on PPAR.

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