Inhibition of Peroxisome Proliferator-Activated Receptor γ Promotes Tumorigenesis Through Activation of the β-Catenin/TCF Pathway in the Mouse Intestine
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概要
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Although peroxisome proliferator-activated receptor γ (PPARγ) is strongly expressed in the intestinal epithelium, the role of PPARγ in intestinal tumorigenesis has not yet been elucidated. To address this issue, we investigated the effect of PPARγ inhibition and its mechanism on intestinal tumorigenesis using a selective antagonist, T0070907. We treated ApcMin/+ mice and carcinogen-induced colon cancer model C57BL/6 mice with T0070907 and counted the number of spontaneous polyps and aberrant crypt foci and observed cell proliferation and β-catenin protein in the colon epithelium. To investigate its mechanism, the changes of β-catenin/TCF (T cell factor) transcriptional activity and location of β-catenin induced by T0070907 were investigated in the colon cancer cell lines. T0070907 promoted polyp formation in the small intestine of ApcMin/+ mice and aberrant crypt foci in the colon of C57BL/6 mice. PPARγ inhibition promoted cell proliferation and increased expressions of the c-myc and cyclin D1 genes and the β-catenin protein in the colon epithelium. In vitro, cell proliferation was promoted, but it was inhibited by the transfection of dominant-negative Tcf4. T0070907 increased β-catenin/TCF transcriptional activity and β-catenin protein in the cytsol and nucleus, but relatively decreased it on the cell membrane. PPARγ antagonist promotes tumorigenesis in the small intestine and colon through stimulation of epithelial cell proliferation. β-Catenin contributes to the promotion of tumorigenesis by PPARγ antagonist due to activation of TCF/LEF (lymphoid enhancer factor) transcriptional factor.
著者
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Yoneda Kyoko
Division of Gastroenterology, Yokohama City University Graduate School of Medicine
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Endo Hiroki
Division Of Gastroenterology Yokohama City University Graduate School Of Medicine
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Inamori Masahiko
Division Of Gastroenterology Yokohama City University Graduate School Of Medicine
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Fujisawa Toshio
Division Of Gastroenterology Yokohama City University School Of Medicine
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Nakagama Hitoshi
Biochemistry Division National Cancer Center Research Institute
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Saito Satoru
Division Of Gastroenterology Yokohama City University Graduate School Of Medicine
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Tomimoto Ayako
Division Of Gastroenterology Yokohama City University School Of Medicine
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Tsuchiya Naoto
Biochemistry Division National Cancer Center Research Institute
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Wada Koichiro
Department Of Mathematical And Computing Sciences Tokyo Institute Of Technology
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Sugiyama Michiko
Division Of Adult Health Science The National Institute Of Health And Nutrition
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Yoneda Masato
Division Of Gastroenterology Yokohama City University
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Takahashi Hirokazu
Division Of Biolobical Sciences Graduate School Of Science Hokkaido University
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Terauchi Yasuo
Division Of Cardiology Department Of Internal Medicine Showa University Fujigaoka Hospital
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Kadowaki Takashi
Department Of Cardiology Kawasaki Medical School
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NAKAJIMA Atsushi
Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University
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Inamori Masahiko
Division of Gastroenterology, Yokohama City University School of Medicine, Japan
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Nakagama Hitoshi
Biochemistry Division, National Cancer Center Research Institute, Japan
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Tomimoto Ayako
Division of Gastroenterology, Yokohama City University School of Medicine, Japan
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Yoneda Kyoko
Division of Gastroenterology, Yokohama City University School of Medicine, Japan
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Terauchi Yasuo
Division of Endocrinology and Metabolism, Yokohama City University School of Medicine, Japan
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Fujisawa Toshio
Division of Gastroenterology, Yokohama City University School of Medicine, Japan
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Kadowaki Takashi
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Japan
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Tsuchiya Naoto
Biochemistry Division, National Cancer Center Research Institute, Japan
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