Inhibition of peroxisome proliferator-activated receptor gamma promotes tumorigenesis through activation of the beta-catenin / T cell factor (TCF) pathway in the mouse intestine.
Although peroxisome proliferator-activated receptor gamma (PPARgamma) is strongly expressed in the intestinal epithelium, the role of PPARgamma in intestinal tumorigenesis has not yet been elucidated. To address this issue, we investigated the effect of PPARgamma inhibition and its mechanism on intestinal tumorigenesis using a selective antagonist, T0070907. We treated Apc(Min/+) 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 beta-catenin protein in the colon epithelium. To investigate its mechanism, the changes of beta-catenin/TCF (T cell factor) transcriptional activity and location of beta-catenin induced by T0070907 were investigated in the colon cancer cell lines. T0070907 promoted polyp formation in the small intestine of Apc(Min/+) mice and aberrant crypt foci in the colon of C57BL/6 mice. PPARgamma inhibition promoted cell proliferation and increased expressions of the c-myc and cyclin D1 genes and the beta-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 beta-catenin/TCF transcriptional activity and beta-catenin protein in the cytsol and nucleus, but relatively decreased it on the cell membrane. PPARgamma antagonist promotes tumorigenesis in the small intestine and colon through stimulation of epithelial cell proliferation. beta-Catenin contributes to the promotion of tumorigenesis by PPARgamma antagonist due to activation of TCF/LEF (lymphoid enhancer factor) transcriptional factor.
Fujisawa
Toshio
T
Division of Gastroenterology, Yokohama City University School of Medicine, Japan.
Sugiyama
Michiko
M
Tomimoto
Ayako
A
Wada
Koichiro
K
Endo
Hiroki
H
Takahashi
Hirokazu
H
Yoneda
Kyoko
K
Yoneda
Masato
M
Inamori
Masahiko
M
Saito
Satoru
S
Terauchi
Yasuo
Y
Kadowaki
Takashi
T
Tsuchiya
Naoto
N
Nakagama
Hitoshi
H
Nakajima
Atsushi
A
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003106:Colon / Q000503:physiopathology; D003110:Colonic Neoplasms / Q000503:physiopathology*; D003111:Colonic Polyps / Q000503:physiopathology; D019938:Cyclin D1 / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011230:Precancerous Conditions / Q000503:physiopathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D051820:TCF Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D001549:Benzamides; D047495:PPAR gamma; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; C458508:T 0070907; D051820:TCF Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1