Carcinogenesis Advance Access originally published online on January 19, 2008
Carcinogenesis 2008 29(3):666-672; doi:10.1093/carcin/bgn001
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Further upregulation of β-catenin/Tcf transcription is involved in the development of macroscopic tumors in the colon of ApcMin/+ mice
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
1 Division of Animal Experiment, Life Science Research Center, Gifu University, Yanagido 1-1, Gifu, 501-1193, Japan
2 Department of Tissue and Organ Development, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
3 Carcinogenesis Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan
* To whom correspondence should be addressed. Email: y-yamada{at}gifu-u.ac.jp
ApcMin/+ mouse, a mouse model for human familial adenomatosis polyposis, contains a truncating mutation in the Apc gene and spontaneously develops intestinal tumors. Our previous study revealed two distinct stages of tumorigenesis in the colon of ApcMin/+ mouse: microadenomas and macroscopic tumors. Microadenomas already have lost their remaining allele of the Apc and all microadenomas show accumulation of β-catenin, indicating that activation of the canonical Wnt pathway is an initiating event in the tumorigenesis. This study shows that expression of nuclear β-catenin in macroscopic tumors is further upregulated in comparison with that in microadenomas. Furthermore, transcriptional activity of β-catenin/T-cell factor (Tcf) signaling, assessed using β-catenin/Tcf reporter transgenic mice, is higher in the macroscopic tumors than that in microadenomas. In addition, the expression level of Dickkopf-1, which is known to be a negative modifier of the canonical Wnt pathway, was reduced only in colon tumors. These results suggest that activation of β-catenin/Tcf transcription plays a role not only in the initiation stage but also in the promotion stage of colon carcinogenesis in ApcMin/+ mice.
Abbreviations: Dkk1, Dickkopf-1; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; RT–PCR, reverse transcription—polymerase chain reaction; Tcf, T-cell factor
Received July 11, 2007; revised December 16, 2007; accepted December 28, 2007.
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