Oyama Takeru, Yamada Yasuhiro, Hata Kazuya, Tomita Hiroyuki, Hirata Akihiro, Sheng Hongqiang, Hara Akira, Aoki Hitomi, Kunisada Takahiro, Yamashita Satoshi, Mori Hideki
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Carcinogenesis. 2008 Mar;29(3):666-72. doi: 10.1093/carcin/bgn001. Epub 2008 Jan 19.
Apc(Min/+) 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 Apc(Min/+) mouse: microadenomas and macroscopic tumors. Microadenomas already have lost their remaining allele of the Apc and all microadenomas show accumulation of beta-catenin, indicating that activation of the canonical Wnt pathway is an initiating event in the tumorigenesis. This study shows that expression of nuclear beta-catenin in macroscopic tumors is further upregulated in comparison with that in microadenomas. Furthermore, transcriptional activity of beta-catenin/T-cell factor (Tcf) signaling, assessed using beta-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 beta-catenin/Tcf transcription plays a role not only in the initiation stage but also in the promotion stage of colon carcinogenesis in Apc(Min/+) mice.
Apc(Min/+)小鼠是一种人类家族性腺瘤性息肉病的小鼠模型，其Apc基因存在截短突变，并会自发形成肠道肿瘤。我们之前的研究揭示了Apc(Min/+)小鼠结肠肿瘤发生的两个不同阶段：微腺瘤和肉眼可见的肿瘤。微腺瘤已经失去了其Apc基因的剩余等位基因，并且所有微腺瘤都显示出β-连环蛋白的积累，这表明经典Wnt信号通路的激活是肿瘤发生的起始事件。本研究表明，与微腺瘤相比，肉眼可见肿瘤中核β-连环蛋白的表达进一步上调。此外，使用β-连环蛋白/T细胞因子（Tcf）报告基因转基因小鼠评估，β-连环蛋白/Tcf信号的转录活性在肉眼可见肿瘤中高于微腺瘤。另外，已知作为经典Wnt信号通路负调节因子的Dickkopf-1的表达水平仅在结肠肿瘤中降低。这些结果表明，β-连环蛋白/Tcf转录的激活不仅在Apc(Min/+)小鼠结肠癌发生的起始阶段起作用，而且在促进阶段也起作用。
