Further upregulation of β-catenin/Tcf transcription is involved in the development of macroscopic tumors in the colon of ApcMin/+ mice
Further upregulation of β-catenin/Tcf transcription is involved in the development of macroscopic tumors in the colon of ApcMin/+ mice
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DOI：
10.1093/carcin/bgn001
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发表时间：
2008-03-01
期刊：
影响因子：
4.7
通讯作者：
Mori, Hideki
中科院分区：
文献类型：
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作者：
Oyama, Takeru;Yamada, Yasuhiro;Mori, Hideki
Apc（Min/+）小鼠是人类家族性腺瘤性息肉病的小鼠模型，在Apc基因中含有截短突变，并自发发生肠道肿瘤。我们先前的研究揭示了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Apc的剩余等位基因，所有微腺瘤都显示β-连环蛋白的积累，表明经典Wnt途径的激活是肿瘤发生中的起始事件。这项研究表明，与微腺瘤相比，肉眼可见的肿瘤中细胞核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的β-连环蛋白/Tcf信号传导的转录活性在肉眼可见的肿瘤中高于微腺瘤中。此外，Dickkopf-1的表达水平仅在结肠肿瘤中降低，Dickkopf-1已知是经典Wnt途径的负调节剂。提示β-catenin/Tcf转录激活不仅在Apc（Min/+）小鼠结肠癌发生的起始阶段起作用，而且在结肠癌发生的促进阶段起作用。
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.