Development of gastric tumors in ApcMin/+ mice by the activation of the β-catenin/Tcf signaling pathway
Development of gastric tumors in ApcMin/+ mice by the activation of the β-catenin/Tcf signaling pathway
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DOI：
10.1158/0008-5472.can-06-4025
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Mori, Hideki
中科院分区：
文献类型：
--
作者：
Tomita, Hiroyuki;Yamada, Yasuhiro;Mori, Hideki
虽然有证据表明Writ通路参与胃癌的发生，但该通路在胃癌发生中的功能意义仍不明确。为了研究Apc/β连环蛋白信号通路在胃癌发生中的作用，我们研究了Apc（Min/+）小鼠的胃粘膜，该小鼠是家族性腺瘤性息肉病的小鼠模型，在Apc的密码子850处携带种系突变。我们发现，老年Apc（Min/+）小鼠自发地在胃中发生多个肿瘤，这伴随着Apc的杂合性丢失。这种肿瘤由β-连环蛋白在细胞核内大量积聚的腺瘤样腺体组成。即使是单个腺瘤性腺体也已经显示出β-连环蛋白的核积聚，这表明Apc/β-连环蛋白途径是Apc（Min/+）小鼠中胃肿瘤发生的起始事件。Myc和细胞周期蛋白D1的表达是β-连环蛋白/Tcf的转录靶点，在腺瘤性病变中增加。此外，具有Apc（Min）等位基因的β-catenin/Tcf报告基因转基因小鼠在胃肿瘤中表现出更高水平的β-catenin/Tcf转录活性。我们还用N-甲基-N-亚硝基脲（AINU）处理Apc（Min/+）和野生型小鼠，AINU是一种诱导胃腺瘤和腺癌的烷化剂。因此，与Apc（Min/+）小鼠或MNU处理的野生型小鼠相比，MNU处理的Apc（Min/+）小鼠显著增强了肿瘤发展。NINU处理的Apc（Min/+）小鼠中的几种胃肿瘤显示侵入粘膜下层。这些结果表明，Apc/β-catenin途径可能发挥重要作用，至少在胃癌的子集。此外，ApcMin/+小鼠与MNU组合可能是一个有用的短期模型，以研究多阶段胃癌发生。
Although several lines of evidence suggest the involvement of the Writ pathway in the development of gastric cancers, the functional significance of the pathway in gastric carcinogenesis is still poorly defined. To examine the role of the Apc/beta catenin signaling pathway in the development of gastric cancers, we investigated the gastric mucosa of the Apc(Min/+) mouse, which is a murine model for familial adenomatous polyposis, carrying a germ-line mutation at codon 850 of Apc. We found that aged Apc(Min/+) mice spontaneously develop multiple tumors in the stomach, which are accompanied by loss of heterozygosity of Apc. Such tumors consisted of adenomatous glands with strong nuclear accumulation of beta-catenin. Even a single adenomatous gland already showed nuclear accumulation of beta-catenin, suggesting that Apc/beta-catenin pathway is an initiating event in gastric tumorigenesis in Apc(Min/+) mice. Myc and cyclin D1 expressions, which are transcriptional targets of beta-catenin/Tcf, increased in the adenomatous lesions. Furthermore, beta-catenin/Tcf reporter transgenic mice with Apc(Min) allele showed higher levels of the transcriptional activity of beta-catenin/Tcf in the gastric tumors. We also treated Apc(Min/+) and wild-type mice with N-methyl-N-nitrosourea (AINU), an alkylating agent that induces adenomas and adenocarcinomas in the stomach. Consequently, MNU-treated Apc(Min/+) mice significantly enhanced the tumor development in comparison with Apc(Min/+) mice or MNU-treated wild-type mice. Several gastric tumors in NINU-treated Apc(Min/+) mice showed invasion into the submucosal layer. These results indicate that the Apc/beta-catenin pathway may play an important role in at least subset of gastric carcinomas. In addition, ApcMin/+ mice combined with MNU could be a useful short-term model to investigate multistage carcinogenesis in the stomach.