Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway
Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway
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DOI：
10.1053/j.gastro.2006.07.014
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发表时间：
2006-10-01
期刊：
影响因子：
29.4
通讯作者：
Oshima, Masanobu
中科院分区：
文献类型：
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作者：
Oshima, Hiroko;Matsunaga, Akihiro;Oshima, Masanobu
背景和目标：越来越多的证据表明，环氧化酶2（考克斯-2）的下游产物前列腺素E-2（PGE（2））在胃肿瘤的发生中起着关键作用。Writ通路也被认为在胃癌发生中起着因果作用。然而，Writ和PGE 2通路如何促进胃肿瘤发生的分子机制仍然知之甚少。为了研究Writ和PGE 2在胃癌中的作用，我们产生了激活这两种途径的转基因小鼠，并检查了它们的表型。方法：构建K19-Wnt 1转基因小鼠，利用K19启动子在胃黏膜中表达Wnt 1。将K19-Wnt 1小鼠与另一转基因品系K19-C2mE杂交，获得K19-Wnt 1/C2mE复合转基因小鼠。K19-C2mE小鼠在胃中表达考克斯-2和微粒体前列腺素E合酶-1（mPGES-1），显示胃PGE 2水平升高。我们检查了K19-Wnt 1和K19-Wnt 1/C2mE小鼠的胃表型。结果如下：K19-Wnt 1小鼠的上皮分化受到显著抑制，并出现了由未分化上皮细胞和巨噬细胞积聚组成的小的癌前病变。重要的是，额外表达考克斯-2和mPGES-1将K19-Wnt 1小鼠的癌前病变在20周龄时转化为发育不良的胃肿瘤。值得注意的是，我们发现早在5周龄的K19-Wnt 1/C2mE小鼠的腺胃中的粘液细胞化生，在发育不良的肿瘤发展之前。结论：Writ信号通路维持胃前体细胞未分化。Writ和PGE 2途径的同时激活通过化生-癌序列引起发育不良的胃肿瘤。
Background & Aims: Accumulating evidence indicates that prostaglandin E-2 (PGE(2)), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. The Writ pathway is also suggested to play a causal role in gastric carcinogenesis. However, the molecular mechanism remains poorly understood of how the Writ and PGE2 pathways contribute to gastric tumorigenesis. To investigate the role of Writ and PGE2 in gastric cancer, we have generated transgenic mice that activate both pathways and examined their phenotypes. Methods: We constructed K19-Wnt1 transgenic mice expressing Wnt1 in the gastric mucosa using the keratin 19 promoter. We then crossed K19-Wnt1 mice with another transgenic line, K19-C2mE, to obtain K19-Wnt1/C2mE compound transgenic mice. The K19-C2mE mice express COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach, showing an increased gastric PGE2 level. We examined the gastric phenotypes of both K19-Wnt1 and K19-Wnt1/C2mE mice. Results: K19-Wnt1 mice had a significant suppression of epithelial differentiation and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. Importantly, additional expression of COX-2 and mPGES-1 converted the preneoplastic lesions in the K19-Wnt1 mice into dysplastic gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the K19-Wnt1/C2mE mice as early as 5 weeks of age, before the dysplastic tumor development. Conclusions: Writ signaling keeps the gastric progenitor cells undifferentiated. Simultaneous activation of both Writ and PGE2 pathways causes dysplastic gastric tumors through the metaplasia-carcinoma sequence.