1. WntシグナルとCOX-2経路の活性化による新規胃がん発生モデルマウス
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Prostaglandin E2 (PGE<SUB>2</SUB>) and Wnt signaling are two indispensable pathways for gastrointestinal tumorigenesis. As a downstream product of cyclooxygenase 2 (COX-2), PGE<SUB>2</SUB> plays a key role in gastric tumorigenesis. The Wnt pathway also plays a causal role in gastric carcinogenesis. However, crosstalk or cooperation of these pathways for tumorigenesis remains poorly understood yet. To investigate their roles in gastric cancer development, we have generated two transgenic lines that activate either of two pathways in the gastric epithelial cells. First, we constructed <I>K19-C2mE</I> mice that expressed COX-2 and mPGES-1 simultaneously using the keratin 19 (K19) promoter. <I>K19-C2mE</I> mice showed increased PGE<SUB>2</SUB> level in the gastric mucosa that caused mucous cell metaplasia and hyperplasia. We next constructed <I>K19-Wnt1</I> transgenic mice expressing Wntl in the gastric mucosa driven by K19 promoter. <I>K19- Wnt1</I> mice had a significant suppression of epithelial differentiation, and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. However, <I>K19-Wnt1</I> mice did not develop gastric tumors. We then crossed <I>K19-Wnt1</I> mice with <I>K19-C2mE</I> to obtain <I>K19-Wnt1/C2mE</I> compound transgenic mice. Importantly, simultaneous activation of PGE<SUB>2</SUB> and Wnt pathways converted the preneoplastic lesions in the <I>K19-Wntl</I> mice into malignant gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the compound <I>K19-Wnt1/ C2mE</I> mice as early as 5 weeks of age, before the dysplastic tumor development. These results indicate that cooperation of Wnt and PGE<SUB>2</SUB> pathways causes malignant gastric tumor development through the metaplasia-carcinoma sequence. Accordingly, <I>K19- Wnt1/ C2mE</I> mouse model is a useful tool to study the genetic mechanism of gastric carcinogenesis through activation of the Wnt and PGE<SUB>2</SUB> pathways.
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