Oshima Hiroko, Matsunaga Akihiro, Fujimura Takashi, Tsukamoto Tetsuya, Taketo Makoto M, Oshima Masanobu
Division of Genetics, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan.
Gastroenterology. 2006 Oct;131(4):1086-95. doi: 10.1053/j.gastro.2006.07.014.
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 Wnt pathway is also suggested to play a causal role in gastric carcinogenesis. However, the molecular mechanism remains poorly understood of how the Wnt and PGE(2) pathways contribute to gastric tumorigenesis. To investigate the role of Wnt and PGE(2) in gastric cancer, we have generated transgenic mice that activate both pathways and examined their phenotypes.
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 PGE(2) level. We examined the gastric phenotypes of both K19-Wnt1 and K19-Wnt1/C2mE mice.
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.
Wnt signaling keeps the gastric progenitor cells undifferentiated. Simultaneous activation of both Wnt and PGE(2) pathways causes dysplastic gastric tumors through the metaplasia-carcinoma sequence.
越来越多的证据表明，前列腺素E2（PGE2）作为环氧化酶2（COX-2）的下游产物，在胃癌发生过程中起关键作用。Wnt信号通路也被认为在胃癌发生中起因果作用。然而，Wnt和PGE2通路如何促进胃癌发生的分子机制仍知之甚少。为了研究Wnt和PGE2在胃癌中的作用，我们构建了激活这两条通路的转基因小鼠并观察其表型。
我们利用角蛋白19启动子构建了在胃黏膜中表达Wnt1的K19-Wnt1转基因小鼠。然后将K19-Wnt1小鼠与另一个转基因品系K19-C2mE杂交，获得K19-Wnt1/C2mE复合转基因小鼠。K19-C2mE小鼠在胃中表达COX-2和微粒体前列腺素E合酶-1（mPGES-1），胃内PGE2水平升高。我们观察了K19-Wnt1和K19-Wnt1/C2mE小鼠的胃表型。
K19-Wnt1小鼠上皮分化受到显著抑制，并形成由未分化上皮细胞和巨噬细胞聚集组成的小的癌前病变。重要的是，COX-2和mPGES-1的额外表达使K19-Wnt1小鼠的癌前病变在20周龄时转变为发育异常的胃肿瘤。值得注意的是，早在发育异常肿瘤形成之前，我们就在5周龄的K19-Wnt1/C2mE小鼠的腺胃中发现了黏液细胞化生。
Wnt信号使胃祖细胞保持未分化状态。Wnt和PGE2通路的同时激活通过化生-癌变序列导致发育异常的胃肿瘤。
