Oshima Hiroko, Oguma Keisuke, Du Yu-Chen, Oshima Masanobu
Division of Genetics, Cancer Research Institute, Kanazawa University, Takara-machi, Kanazawa, Japan.
Cancer Sci. 2009 Oct;100(10):1779-85. doi: 10.1111/j.1349-7006.2009.01258.x. Epub 2009 Jun 23.
The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced in H. pylori-associated chronic gastritis, which thus results in the induction of proinflammatory prostaglandin, PGE(2). The COX-2/PGE(2) pathway plays a key role in gastric tumorigenesis. On the other hand, several oncogenic pathways have been shown to trigger gastric tumorigenesis. The activation of Wnt/beta-catenin signaling is found in 30-50% of gastric cancers, thus suggesting that Wnt signaling plays a causal role in gastric cancer development. Mutations in the bone morphogenetic protein (BMP) signaling pathway are responsible for the subset of juvenile polyposis syndrome (JPS) that develops hamartomas in the gastrointestinal tract. BMP suppression appears to contribute to gastric cancer development because gastric cancer risk is increased in JPS. Wnt signaling is important for the maintenance of gastrointestinal stem cells, while BMP promotes epithelial cell differentiation. Accordingly, it is possible that both Wnt activation and BMP suppression can cause gastric tumorigenesis through enhancement of the undifferentiated status of epithelial cells. Recent mouse model studies have indicated that induction of the PGE(2) pathway is required for the development of both gastric adenocarcinoma and hamartoma in the Wnt-activated and BMP-suppressed gastric mucosa, respectively. This article reviews the involvement of the PGE(2), Wnt, and BMP pathways in the development of gastric cancer, and gastric phenotypes that are found in transgenic mouse models of PGE(2) induction, Wnt activation, BMP suppression, or a combination of these pathways.
胃癌的发生与幽门螺杆菌（H. pylori）感染密切相关。环氧化酶-2（COX-2）是前列腺素生物合成的限速酶，其表达在幽门螺杆菌相关的慢性胃炎中被诱导，从而导致促炎前列腺素PGE(2)的诱导。COX-2/PGE(2)途径在胃癌发生中起关键作用。另一方面，已显示几种致癌途径可引发胃癌发生。在30%-50%的胃癌中发现Wnt/β-连环蛋白信号激活，这表明Wnt信号在胃癌发展中起因果作用。骨形态发生蛋白（BMP）信号通路的突变是导致在胃肠道发生错构瘤的青少年息肉病综合征（JPS）子集的原因。BMP抑制似乎有助于胃癌发展，因为JPS患者的胃癌风险增加。Wnt信号对于维持胃肠道干细胞很重要，而BMP促进上皮细胞分化。因此，Wnt激活和BMP抑制都有可能通过增强上皮细胞的未分化状态而导致胃癌发生。最近的小鼠模型研究表明，分别在Wnt激活和BMP抑制的胃黏膜中，PGE(2)途径的诱导是胃腺癌和错构瘤发生所必需的。本文综述了PGE(2)、Wnt和BMP途径在胃癌发生中的作用，以及在PGE(2)诱导、Wnt激活、BMP抑制或这些途径组合的转基因小鼠模型中发现的胃表型。
