COX-2 and mPGES on proliferation-differentiation cycle of epithelial cells

环氧合酶-2(COX-2)是前列腺素生物合成的限速酶，在肿瘤的发生发展中起重要作用。微粒体前列腺素E合成酶(MPGES)-1是PGE_2合成的诱导性酶，与COX-2在功能上偶联，在某些肿瘤中表达上调。COX-2和mPGES-1在胃癌组织和结肠癌组织中的表达均上调。为了探讨前列腺素E_2在胃肿瘤发生中的作用，我们构建了腺胃同时表达COX-2和mPGES-1的转基因小鼠(K19-C2mE小鼠)。转基因小鼠出现了增生性肿瘤，并伴有大量巨噬细胞浸润。尽管转基因小鼠的胃细菌计数在正常范围内，但抗生素治疗显著抑制了巨噬细胞的激活和肿瘤的增殖。重要的是，抗生素处理并没有影响巨噬细胞的聚集。值得注意的是，细菌脂多糖处理胃上皮细胞通过Toll样受体诱导肿瘤坏死因子-α。这些结果表明，PGE_2的增加促进了巨噬细胞的聚集，胃内菌群刺激上皮细胞激活巨噬细胞，导致增生性肿瘤的发生。为了进一步研究促炎细胞因子的作用，我们将肿瘤坏死因子-α和白介素1-β受体的基因敲除突变分别导入K19-C2mE小鼠。阻断肿瘤坏死因子-α显著抑制胃肿瘤的形成，而IL-1β基因敲除不影响胃表型。因此，这些结果表明肿瘤坏死因子-α相关的炎症与增生性胃肿瘤的发生有关。抑制肿瘤坏死因子-α有可能阻止炎症相关的胃肿瘤的发生。

Cyclooxygenase-2(COX-2), a rate-limiting enzyme for prostanoid biosynthesis, plays an important role in tumor development. Microsomal prostaglandin E synthase (mPGES)-1, an inducible enzyme for PGE_2 synthesis, is functionally coupled with COX-2, and upregulated in some tumors. Expression of both COX-2 and mPGES-1 is up-regulated in the gastric cancer tissues as well as colon cancer. To investigate the role of PGE_2 in gastric tumorigenesis, we constructed transgenic mice (K19-C2mE mice) expressing COX-2 and mPGES-1 simultaneously in the glandular stomach. The transgenic mice developed hyperplastic tumors with heavy macrophage infiltrations. Although gastric bacterial counts in the transgenic mice were within the normal range, treatment with antibiotics significantly suppressed activation of the macrophages and tumorous hyperplasia. Importantly, the antibiotics-treatment did not affect the macrophage accumulation. Notably, treatment of the gastric epithelial cells with bacterial LPS induced TNF-α through Toll-like receptor4. These results indicate that an increased PGE_2 enhances macrophage accumulation, and that gastric flora stimulates epithelial cells to activate macrophages, resulting in hyperplastic tumor development. To investigate furher the role of proinflammatory cytokines, we introduced respective knockout mutations of TNF-α and IL-1β receptor into the K19-C2mE mice. Disruption of TNF-α suppressed gastric tumor formation significantly, while IL-1β knockout did not affect the gastric phenotypes. Accordingly, these results demonstrate that TNF-α-associated inflammation is responsible for hyperplastic gastric tumorigenesis. It is possible that inhibition of TNF-α prevents inflammation-associated gastric tumorigenesis.