The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia
The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia
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DOI：
10.1038/s42003-020-0847-y
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发表时间：
2020-03-18
影响因子：
5.9
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
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作者：
Sato, Nanami;Yako, Yuta;Fujita, Yasuyuki
在癌变初期，当RasV12转化的细胞被正常上皮细胞包围时，通过与周围正常细胞的竞争，RasV12细胞从上皮细胞顶端挤出。在这项研究中，我们证明了环氧化酶(COX)-2的表达在rasv12转化细胞周围的正常细胞中上调。添加COX抑制剂或敲除COX-2可促进RasV12细胞的顶端挤压。此外，在RasV12细胞周围的正常细胞中，COX-2的下游类前列腺素（PG） E-2的产生升高，PGE(2)的加入抑制了RasV12细胞的顶端挤压。在细胞竞争小鼠模型中，COX-2在含有RasV12表达细胞的胰腺上皮中表达升高，COX抑制剂布洛芬促进RasV12细胞的顶端挤压。此外，小蛋白诱导的慢性炎症实质上抑制了RasV12细胞的根尖消除。这些结果表明，内在或外部介导的炎症可以通过减少正常细胞和转化细胞之间的细胞竞争来促进肿瘤的发生。Sato等人发现，在含有一些rasv12转化细胞的上皮细胞片中，在转化细胞周围的正常细胞中，环氧化酶-2的表达和其下游产物前列腺素E2的产生增加，并抑制后者的挤压。这项研究揭示了转化细胞是如何从上皮细胞中消除的。
At the initial stage of carcinogenesis, when RasV12-transformed cells are surrounded by normal epithelial cells, RasV12 cells are apically extruded from epithelia through cell competition with the surrounding normal cells. In this study, we demonstrate that expression of cyclooxygenase (COX)-2 is upregulated in normal cells surrounding RasV12-transformed cells. Addition of COX inhibitor or COX-2-knockout promotes apical extrusion of RasV12 cells. Furthermore, production of Prostaglandin (PG) E-2, a downstream prostanoid of COX-2, is elevated in normal cells surrounding RasV12 cells, and addition of PGE(2) suppresses apical extrusion of RasV12 cells. In a cell competition mouse model, expression of COX-2 is elevated in pancreatic epithelia harbouring RasV12-exressing cells, and the COX inhibitor ibuprofen promotes apical extrusion of RasV12 cells. Moreover, caerulein-induced chronic inflammation substantially suppresses apical elimination of RasV12 cells. These results indicate that intrinsically or extrinsically mediated inflammation can promote tumour initiation by diminishing cell competition between normal and transformed cells.Sato et al find that in an epithelial cell sheet containing some RasV12-transformed cells, expression of cyclooxygenase-2 and production of its downstream product prostaglandin E2 are increased in normal cells surrounding transformed cells, and suppress extrusion of the latter. This study sheds light on how transformed cells are eliminated from epithelia.