Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo, Hokkaido, 060-0815, Japan.
Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Commun Biol. 2020 Mar 18;3(1):132. doi: 10.1038/s42003-020-0847-y.
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, a downstream prostanoid of COX-2, is elevated in normal cells surrounding RasV12 cells, and addition of PGE 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.
在致癌作用的初始阶段，当 RasV12 转化的细胞被正常上皮细胞包围时，RasV12 细胞通过与周围正常细胞的细胞竞争从上皮细胞的顶端被挤出。在本研究中，我们证明了 COX-2（环氧化酶）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 COX-2 敲除可促进 RasV12 细胞的顶端挤出。此外，PG（前列腺素）E 的产生，COX-2 的下游产物，在 RasV12 细胞周围的正常细胞中升高，添加 PGE 可抑制 RasV12 细胞的顶端挤出。在细胞竞争小鼠模型中，在含有 RasV12 表达细胞的胰腺上皮中 COX-2 的表达升高，COX 抑制剂布洛芬可促进 RasV12 细胞的顶端挤出。此外，鹅去氧胆酸诱导的慢性炎症会显著抑制 RasV12 细胞的顶端消除。这些结果表明，内在或外在介导的炎症可以通过减少正常和转化细胞之间的细胞竞争来促进肿瘤起始。
