TY - JOUR
T1 - The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia
AU - Sato, Nanami
AU - Yako, Yuta
AU - Maruyama, Takeshi
AU - Ishikawa, Susumu
AU - Kuromiya, Keisuke
AU - Tokuoka, Suzumi M.
AU - Kita, Yoshihiro
AU - Fujita, Yasuyuki
N1 - Funding Information:
We thank Dr. Masaki Yamada for the assistance of lipidomics analyses. This work was supported by Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research on Innovative Areas 26114001, the Scientific Research (A) 18H03994, Strategic Japanese-Swiss Science and Technology Program, AMED under Grant Numbers JP19ck0106361h0003 and JP19cm0106234h0002, SAN-ESU GIKEN CO. LTD and the Takeda Science Foundation (to Y.F.) and Grant-in-Aid for JSPS Research Fellow JP19J10318 (to N.S.).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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) E2, a downstream prostanoid of COX-2, is elevated in normal cells surrounding RasV12 cells, and addition of PGE2 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.
AB - 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) E2, a downstream prostanoid of COX-2, is elevated in normal cells surrounding RasV12 cells, and addition of PGE2 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.
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U2 - 10.1038/s42003-020-0847-y
DO - 10.1038/s42003-020-0847-y
M3 - Article
C2 - 32188886
AN - SCOPUS:85082109122
SN - 2399-3642
VL - 3
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 132
ER -