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The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia
Nanami Sato1, Yuta Yako1, Takeshi Maruyama1
1Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo, Hokkaido, 060-0815, Japan.
Abstract:
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.
Insights
Inflammation, driven by cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), hinders cell competition, allowing RasV12-transformed cells to evade elimination and promoting tumor initiation.
Area of Science:
- Oncology
- Cell Biology
- Inflammation Research
Background:
- RasV12-transformed cells are initially eliminated by normal epithelial cells via apical extrusion.
- Cell competition is a crucial mechanism for early tumor suppression.
Purpose of the Study:
- To investigate the role of cyclooxygenase-2 (COX-2) and its downstream products in regulating cell competition during early carcinogenesis.
- To determine if inflammation influences the elimination of Ras-transformed cells.
Main Methods:
- Utilized cell culture models with RasV12-transformed cells and normal epithelial cells.
- Administered COX inhibitors and Prostaglandin E2 (PGE2).
- Employed a mouse model of pancreatic carcinogenesis and induced chronic inflammation.
Main Results:
- COX-2 expression was upregulated in normal cells surrounding RasV12 cells.
- COX inhibition or COX-2 knockout enhanced the apical extrusion of RasV12 cells.
- PGE2 production increased in normal cells, and exogenous PGE2 suppressed RasV12 cell extrusion.
- Inflammation, induced by caerulein, significantly reduced the elimination of RasV12 cells in vivo.
Conclusions:
- Inflammation, mediated by COX-2 and PGE2, suppresses cell competition.
- This suppression of cell competition by inflammation promotes tumor initiation by allowing transformed cells to survive.
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