The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia

Nanami Sato,Suzumi M Tokuoka,Yoshihiro Kita,Yoshihiro Kita,Keisuke Kuromiya,Yasuyuki Fujita,Susumu Ishikawa,Yuta Yako,Takeshi Maruyama

doi:10.1038/s42003-020-0847-y

Nanami Sato, Suzumi M Tokuoka + Show 7 more

Open Access

https://doi.org/10.1038/s42003-020-0847-y

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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.

Highlights

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
We demonstrate that COX-2 expression and PGE2 production are upregulated in normal cells neighbouring RasV12-transformed cells in a non-cell-autonomous fashion, which plays an inhibitory role in apical extrusion of transformed cells from epithelia
green fluorescent protein (GFP)-negative normal Madin–Darby canine kidney (MDCK) cells were collected by fluorescence-activated cell sorting (FACS), and expression of various genes was compared between the two conditions (Fig. 1a)

Summary

Introduction

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. We demonstrate that expression of cyclooxygenase (COX)−2 is upregulated in normal cells surrounding RasV12-transformed cells. 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. Normal cells are able to sense the presence of the neighbouring transformed cells and actively eliminate them from epithelia, a process termed ‘epithelial defence against cancer’ (EDAC) Despite this anti-tumour activity, cancer often arises from epithelial tissues, suggesting that there may be molecular mechanisms that diminish EDAC. We demonstrate that COX-2 expression and PGE2 production are upregulated in normal cells neighbouring RasV12-transformed cells in a non-cell-autonomous fashion, which plays an inhibitory role in apical extrusion of transformed cells from epithelia

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