並列タイトル等RasV12変異細胞の上皮層からの排除に作用するCOX-2/PGE2経路に関する研究
一般注記At the initial stage of carcinogenesis, when RasV12-transformed cells are surrounded by normal epithelial cells, RasV12 cells are often extruded from the apical lumen of the epithelial layer through cell competition with the surrounding normal cells. However, the underlying molecular mechanisms of this cancer preventive process are not fully understood. In this study, we first demonstrate that expression of cyclooxygenase (COX)2 is transcriptionally upregulated in normal epithelial cells that surround RasV12transformed cells in a non-cell-autonomous manner. Addition of COX inhibitor or COX2-knockout in normal cells 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. Addition of PGE2 suppresses apical extrusion of RasV12 cells, while PGE2 synthase inhibitor enhances it. In a cell competition mouse model, expression of COX-2 is elevated in pancreatic epithelia harbouring RasV12exressing cells, and administration of 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.
(主査) 教授 村上 洋太, 教授 藤田 恭之, 教授 石森 浩一郎, 教授 坂口 和靖, 教授 大利 徹
総合化学院(総合化学専攻)
コレクション(個別)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
受理日(W3CDTF)2020-08-11T22:41:34+09:00
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