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Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma
Cancer-promoting inflammation is an important event in cancer development. Canine urothelial carcinoma (cUC) overexpresses prostaglandin E(2) (PGE(2)) and has a unique sensitivity to cyclooxygenase 2 (COX2)-inhibiting therapy. In addition, majority of cUC harbour BRAF(V595E) mutation. However, mecha...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210937/ https://www.ncbi.nlm.nih.gov/pubmed/32385388 http://dx.doi.org/10.1038/s41598-020-64832-5 |
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author | Yoshitake, Ryohei Saeki, Kohei Eto, Shotaro Shinada, Masahiro Nakano, Rei Sugiya, Hiroshi Endo, Yoshifumi Fujita, Naoki Nishimura, Ryohei Nakagawa, Takayuki |
author_facet | Yoshitake, Ryohei Saeki, Kohei Eto, Shotaro Shinada, Masahiro Nakano, Rei Sugiya, Hiroshi Endo, Yoshifumi Fujita, Naoki Nishimura, Ryohei Nakagawa, Takayuki |
author_sort | Yoshitake, Ryohei |
collection | PubMed |
description | Cancer-promoting inflammation is an important event in cancer development. Canine urothelial carcinoma (cUC) overexpresses prostaglandin E(2) (PGE(2)) and has a unique sensitivity to cyclooxygenase 2 (COX2)-inhibiting therapy. In addition, majority of cUC harbour BRAF(V595E) mutation. However, mechanisms underlying aberrant PGE(2) production in BRAF(V595E) cUC patients remain unclear. Drug screening revealed that inhibition of RAF/MEK/ERK pathway, p38 and JNK pathway reduced PGE(2) production in cUC cells. By pharmacological inhibition of the multiple components in the pathway, activation of the ERK MAPK pathway was shown to mediate overexpression of COX2 and production of PGE(2) in BRAF(V595E) cUC cells. In silico gain-of-function analysis of the BRAF mutation also implicated involvement of mutation in the process. The positive association between ERK activation and COX2 expression was further validated in the clinical patients. Moreover, it was also suggested that p38 and JNK regulates PGE(2) production independently of ERK pathway, possibly through COX2-dependent and COX1-/COX2- independent manner, respectively. In conclusion, this study demonstrated that activation of ERK induces production of PGE(2) in BRAF(V595E) cUC cells, which is also independently regulated by p38 and JNK. With its unique vulnerability to COX-targeted therapy, BRAF(V595E) cUC may serve as a valuable model to study the tumour-promoting inflammation. |
format | Online Article Text |
id | pubmed-7210937 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-72109372020-05-15 Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma Yoshitake, Ryohei Saeki, Kohei Eto, Shotaro Shinada, Masahiro Nakano, Rei Sugiya, Hiroshi Endo, Yoshifumi Fujita, Naoki Nishimura, Ryohei Nakagawa, Takayuki Sci Rep Article Cancer-promoting inflammation is an important event in cancer development. Canine urothelial carcinoma (cUC) overexpresses prostaglandin E(2) (PGE(2)) and has a unique sensitivity to cyclooxygenase 2 (COX2)-inhibiting therapy. In addition, majority of cUC harbour BRAF(V595E) mutation. However, mechanisms underlying aberrant PGE(2) production in BRAF(V595E) cUC patients remain unclear. Drug screening revealed that inhibition of RAF/MEK/ERK pathway, p38 and JNK pathway reduced PGE(2) production in cUC cells. By pharmacological inhibition of the multiple components in the pathway, activation of the ERK MAPK pathway was shown to mediate overexpression of COX2 and production of PGE(2) in BRAF(V595E) cUC cells. In silico gain-of-function analysis of the BRAF mutation also implicated involvement of mutation in the process. The positive association between ERK activation and COX2 expression was further validated in the clinical patients. Moreover, it was also suggested that p38 and JNK regulates PGE(2) production independently of ERK pathway, possibly through COX2-dependent and COX1-/COX2- independent manner, respectively. In conclusion, this study demonstrated that activation of ERK induces production of PGE(2) in BRAF(V595E) cUC cells, which is also independently regulated by p38 and JNK. With its unique vulnerability to COX-targeted therapy, BRAF(V595E) cUC may serve as a valuable model to study the tumour-promoting inflammation. Nature Publishing Group UK 2020-05-08 /pmc/articles/PMC7210937/ /pubmed/32385388 http://dx.doi.org/10.1038/s41598-020-64832-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Yoshitake, Ryohei Saeki, Kohei Eto, Shotaro Shinada, Masahiro Nakano, Rei Sugiya, Hiroshi Endo, Yoshifumi Fujita, Naoki Nishimura, Ryohei Nakagawa, Takayuki Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma |
title | Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma |
title_full | Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma |
title_fullStr | Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma |
title_full_unstemmed | Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma |
title_short | Aberrant expression of the COX2/PGE(2) axis is induced by activation of the RAF/MEK/ERK pathway in BRAF(V595E) canine urothelial carcinoma |
title_sort | aberrant expression of the cox2/pge(2) axis is induced by activation of the raf/mek/erk pathway in braf(v595e) canine urothelial carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210937/ https://www.ncbi.nlm.nih.gov/pubmed/32385388 http://dx.doi.org/10.1038/s41598-020-64832-5 |
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