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Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation
Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748213/ https://www.ncbi.nlm.nih.gov/pubmed/34724284 http://dx.doi.org/10.1111/cas.15187 |
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author | Iwasaki, Takeshi Hayashi, Kazuhiko Matsushita, Michiko Nonaka, Daisuke Kohashi, Kenichi Kuwamoto, Satoshi Umekita, Yoshihisa Oda, Yoshinao |
author_facet | Iwasaki, Takeshi Hayashi, Kazuhiko Matsushita, Michiko Nonaka, Daisuke Kohashi, Kenichi Kuwamoto, Satoshi Umekita, Yoshihisa Oda, Yoshinao |
author_sort | Iwasaki, Takeshi |
collection | PubMed |
description | Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK‐ERK and JAK‐STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV‐positive and 20 MCPyV‐negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK‐ERK and JAK‐STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV‐negative than in MCPyV‐positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P < .001), negative MCPyV status (HR 0.324, P = .013), and advanced cancer stage (HR 2.672, P = .041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV‐negative MCC cell lines than in an MCPyV‐positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV‐negative than in MCPyV‐positive cell lines. These results suggest that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC and the JAK inhibitor ruxolitinib inhibited MEK‐ERK pathway activation. Consequently, the JAK‐STAT and MEK‐ERK signaling pathways may be potential targets for MCPyV‐negative MCC treatment. |
format | Online Article Text |
id | pubmed-8748213 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-87482132022-01-14 Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation Iwasaki, Takeshi Hayashi, Kazuhiko Matsushita, Michiko Nonaka, Daisuke Kohashi, Kenichi Kuwamoto, Satoshi Umekita, Yoshihisa Oda, Yoshinao Cancer Sci Original Articles Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK‐ERK and JAK‐STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV‐positive and 20 MCPyV‐negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK‐ERK and JAK‐STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV‐negative than in MCPyV‐positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P < .001), negative MCPyV status (HR 0.324, P = .013), and advanced cancer stage (HR 2.672, P = .041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV‐negative MCC cell lines than in an MCPyV‐positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV‐negative than in MCPyV‐positive cell lines. These results suggest that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC and the JAK inhibitor ruxolitinib inhibited MEK‐ERK pathway activation. Consequently, the JAK‐STAT and MEK‐ERK signaling pathways may be potential targets for MCPyV‐negative MCC treatment. John Wiley and Sons Inc. 2021-11-24 2022-01 /pmc/articles/PMC8748213/ /pubmed/34724284 http://dx.doi.org/10.1111/cas.15187 Text en © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Iwasaki, Takeshi Hayashi, Kazuhiko Matsushita, Michiko Nonaka, Daisuke Kohashi, Kenichi Kuwamoto, Satoshi Umekita, Yoshihisa Oda, Yoshinao Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation |
title | Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation |
title_full | Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation |
title_fullStr | Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation |
title_full_unstemmed | Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation |
title_short | Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation |
title_sort | merkel cell polyomavirus–negative merkel cell carcinoma is associated with jak‐stat and mek‐erk pathway activation |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748213/ https://www.ncbi.nlm.nih.gov/pubmed/34724284 http://dx.doi.org/10.1111/cas.15187 |
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