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Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase

Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs...

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Autores principales: Okamoto, Michio, Mizuno, Rei, Kawada, Kenji, Itatani, Yoshiro, Kiyasu, Yoshiyuki, Hanada, Keita, Hirata, Wataru, Nishikawa, Yasuyo, Masui, Hideyuki, Sugimoto, Naoko, Tamura, Takuya, Inamoto, Susumu, Sakai, Yoshiharu, Obama, Kazutaka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867023/
https://www.ncbi.nlm.nih.gov/pubmed/36674635
http://dx.doi.org/10.3390/ijms24021118
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author Okamoto, Michio
Mizuno, Rei
Kawada, Kenji
Itatani, Yoshiro
Kiyasu, Yoshiyuki
Hanada, Keita
Hirata, Wataru
Nishikawa, Yasuyo
Masui, Hideyuki
Sugimoto, Naoko
Tamura, Takuya
Inamoto, Susumu
Sakai, Yoshiharu
Obama, Kazutaka
author_facet Okamoto, Michio
Mizuno, Rei
Kawada, Kenji
Itatani, Yoshiro
Kiyasu, Yoshiyuki
Hanada, Keita
Hirata, Wataru
Nishikawa, Yasuyo
Masui, Hideyuki
Sugimoto, Naoko
Tamura, Takuya
Inamoto, Susumu
Sakai, Yoshiharu
Obama, Kazutaka
author_sort Okamoto, Michio
collection PubMed
description Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase–DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.
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spelling pubmed-98670232023-01-22 Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase Okamoto, Michio Mizuno, Rei Kawada, Kenji Itatani, Yoshiro Kiyasu, Yoshiyuki Hanada, Keita Hirata, Wataru Nishikawa, Yasuyo Masui, Hideyuki Sugimoto, Naoko Tamura, Takuya Inamoto, Susumu Sakai, Yoshiharu Obama, Kazutaka Int J Mol Sci Article Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase–DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases. MDPI 2023-01-06 /pmc/articles/PMC9867023/ /pubmed/36674635 http://dx.doi.org/10.3390/ijms24021118 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Okamoto, Michio
Mizuno, Rei
Kawada, Kenji
Itatani, Yoshiro
Kiyasu, Yoshiyuki
Hanada, Keita
Hirata, Wataru
Nishikawa, Yasuyo
Masui, Hideyuki
Sugimoto, Naoko
Tamura, Takuya
Inamoto, Susumu
Sakai, Yoshiharu
Obama, Kazutaka
Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase
title Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase
title_full Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase
title_fullStr Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase
title_full_unstemmed Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase
title_short Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase
title_sort neutrophil extracellular traps promote metastases of colorectal cancers through activation of erk signaling by releasing neutrophil elastase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867023/
https://www.ncbi.nlm.nih.gov/pubmed/36674635
http://dx.doi.org/10.3390/ijms24021118
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