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Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response
BACKGROUND: The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs a...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945602/ https://www.ncbi.nlm.nih.gov/pubmed/31907001 http://dx.doi.org/10.1186/s13045-019-0836-0 |
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author | Yang, Lu-Yu Luo, Qin Lu, Lu Zhu, Wen-Wei Sun, Hao-Ting Wei, Ran Lin, Zhi-Fei Wang, Xiang-Yu Wang, Chao-Qun Lu, Ming Jia, Hu-Liang Chen, Jin-Hong Zhang, Ju-Bo Qin, Lun-Xiu |
author_facet | Yang, Lu-Yu Luo, Qin Lu, Lu Zhu, Wen-Wei Sun, Hao-Ting Wei, Ran Lin, Zhi-Fei Wang, Xiang-Yu Wang, Chao-Qun Lu, Ming Jia, Hu-Liang Chen, Jin-Hong Zhang, Ju-Bo Qin, Lun-Xiu |
author_sort | Yang, Lu-Yu |
collection | PubMed |
description | BACKGROUND: The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. METHODS: The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays. RESULTS: NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. CONCLUSIONS: NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis. |
format | Online Article Text |
id | pubmed-6945602 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69456022020-01-07 Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response Yang, Lu-Yu Luo, Qin Lu, Lu Zhu, Wen-Wei Sun, Hao-Ting Wei, Ran Lin, Zhi-Fei Wang, Xiang-Yu Wang, Chao-Qun Lu, Ming Jia, Hu-Liang Chen, Jin-Hong Zhang, Ju-Bo Qin, Lun-Xiu J Hematol Oncol Research BACKGROUND: The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. METHODS: The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays. RESULTS: NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. CONCLUSIONS: NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis. BioMed Central 2020-01-06 /pmc/articles/PMC6945602/ /pubmed/31907001 http://dx.doi.org/10.1186/s13045-019-0836-0 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Yang, Lu-Yu Luo, Qin Lu, Lu Zhu, Wen-Wei Sun, Hao-Ting Wei, Ran Lin, Zhi-Fei Wang, Xiang-Yu Wang, Chao-Qun Lu, Ming Jia, Hu-Liang Chen, Jin-Hong Zhang, Ju-Bo Qin, Lun-Xiu Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response |
title | Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response |
title_full | Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response |
title_fullStr | Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response |
title_full_unstemmed | Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response |
title_short | Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response |
title_sort | increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945602/ https://www.ncbi.nlm.nih.gov/pubmed/31907001 http://dx.doi.org/10.1186/s13045-019-0836-0 |
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