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Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

BACKGROUND: Colorectal cancer (CRC) is one of the most common forms of cancer worldwide. The tumor microenvironment plays a key role in promoting the occurrence of chemoresistance in solid cancers. Effective targets to overcome resistance are necessary to improve the survival and prognosis of CRC pa...

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Autores principales: Wang, Dan, Yang, Li, Yu, Weina, Wu, Qian, Lian, Jingyao, Li, Feng, Liu, Shasha, Li, Aitian, He, Zhiang, Liu, Jinbo, Sun, Zhenqiang, Yuan, Weitang, Zhang, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688336/
https://www.ncbi.nlm.nih.gov/pubmed/31395078
http://dx.doi.org/10.1186/s40425-019-0701-2
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author Wang, Dan
Yang, Li
Yu, Weina
Wu, Qian
Lian, Jingyao
Li, Feng
Liu, Shasha
Li, Aitian
He, Zhiang
Liu, Jinbo
Sun, Zhenqiang
Yuan, Weitang
Zhang, Yi
author_facet Wang, Dan
Yang, Li
Yu, Weina
Wu, Qian
Lian, Jingyao
Li, Feng
Liu, Shasha
Li, Aitian
He, Zhiang
Liu, Jinbo
Sun, Zhenqiang
Yuan, Weitang
Zhang, Yi
author_sort Wang, Dan
collection PubMed
description BACKGROUND: Colorectal cancer (CRC) is one of the most common forms of cancer worldwide. The tumor microenvironment plays a key role in promoting the occurrence of chemoresistance in solid cancers. Effective targets to overcome resistance are necessary to improve the survival and prognosis of CRC patients. This study aimed to evaluate the molecular mechanisms of the tumor microenvironment that might be involved in chemoresistance in patients with CRC. METHODS: We evaluated the effects of CCL20 on chemoresistance of CRC by recruitment of regulatory T cells (Tregs) in vitro and in vivo. RESULTS: We found that the level of CCL20 derived from tumor cells was significantly higher in Folfox-resistant patients than in Folfox-sensitive patients. The high level of CCL20 was closely associated with chemoresistance and poor survival in CRC patients. Among the drugs in Folfox chemotherapy, we confirmed that 5-FU increased the expression of CCL20 in CRC. Moreover, CCL20 derived from 5-FU-resistant CRC cells promoted recruitment of Tregs. Tregs further enhanced the chemoresistance of CRC cells to 5-FU. FOXO1/CEBPB/NF-κB signaling was activated in CRC cells after 5-FU treatment and was required for CCL20 upregulation mediated by 5-FU. Furthermore, CCL20 blockade suppressed tumor progression and restored 5-FU sensitivity in CRC. Lastly, the expression of these signaling molecules mediating chemoresistance was closely correlated with poor survival of CRC patients. CONCLUSIONS: CRC cell-secreted CCL20 can recruit Tregs to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling, indicating that the FOXO1/CEBPB/NF-κB/CCL20 axis might provide a promising target for CRC treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0701-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-66883362019-08-14 Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling Wang, Dan Yang, Li Yu, Weina Wu, Qian Lian, Jingyao Li, Feng Liu, Shasha Li, Aitian He, Zhiang Liu, Jinbo Sun, Zhenqiang Yuan, Weitang Zhang, Yi J Immunother Cancer Research Article BACKGROUND: Colorectal cancer (CRC) is one of the most common forms of cancer worldwide. The tumor microenvironment plays a key role in promoting the occurrence of chemoresistance in solid cancers. Effective targets to overcome resistance are necessary to improve the survival and prognosis of CRC patients. This study aimed to evaluate the molecular mechanisms of the tumor microenvironment that might be involved in chemoresistance in patients with CRC. METHODS: We evaluated the effects of CCL20 on chemoresistance of CRC by recruitment of regulatory T cells (Tregs) in vitro and in vivo. RESULTS: We found that the level of CCL20 derived from tumor cells was significantly higher in Folfox-resistant patients than in Folfox-sensitive patients. The high level of CCL20 was closely associated with chemoresistance and poor survival in CRC patients. Among the drugs in Folfox chemotherapy, we confirmed that 5-FU increased the expression of CCL20 in CRC. Moreover, CCL20 derived from 5-FU-resistant CRC cells promoted recruitment of Tregs. Tregs further enhanced the chemoresistance of CRC cells to 5-FU. FOXO1/CEBPB/NF-κB signaling was activated in CRC cells after 5-FU treatment and was required for CCL20 upregulation mediated by 5-FU. Furthermore, CCL20 blockade suppressed tumor progression and restored 5-FU sensitivity in CRC. Lastly, the expression of these signaling molecules mediating chemoresistance was closely correlated with poor survival of CRC patients. CONCLUSIONS: CRC cell-secreted CCL20 can recruit Tregs to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling, indicating that the FOXO1/CEBPB/NF-κB/CCL20 axis might provide a promising target for CRC treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0701-2) contains supplementary material, which is available to authorized users. BioMed Central 2019-08-08 /pmc/articles/PMC6688336/ /pubmed/31395078 http://dx.doi.org/10.1186/s40425-019-0701-2 Text en © The Author(s). 2019 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 Article
Wang, Dan
Yang, Li
Yu, Weina
Wu, Qian
Lian, Jingyao
Li, Feng
Liu, Shasha
Li, Aitian
He, Zhiang
Liu, Jinbo
Sun, Zhenqiang
Yuan, Weitang
Zhang, Yi
Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling
title Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling
title_full Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling
title_fullStr Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling
title_full_unstemmed Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling
title_short Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling
title_sort colorectal cancer cell-derived ccl20 recruits regulatory t cells to promote chemoresistance via foxo1/cebpb/nf-κb signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688336/
https://www.ncbi.nlm.nih.gov/pubmed/31395078
http://dx.doi.org/10.1186/s40425-019-0701-2
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