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S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma

Myeloid-derived suppressor cells (MDSCs) are a major component of the immunosuppressive tumor microenvironment (TME) and have been recognized as a contributing factor to inflammation-related cancers. However, the molecular mechanisms of MDSCs accumulation and activation remain elusive. We previously...

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Autores principales: Huang, Mao, Wu, Rui, Chen, Lu, Peng, Qi, Li, Shue, Zhang, Yan, Zhou, Lan, Duan, Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759487/
https://www.ncbi.nlm.nih.gov/pubmed/31620141
http://dx.doi.org/10.3389/fimmu.2019.02243
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author Huang, Mao
Wu, Rui
Chen, Lu
Peng, Qi
Li, Shue
Zhang, Yan
Zhou, Lan
Duan, Liang
author_facet Huang, Mao
Wu, Rui
Chen, Lu
Peng, Qi
Li, Shue
Zhang, Yan
Zhou, Lan
Duan, Liang
author_sort Huang, Mao
collection PubMed
description Myeloid-derived suppressor cells (MDSCs) are a major component of the immunosuppressive tumor microenvironment (TME) and have been recognized as a contributing factor to inflammation-related cancers. However, the molecular mechanisms of MDSCs accumulation and activation remain elusive. We previously showed that the proinflammatory molecule S100A9 in TME exerts a tumor-promoting effect in colorectal carcinoma (CRC). In this report, we investigated the effect and molecular mechanisms of S100A9 on the accumulation and immunosuppressive function of MDSCs in CRC. Elevated S100A9 and MDSCs were found in tumor tissue and peripheral blood from CRC patients. Circulating S100A9 and MDSCs were positively associated to each other, and both S100A9 and MDSCs were correlated to neoplastic progression. Using a CRC cell line LoVo-induced MDSCs model, we found that S100A9 stimulated chemotaxis and activation but not viability of MDSCs. Mechanistic studies demonstrated that activation of RAGE-mediated p38 MAPK and TLR4-mediated NF-κB signaling pathways were involved in S100A9-induced chemotaxis and MDSCs activation, respectively. Furthermore, ROC analysis showed that combination detection of S100A9 and MDSCs was superior to individual detection of these two factors for diagnosing CRC patients with advanced staging and lymphatic metastasis, which yielded an area under the ROC curve (AUC) of 0.92 with 86.7% sensitivity and 86.4% specificity, and an AUC of 0.82 with 75% sensitivity and 77.1% specificity, respectively. Collectively, our study suggests that the S100A9 plays a pivotal role in immunosuppressive TME by stimulating MDSCs chemotaxis and activation, and combination detection of S100A9 and MDSCs may serve as a potential marker for diagnosis of CRC progression.
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spelling pubmed-67594872019-10-16 S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma Huang, Mao Wu, Rui Chen, Lu Peng, Qi Li, Shue Zhang, Yan Zhou, Lan Duan, Liang Front Immunol Immunology Myeloid-derived suppressor cells (MDSCs) are a major component of the immunosuppressive tumor microenvironment (TME) and have been recognized as a contributing factor to inflammation-related cancers. However, the molecular mechanisms of MDSCs accumulation and activation remain elusive. We previously showed that the proinflammatory molecule S100A9 in TME exerts a tumor-promoting effect in colorectal carcinoma (CRC). In this report, we investigated the effect and molecular mechanisms of S100A9 on the accumulation and immunosuppressive function of MDSCs in CRC. Elevated S100A9 and MDSCs were found in tumor tissue and peripheral blood from CRC patients. Circulating S100A9 and MDSCs were positively associated to each other, and both S100A9 and MDSCs were correlated to neoplastic progression. Using a CRC cell line LoVo-induced MDSCs model, we found that S100A9 stimulated chemotaxis and activation but not viability of MDSCs. Mechanistic studies demonstrated that activation of RAGE-mediated p38 MAPK and TLR4-mediated NF-κB signaling pathways were involved in S100A9-induced chemotaxis and MDSCs activation, respectively. Furthermore, ROC analysis showed that combination detection of S100A9 and MDSCs was superior to individual detection of these two factors for diagnosing CRC patients with advanced staging and lymphatic metastasis, which yielded an area under the ROC curve (AUC) of 0.92 with 86.7% sensitivity and 86.4% specificity, and an AUC of 0.82 with 75% sensitivity and 77.1% specificity, respectively. Collectively, our study suggests that the S100A9 plays a pivotal role in immunosuppressive TME by stimulating MDSCs chemotaxis and activation, and combination detection of S100A9 and MDSCs may serve as a potential marker for diagnosis of CRC progression. Frontiers Media S.A. 2019-09-18 /pmc/articles/PMC6759487/ /pubmed/31620141 http://dx.doi.org/10.3389/fimmu.2019.02243 Text en Copyright © 2019 Huang, Wu, Chen, Peng, Li, Zhang, Zhou and Duan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Huang, Mao
Wu, Rui
Chen, Lu
Peng, Qi
Li, Shue
Zhang, Yan
Zhou, Lan
Duan, Liang
S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma
title S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma
title_full S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma
title_fullStr S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma
title_full_unstemmed S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma
title_short S100A9 Regulates MDSCs-Mediated Immune Suppression via the RAGE and TLR4 Signaling Pathways in Colorectal Carcinoma
title_sort s100a9 regulates mdscs-mediated immune suppression via the rage and tlr4 signaling pathways in colorectal carcinoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759487/
https://www.ncbi.nlm.nih.gov/pubmed/31620141
http://dx.doi.org/10.3389/fimmu.2019.02243
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