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Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells
The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins,...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499646/ https://www.ncbi.nlm.nih.gov/pubmed/36142212 http://dx.doi.org/10.3390/ijms231810300 |
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author | Tomonobu, Nahoko Kinoshita, Rie Wake, Hidenori Inoue, Yusuke Ruma, I Made Winarsa Suzawa, Ken Gohara, Yuma Komalasari, Ni Luh Gede Yoni Jiang, Fan Murata, Hitoshi Yamamoto, Ken-ichi Sumardika, I Wayan Chen, Youyi Futami, Junichiro Yamauchi, Akira Kuribayashi, Futoshi Kondo, Eisaku Toyooka, Shinichi Nishibori, Masahiro Sakaguchi, Masakiyo |
author_facet | Tomonobu, Nahoko Kinoshita, Rie Wake, Hidenori Inoue, Yusuke Ruma, I Made Winarsa Suzawa, Ken Gohara, Yuma Komalasari, Ni Luh Gede Yoni Jiang, Fan Murata, Hitoshi Yamamoto, Ken-ichi Sumardika, I Wayan Chen, Youyi Futami, Junichiro Yamauchi, Akira Kuribayashi, Futoshi Kondo, Eisaku Toyooka, Shinichi Nishibori, Masahiro Sakaguchi, Masakiyo |
author_sort | Tomonobu, Nahoko |
collection | PubMed |
description | The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis. |
format | Online Article Text |
id | pubmed-9499646 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94996462022-09-23 Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells Tomonobu, Nahoko Kinoshita, Rie Wake, Hidenori Inoue, Yusuke Ruma, I Made Winarsa Suzawa, Ken Gohara, Yuma Komalasari, Ni Luh Gede Yoni Jiang, Fan Murata, Hitoshi Yamamoto, Ken-ichi Sumardika, I Wayan Chen, Youyi Futami, Junichiro Yamauchi, Akira Kuribayashi, Futoshi Kondo, Eisaku Toyooka, Shinichi Nishibori, Masahiro Sakaguchi, Masakiyo Int J Mol Sci Article The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis. MDPI 2022-09-07 /pmc/articles/PMC9499646/ /pubmed/36142212 http://dx.doi.org/10.3390/ijms231810300 Text en © 2022 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 Tomonobu, Nahoko Kinoshita, Rie Wake, Hidenori Inoue, Yusuke Ruma, I Made Winarsa Suzawa, Ken Gohara, Yuma Komalasari, Ni Luh Gede Yoni Jiang, Fan Murata, Hitoshi Yamamoto, Ken-ichi Sumardika, I Wayan Chen, Youyi Futami, Junichiro Yamauchi, Akira Kuribayashi, Futoshi Kondo, Eisaku Toyooka, Shinichi Nishibori, Masahiro Sakaguchi, Masakiyo Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells |
title | Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells |
title_full | Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells |
title_fullStr | Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells |
title_full_unstemmed | Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells |
title_short | Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells |
title_sort | histidine-rich glycoprotein suppresses the s100a8/a9-mediated organotropic metastasis of melanoma cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499646/ https://www.ncbi.nlm.nih.gov/pubmed/36142212 http://dx.doi.org/10.3390/ijms231810300 |
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