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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,...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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