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Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

Authors :
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
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
Publication Year :
2022

Abstract

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.

Details

Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1375178552
Document Type :
Electronic Resource