Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.

Holothurian glycosaminoglycan (hGAG) is a high-molecular-weight form of fucosylated chondroitin sulfate and has an antithrombotic effect. Our previous studies demonstrated that hGAG efficiently inhibited tumor cell metastasis. The interplays between thrombosis and tumor progression may have a major...

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Autores principales:	Yang Zhao, Daohai Zhang, Sheng Wang, Li Tao, Aiyun Wang, Wenxing Chen, Zhijie Zhu, Shizhong Zheng, Xiang Gao, Yin Lu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/773267de0bc742618ac798b34ffd0db8
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spelling	oai:doaj.org-article:773267de0bc742618ac798b34ffd0db82021-11-18T07:56:36ZHolothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.1932-620310.1371/journal.pone.0056557https://doaj.org/article/773267de0bc742618ac798b34ffd0db82013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23437168/?tool=EBIhttps://doaj.org/toc/1932-6203Holothurian glycosaminoglycan (hGAG) is a high-molecular-weight form of fucosylated chondroitin sulfate and has an antithrombotic effect. Our previous studies demonstrated that hGAG efficiently inhibited tumor cell metastasis. The interplays between thrombosis and tumor progression may have a major impact on hematogenous metastasis. In this study, we demonstrated that the mouse melanoma B16F10 cells treated with hGAG displayed a significant reduction of metastasis and coagulation capacity in vitro and in vivo. Mechanistic studies revealed that hGAG treatment in B16F10 cells remarkably inhibited the formation of fibrin through attenuating the generation of activated Factor Xa (FXa), without affecting the expression of urokinase (uPA) and plasminogen activator inhibitor 1 (PAI-1) that involved in fibrinolysis. Moreover, hGAG treatment downregulated the transcription and protein expression of tissue factor (TF). Promoter deletions, site mutations and functional studies identified that the nuclear transcription factor NF-κB binding region is responsible for hGAG-induced inhibition of TF expression. While the hGAG treatment of B16F10 cells was unable to inhibit NF-κB expression and phosphorylation, hGAG significantly prevented nuclear translocation of NF-κB from the cytosol, a potential mechanism underlying the transcriptional suppression of TF. Moreover, hGAG markedly suppressed the activation of p38MAPK and ERK1/2 signaling pathways, the central regulators for the expression of metastasis-related matrix metalloproteinases (MMPs). Consequently, hGAG exerts a dual function in the inhibition of metastasis and coagulation activity in mouse melanoma B16F10 cells. Our studies suggest hGAG to be a promising therapeutic agent for metastatic cancer treatment.Yang ZhaoDaohai ZhangSheng WangLi TaoAiyun WangWenxing ChenZhijie ZhuShizhong ZhengXiang GaoYin LuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e56557 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yang Zhao Daohai Zhang Sheng Wang Li Tao Aiyun Wang Wenxing Chen Zhijie Zhu Shizhong Zheng Xiang Gao Yin Lu Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.
description	Holothurian glycosaminoglycan (hGAG) is a high-molecular-weight form of fucosylated chondroitin sulfate and has an antithrombotic effect. Our previous studies demonstrated that hGAG efficiently inhibited tumor cell metastasis. The interplays between thrombosis and tumor progression may have a major impact on hematogenous metastasis. In this study, we demonstrated that the mouse melanoma B16F10 cells treated with hGAG displayed a significant reduction of metastasis and coagulation capacity in vitro and in vivo. Mechanistic studies revealed that hGAG treatment in B16F10 cells remarkably inhibited the formation of fibrin through attenuating the generation of activated Factor Xa (FXa), without affecting the expression of urokinase (uPA) and plasminogen activator inhibitor 1 (PAI-1) that involved in fibrinolysis. Moreover, hGAG treatment downregulated the transcription and protein expression of tissue factor (TF). Promoter deletions, site mutations and functional studies identified that the nuclear transcription factor NF-κB binding region is responsible for hGAG-induced inhibition of TF expression. While the hGAG treatment of B16F10 cells was unable to inhibit NF-κB expression and phosphorylation, hGAG significantly prevented nuclear translocation of NF-κB from the cytosol, a potential mechanism underlying the transcriptional suppression of TF. Moreover, hGAG markedly suppressed the activation of p38MAPK and ERK1/2 signaling pathways, the central regulators for the expression of metastasis-related matrix metalloproteinases (MMPs). Consequently, hGAG exerts a dual function in the inhibition of metastasis and coagulation activity in mouse melanoma B16F10 cells. Our studies suggest hGAG to be a promising therapeutic agent for metastatic cancer treatment.
format	article
author	Yang Zhao Daohai Zhang Sheng Wang Li Tao Aiyun Wang Wenxing Chen Zhijie Zhu Shizhong Zheng Xiang Gao Yin Lu
author_facet	Yang Zhao Daohai Zhang Sheng Wang Li Tao Aiyun Wang Wenxing Chen Zhijie Zhu Shizhong Zheng Xiang Gao Yin Lu
author_sort	Yang Zhao
title	Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.
title_short	Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.
title_full	Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.
title_fullStr	Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.
title_full_unstemmed	Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.
title_sort	holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κb/tissue factor/factor xa pathway in melanoma b16f10 cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/773267de0bc742618ac798b34ffd0db8
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Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.

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