Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-κB/tissue factor/Factor Xa pathway in melanoma B16F10 cells.
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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DOI：
10.1371/journal.pone.0056557
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Zhao Y;Zhang D;Wang S;Tao L;Wang A;Chen W;Zhu Z;Zheng S;Gao X;Lu Y
海参糖胺聚糖 (hGAG) 是岩藻糖基化硫酸软骨素的高分子量形式，具有抗血栓作用。我们之前的研究表明hGAG能够有效抑制肿瘤细胞的转移。血栓形成和肿瘤进展之间的相互作用可能对血行转移产生重大影响。在这项研究中，我们证明用 hGAG 处理的小鼠黑色素瘤 B16F10 细胞在体外和体内表现出转移和凝血能力显着降低。机制研究表明，hGAG 处理 B16F10 细胞可通过减弱活化因子 Xa (FXa) 的生成，显着抑制纤维蛋白的形成，而不影响参与纤维蛋白溶解的尿激酶 (uPA) 和纤溶酶原激活剂抑制剂 1 (PAI-1) 的表达。此外，hGAG 治疗下调了组织因子 (TF) 的转录和蛋白表达。启动子缺失、位点突变和功能研究发现核转录因子 NF-κB 结合区负责 hGAG 诱导的 TF 表达抑制。虽然 hGAG 处理 B16F10 细胞无法抑制 NF-κB 表达和磷酸化，但 hGAG 显着阻止 NF-κB 从胞质溶胶中转位，这是抑制 TF 转录的潜在机制。此外，hGAG 显着抑制 p38MAPK 和 ERK1/2 信号通路的激活，这是转移相关基质金属蛋白酶 (MMP) 表达的中央调节因子。因此，hGAG 在抑制小鼠黑色素瘤 B16F10 细胞的转移和凝血活性方面发挥双重功能。我们的研究表明 hGAG 是一种有前途的转移性癌症治疗药物。
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.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
3.7
作者：
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发表时间：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
11.2
作者：
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通讯作者：
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DOI：
10.1016/j.jss.2012.06.050
发表时间：
2012-11
期刊：
The Journal of surgical research
影响因子：
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作者：
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通讯作者：
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