Protease-activated receptors mediate crosstalk between coagulation and fibrinolysis
Protease-activated receptors mediate crosstalk between coagulation and fibrinolysis
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DOI：
10.1182/blood-2010-06-293126
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发表时间：
2010-12-02
期刊：
影响因子：
20.3
通讯作者：
Mackman, Nigel
中科院分区：
文献类型：
--
作者：
McEachron, Troy A.;Pawlinski, Rafal;Mackman, Nigel
凝血和纤溶系统通过增加血管生成、肿瘤生长、肿瘤侵袭和肿瘤转移而促成恶性肿瘤。致癌性转化增加组织因子（TF）的表达，导致局部产生凝血蛋白酶并激活蛋白酶激活受体（PAR）-1和PAR-2。我们比较了PAR依赖的尿激酶纤溶酶原激活物（uPA）和纤溶酶原激活物抑制剂（派）-1在2个小鼠乳腺癌细胞系：转移性4 T1细胞和非转移性67 NR细胞中的表达。4 T1细胞表达TF、PAR-1和PAR-2，67 NR细胞表达TF和PAR-1。我们还沉默了PAR-1或PAR-2在4 T1细胞中的表达。我们发现了PAR依赖性uPA和派-1表达的两种不同机制。首先，我们发现因子Xa或凝血酶激活PAR-1导致储存的细胞内uPA快速释放到培养上清液中。第二，凝血酶反式激活PAR-1/PAR-2复合物导致派-1 mRNA和蛋白表达增加。缺乏PAR-2的细胞不能表达派-1对凝血酶的反应，Xa因子不能激活PAR-1/PAR-2复合物。我们的研究结果揭示了肿瘤细胞上的PAR-1和PAR-2如何介导凝血和纤溶之间的串扰。（血。2010;116（23）：5037-5044）
The coagulation and fibrinolytic systems contribute to malignancy by increasing angiogenesis, tumor growth, tumor invasion, and tumor metastasis. Oncogenic transformation increases the expression of tissue factor (TF) that results in local generation of coagulation proteases and activation of protease-activated receptor (PAR)-1 and PAR-2. We compared the PAR-dependent expression of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI)-1 in 2 murine mammary adencocarcinoma cell lines: metastatic 4T1 cells and nonmetastatic 67NR cells. 4T1 cells expressed TF, PAR-1 and PAR-2 whereas 67NR cells expressed TF and PAR-1. We also silenced PAR-1 or PAR-2 expression in the 4T1 cells. We discovered 2 distinct mechanisms for PAR-dependent expression of uPA and PAI-1. First, we found that factor Xa or thrombin activation of PAR-1 led to a rapid release of stored intracellular uPA into the culture supernatant. Second, thrombin transactivation of a PAR-1/PAR-2 complex resulted in increases in PAI-1 mRNA and protein expression. Cells lacking PAR-2 failed to express PAI-1 in response to thrombin and factor Xa did not activate the PAR-1/PAR-2 complex. Our results reveal how PAR-1 and PAR-2 on tumor cells mediate crosstalk between coagulation and fibrinolysis. (Blood. 2010;116(23):5037-5044)