Protein C and its inhibitor in malignancy
Protein C and its inhibitor in malignancy
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DOI：
10.1055/s-2007-991534
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发表时间：
2007-10-01
影响因子：
5.7
通讯作者：
Hayashi, Tatsuya
中科院分区：
文献类型：
--
作者：
Suzuki, Koji;Hayashi, Tatsuya
活化蛋白C（APC）和蛋白C抑制剂（PCI）是抗凝蛋白C通路的主要成分。近年来，APC和PCI不仅在止血调节中发挥作用，而且在细胞炎症、增殖、凋亡、肿瘤细胞迁移、侵袭和转移中发挥作用。在此，我们总结了APC和PCI在恶性肿瘤中的作用。APC增加卵巢癌细胞和绒毛膜癌细胞的迁移在Transwell侵袭试验中存在的纤溶酶原激活物抑制剂（派）-1;这一发现表明，APC刺激尿激酶型纤溶酶原激活物（uPA）与派-1形成复合物，导致细胞外基质蛋白酶的激活和增加的侵袭。近年来研究发现，APC可能通过激活内皮蛋白C受体（EPCR）和蛋白酶激活受体（PAR）-1介导的特异性信号通路，增强乳腺癌细胞的侵袭和趋化能力，而不依赖于派-1。APC还通过EPCR介导的丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇3-激酶（PI 3 K）和内皮型一氧化氮合酶（eNOS）途径的活化来增加血管内皮细胞的增殖和血管生成。我们以前报道过uPA和PCI都是在肾近端小管上皮细胞（RPTEC）中合成的，并且RPTEC中PCI的表达与UPA和PCI的表达相关。与正常RPTEC相比，衍生的肿瘤细胞显著减少。RPTEC衍生的肾癌细胞系Caki-1也显示PCI表达降低。PCI通过其蛋白酶抑制活性抑制Caki-1和乳腺癌细胞的体外侵袭活性。然而，PCI被发现抑制乳腺癌细胞的生长和转移潜力，独立于其蛋白酶抑制活性在严重的联合免疫缺陷小鼠。PCI还可以抑制血管生成在体内和体外试验中独立于其蛋白酶抑制活性，这些数据表明，APC促进肿瘤细胞的侵袭EPCR介导的和PAR-1介导的蛋白酶活性和PCI抑制肿瘤细胞的侵袭在体外通过其蛋白酶抑制活性和抑制肿瘤细胞的生长，转移，和血管生成独立于其蛋白酶抑制活性。
Activated protein C (APC) and protein C inhibitor (PCI) are the major components of the anticoagulant protein C pathway. Recently, APC and PCI have been demonstrated to play many roles not only in the regulation of hemostasis but also in cell inflammation, proliferation, apoptosis, tumor cell migration, invasion, and metastasis. Here we summarize the role of APC and PCI in malignancy.APC increases migration of ovarian cancer cells and choriocarcinoma cells in a Transwell invasion assay in the presence of plasminogen activator inhibitor (PAI)-1; this finding suggests that APC stimulates urokinase-type plasminogen activator (uPA) by forming a complex with PAI-1 leading to activation of extracellular matrix proteases and increased invasion. It was recently reported that APC, independent of PAI-1, may increase invasion and chemotaxis of breast cancer cells by activating specific signaling pathways through endothelial protein C receptor (EPCR) and protease-activated receptor (PAR)-1. APC also increased proliferation of vascular endothelial cells and anglogenesis by EPCR-mediated activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and endothelial nitric oxide synthase (eNOS) pathways.On the other hand, we have previously reported that both uPA and PCI are synthesized in renal proximal tubular epithelial cells (RPTECs) and that PCI expression in RPTEC-derived tumor cells is significantly decreased compared with normal RPTECs. The RPTEC-derived renal carcinoma cell line Caki-1 also showed decreased expression of PCI. PCI inhibited in vitro invasive activity of Caki-1 and breast cancer cells by its protease inhibitory activity. However, PCI was found to inhibit the growth and metastatic potential of breast cancer cells independent of its protease inhibitory activity in severe combined immunodeficient mice. PCI can also inhibit anglogenesis in vivo and in vitro assays independent of its protease inhibitory activity.Overall, these data show that APC promotes tumor cell invasion by EPCR-mediated and PAR-1-mediated protease activity and that PCI inhibits tumor cell invasion in vitro by its protease inhibitory activity and suppresses tumor cell growth, metastasis, and anglogenesis independent of its protease inhibitory activity.