Integrin αvβ3/vitronectin interaction affects expression of the urokinase system in human ovarian cancer cells
Integrin αvβ3/vitronectin interaction affects expression of the urokinase system in human ovarian cancer cells
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DOI：
10.1074/jbc.m100181200
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发表时间：
2001-07-13
影响因子：
4.8
通讯作者：
Reuning, U
中科院分区：
文献类型：
--
作者：
Hapke, S;Kessler, H;Reuning, U
尿激酶型纤溶酶原激活物(UPA)及其受体uPAR和纤溶酶原激活物抑制物-1(PAI-1)在肿瘤侵袭转移中起着关键作用。整合素通过与细胞外基质(ECM)的相互作用控制细胞的黏附和运动，这两个系统在功能上是联系在一起的，因为uPAR和PAI-1与ECM组分Vitronectin(VN)结合，由于整合素信号改变了基因表达模式，我们研究了uPA、uPAR和PAI-1的表达水平是否受到ECM/整合素相互作用的影响。人卵巢癌细胞(OV-MZ-6)经纤维连接蛋白或胶原型培养后，uPA、uPAR和PAI-1的表达明显增强，而VN诱导uPA和uPAR表达下调，PAI-1表达增加4倍以上。与vN依赖的uPA蛋白减少平行的是uPA启动子活性的显著降低，这在α(V)β(3)过表达时更加明显，并依赖于完整REL蛋白结合位点的存在。在α(V)β(3)介导的细胞与VN的黏附中，REL转录因子的活性也显著降低，而对REL无反应的PAI-1启动子的活性是α(V)β(3)/VN相互作用的5倍。因此，人卵巢癌细胞中uPA、uPAR、PAI-1和整合素的有效浓度之间的平衡可能会在调节其侵袭性表型方面提供一个转换。
The urokinase type plasminogen activator (uPA), together with its receptor uPAR and the plasminogen activator inhibitor type-1 (PAI-1) plays a pivotal role during tumor invasion and metastasis. Integrins, via interaction with the extracellular matrix (ECM), control cell adhesion and motility, The two systems are functionally linked because uPAR and PAI-1 bind to the ECM component vitronectin (VN), Because integrin signaling alters gene expression patterns, we investigated whether the expression levels of uPA, uPAR, and PAI-1 are affected by ECM/integrin interactions. Expression of uPA, uPAR, and PAI-1 was significantly enhanced when human ovarian cancer cells (OV-MZ-6) were cultivated on fibronectin or collagen type , In contrast, VN induced down-regulation of uPA and uPAR while increasing PAI-1 by up to 4-fold. VN-dependent decrease of uPA protein was paralleled by a significant reduction of uPA promoter activity that was even more pronounced upon alpha (v)beta (3) overexpression and depended on the presence of intact Rel protein-binding sites. The activity of Rel transcription factors was also significantly reduced upon alpha (v)beta (3)-mediated cell adhesion to VN, The activity of the Rel-unresponsive PAI-1 promoter was up to 5-fold induced as a function of alpha (v)beta (3)/VN interaction. Thus, the balance between available concentrations of uPA, uPAR, PAI-1, and integrins in human ovarian cancer cells might provide a switch within the regulation of their invasive phenotype.