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首页> 外文期刊>Molecular cancer research: MCR >Sphingosine-1-phosphate and interleukin-1 independently regulate plasminogen activator inhibitor-1 and urokinase-type plasminogen activator receptor expression in glioblastoma cells: implications for invasiveness.
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Sphingosine-1-phosphate and interleukin-1 independently regulate plasminogen activator inhibitor-1 and urokinase-type plasminogen activator receptor expression in glioblastoma cells: implications for invasiveness.

机译：鞘氨醇-1-磷酸和白介素-1独立调节胶质母细胞瘤细胞中的纤溶酶原激活物抑制剂-1和尿激酶型纤溶酶原激活物受体的表达：对侵袭性的影响。

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Glioblastoma multiforme is an invasive primary brain tumor, which evades the current standard treatments. The invasion of glioblastoma cells into healthy brain tissue partly depends on the proteolytic and nonproteolytic activities of the plasminogen activator system proteins, including the urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and a receptor for uPA (uPAR). Here we show that sphingosine-1-phosphate (S1P) and the inflammatory mediator interleukin-1 (IL-1) increase the mRNA and protein expression of PAI-1 and uPAR and enhance the invasion of U373 glioblastoma cells. Although IL-1 enhanced the expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, down-regulation of SphK1 had no effect on the IL-1-induced uPAR or PAI-1 mRNA expression, suggesting that these actions of IL-1 are independent of S1P production. Indeed, the S1P-induced mRNA expression of uPAR and PAI-1 was blocked by the S1P(2) receptor antagonist JTE013 and by the down-regulation of S1P(2) using siRNA. Accordingly, the inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and Rho-kinase, two downstream signaling cascades activated by S1P(2), blocked the activation of PAI-1 and uPAR mRNA expression by S1P. More importantly, the attachment of glioblastoma cells was inhibited by the addition of exogenous PAI-1 or siRNA to uPAR, whereas the invasion of glioblastoma cells induced by S1P or IL-1 correlated with their ability to enhance the expression of PAI-1 and uPAR. Collectively, these results indicate that S1P and IL-1 activate distinct pathways leading to the mRNA and protein expression of PAI-1 and uPAR, which are important for glioblastoma invasiveness.
机译：胶质母细胞瘤是一种侵袭性原发性脑肿瘤，它逃避了目前的标准治疗方法。胶质母细胞瘤细胞侵袭到健康的脑组织中，部分取决于纤溶酶原激活剂系统蛋白的蛋白水解和非蛋白水解活性，包括尿激酶型纤溶酶原激活剂（uPA），纤溶酶原激活剂抑制剂1（PAI-1）和uPA受体。 （uPAR）。在这里，我们显示鞘氨醇-1-磷酸（S1P）和炎症介质白介素1（IL-1）增加PAI-1和uPAR的mRNA和蛋白表达，并增强U373胶质母细胞瘤细胞的侵袭。尽管IL-1增强了鞘氨醇激酶1（SphK1）的表达，该酶产生S1P，但SphK1的下调对IL-1诱导的uPAR或PAI-1 mRNA表达没有影响，表明IL的这些作用-1与S1P生产无关。确实，S1P（2）受体拮抗剂JTE013和使用siRNA下调S1P（2）阻止了S1P诱导的uPAR和PAI-1的mRNA表达。因此，抑制丝裂原活化的蛋白激酶/细胞外信号调节激酶激酶1/2和Rho激酶，两个下游信号级联被S1P（2）激活，阻止了PA1-1和uPAR mRNA表达的激活。更重要的是，通过向uPAR中添加外源PAI-1或siRNA来抑制胶质母细胞瘤细胞的附着，而S1P或IL-1诱导的胶质母细胞瘤细胞的侵袭与其增强PAI-1和uPAR表达的能力有关。总的来说，这些结果表明，S1P和IL-1激活了导致PAI-1和uPAR的mRNA和蛋白质表达的不同途径，这对于胶质母细胞瘤的侵袭性很重要。

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