β-Catenin and NF-κB cooperate to regulate the uPA/uPAR system in cancer cells
β-Catenin and NF-κB cooperate to regulate the uPA/uPAR system in cancer cells
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DOI：
10.1002/ijc.25455
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发表时间：
2011-03-15
影响因子：
6.4
通讯作者：
Dosquet, Christine
中科院分区：
文献类型：
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作者：
Moreau, Marie;Mourah, Samia;Dosquet, Christine
尿激酶型纤溶酶原激活物（uPA）和尿激酶型纤溶酶原激活物受体（uPAR）的表达最近已经显示出在结肠癌细胞中通过β-连环蛋白结合至存在于其基因启动子中的T细胞因子结合元件基序而由Wnt/β-连环蛋白信号传导途径直接调节。在我们的研究中，我们提出的证据表明，β-连环蛋白的抑制导致uPA/uPAR基因表达上调，增强侵袭潜力。使用MCF-7、MDA-MB- 231（乳腺癌细胞）和SW 480（结肠癌细胞），我们发现siRNA介导的β-连环蛋白沉默在mRNA和蛋白水平上增加uPA、uPAR和纤溶酶原激活物抑制剂-1（派-1）的表达。这种增加是观察到的MDA-MB- 231和SW 480癌细胞侵袭能力增强的原因。此外，通过氯化锂处理（一种众所周知的糖原合成酶激酶-3 β（GSK-3 β）抑制剂）或通过β-连环蛋白/T细胞因子-4表达载体转染，β-连环蛋白稳定和积累导致所研究的癌症模型中uPA、uPAR和派-1 mRNA表达降低。用核因子-κ B（NF-κ B）的特异性抑制剂SN 50处理β-连环蛋白siRNA转染的细胞，显著降低了在β-连环蛋白siRNA转染的细胞中观察到的uPA、uPAR和派-1表达的增强和癌细胞侵袭。此外，β-连环蛋白siRNA处理的细胞表现出NF-κ B核积聚。这些数据表明，β-连环蛋白调节uPA/uPAR系统与NF-κ B转录因子合作，这构成了一种新的调节机制。
Expression of the urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) has recently been shown to be directly regulated by the Wnt/beta-catenin signaling pathway in colon cancer cells, through beta-catenin binding to T-cell factor binding element motifs present in their gene promoters. In our study, we present evidence that inhibition of beta-catenin causes upregulation of uPA/uPAR gene expression enhancing invasive potential. Using MCF-7, MDA-MB- 231 (breast cancer cells) and SW480 (colon cancer cells), we found that siRNA-mediated silencing of beta-catenin increased uPA, uPAR and plasminogen activator inhibitor-1 (PAI-1) expression at the mRNA and protein levels. This increase was responsible for the observed enhanced invasive capacity of MDA-MB- 231 and SW480 cancer cells. In addition, beta-catenin stabilization and accumulation by lithium chloride treatment, a well-known inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), or by beta-catenin/T-cell factor-4 expression vectors transfection led to a decrease in uPA, uPAR and PAI-1 mRNA expression in the studied cancer models. Treatment of beta-catenin siRNA-transfected cells with a specific inhibitor of nuclear factor-kappaB (NF-kappa B), SN50, significantly reduced enhancement of uPA, uPAR and PAI-1 expression and cancer cell invasion, observed in beta-catenin siRNA-transfected cells. Furthermore, beta-catenin siRNA-treated cells exhibited NF-kappa B nuclear accumulation. These data suggest that beta-catenin regulates the uPA/uPAR system in cooperation with NF-kappa B transcription factor, which constitutes a novel mechanism of regulation.