ROS-NFκI' mediates TGF-β1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion

TGF-beta 1 has been postulated as a pro-oncogenic factor in the late step of the tumoral progression. In transformed cells, TGF-beta 1 enhances the capacity to degrade the extracellular matrix, cell invasiveness and epithelial-mesenchymal transition, which are crucial steps for metastasis. Urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) are critical components in cell migration and invasion induced by TGF-beta 1, however, the exact mechanism by which TGF-beta 1 regulates uPA and MMP-9 is not well elucidated so far. In the present study, we analyzed the role of ROS-NF kappa I', signal as mediator in the cell malignity enhancement by TGF-beta 1. We found that TGF-beta 1 activates NF kappa I', through Rac1-NOXs-ROS-dependent mechanism. Our results shows that TGF-beta 1 stimulation of uPA and MMP-9 expression involve NOXs-dependent ROS and NF kappa I', activation, demonstrated by using DPI, NOXs inhibitor, ROS scavenger N-acetylcysteine and SN50, an NFkb inhibitor. Furthermore, we found that the inhibition of ROS and NF kappa I', abrogates TGF-beta 1 stimulation of EMT, cell motility and invasion. Thus, ROS-NF kappa I' acts as the crucial signal in TGF-beta 1-induced uPA and MMP-9 expression thereby mediating the enhancement of cellular malignity by TGF-beta 1.