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

Abstract

TGF-beta1 has been postulated as a pro-oncogenic factor in the late step of the tumoral progression. In transformed cells, TGF-beta1 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-beta1, however, the exact mechanism by which TGF-beta1 regulates uPA and MMP-9 is not well elucidated so far. In the present study, we analyzed the role of ROS-NFkappaB, signal as mediator in the cell malignity enhancement by TGF-beta1. We found that TGF-beta1 activates NFkappaB, through Rac1-NOXs-ROS-dependent mechanism. Our results shows that TGF-beta1 stimulation of uPA and MMP-9 expression involve NOXs-dependent ROS and NFkappaB, 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 NFkappaB, abrogates TGF-beta1 stimulation of EMT, cell motility and invasion. Thus, ROS-NFkappaB acts as the crucial signal in TGF-beta1-induced uPA and MMP-9 expression thereby mediating the enhancement of cellular malignity by TGF-beta1.

Loss of BRMS1 Promotes a Mesenchymal Phenotype through NF-κB-Dependent Regulation of Twist1

“…This loss of BRMS1 further enhances aberrant activation of NF-B and deregulates NF-B-dependent genes. NF-B plays an essential role in the induction and maintenance of EMT in malignant epithelial cells in response to stimulation by the inflammatory cytokines TGF-␤ and TNF (12,50,51). We observed that knockdown of BRMS1 significantly magnified TGF-␤-stimulated EMT in NSCLC cells.…”

Butein impairs the protumorigenic activity of malignant pleural mesothelioma cells

“…[47][48][49] In addition, we found reduced levels of the MMP-9 mRNA. Levels of MMP-9 are elevated in invasive cells 50 ( Fig. 3A).…”

Inflammasome-Independent NLRP3 Augments TGF-β Signaling in Kidney Epithelium

“…5A-C). In addition to control by TGF-b1 and Smad signaling, MMP-9 can be regulated by the NF-kB pathway (38,39). Accordingly, IL-1b and IL-18, alone or together, promoted the ability of TGF-b1 to induce MMP-9 expression (Fig.…”