β-Catenin and NF-κB cooperate to regulate the uPA/uPAR system in cancer cells.
Expression of the urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) has recently been shown to be directly regulated by the Wnt/β-catenin signaling pathway in colon cancer cells, through β-catenin binding to T-cell factor binding element motifs present in their gene promoters. In our study, we present evidence that inhibition of β-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 β-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, β-catenin stabilization and accumulation by lithium chloride treatment, a well-known inhibitor of glycogen synthase kinase-3β (GSK-3β), or by β-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 β-catenin siRNA-transfected cells with a specific inhibitor of nuclear factor-kappaB (NF-κB), SN50, significantly reduced enhancement of uPA, uPAR and PAI-1 expression and cancer cell invasion, observed in β-catenin siRNA-transfected cells. Furthermore, β-catenin siRNA-treated cells exhibited NF-κB nuclear accumulation. These data suggest that β-catenin regulates the uPA/uPAR system in cooperation with NF-κB transcription factor, which constitutes a novel mechanism of regulation.
Moreau
Marie
M
INSERM, UMR-S 940, Paris, France.
Mourah
Samia
S
Dosquet
Christine
C
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D051176:beta Catenin; D014568:Urokinase-Type Plasminogen Activator