Spred2 inhibits TGF-beta1-induced urokinase type plasminogen activator expression, cell motility and epithelial mesenchymal transition

Victor Villar, Jelena Kocić, Juan F Santibanez

Research output: Contribution to journalArticlepeer-review


TGF-beta1 is a potent inductor of malignance in cancer cells. TGF-beta1 stimulates the expression of extracellular matrix degrading proteases, cell migration and it is also involved in the epithelial-mesenchymal transition (EMT). In the present work, we analyzed the role of Spred2 in the urokinase-type plasminogen activator (uPA) stimulation, EMT and cell migration by TGF-beta1. We found that both the expression of mRNA and the protein level of Spred2 were lower in transformed keratinocytes PDV compared with immortalized keratinocytes MCA-3D. The transient ectopic expression of Spred2 in PDV cells inhibited the TGF-beta1-transactivated SRE-Luc reporter which is related with the ERK1,2 signal. The stable ectopic expression of Spred2 in PDV cells (SP cells) led to the loss of ERK 1,2 activation by TGF-beta1, although Smad2 activation was not affected, and the knockdown of Spred2 enhanced the activation of ERK1,2 signal by TGF-beta1. The increment of uPA expression induced by TGF-beta1 was suppressed in SP cells. In contrast, the stimulus on PAI-1 expression was not affected and comparable to parental PDV cells. SP cells under TGF-beta1 treatment were unable to display the EMT, since the overexpression of Spred2 abolished the TGF-beta1-induced disruption of the E-cadherin cell to cell interactions, reorganization of the actin cytoskeleton and upregulation of the mesenchymal marker vimentin. Finally, SP cells could not respond to the TGF-beta1 stimulus on cell migration. Taken together, the data in the present study suggests that Spred2 is a regulator of TGF-beta1-induced malignance in transformed keratinocytes.

Original languageEnglish
Pages (from-to)77-85
Number of pages9
JournalInternational Journal of Cancer
Issue number1
Publication statusPublished - 1 Jul 2010


  • Base Sequence
  • Cell Movement/physiology
  • DNA Primers
  • Enzyme Activation
  • Epithelial Cells/cytology
  • Extracellular Signal-Regulated MAP Kinases/metabolism
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Humans
  • Mesoderm/cytology
  • Repressor Proteins/genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta1/physiology
  • Urokinase-Type Plasminogen Activator/metabolism


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