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Spred2 inhibits TGF‐β1‐induced urokinase type plasminogen activator expression, cell motility and epithelial mesenchymal transition

TGF‐β1 is a potent inductor of malignance in cancer cells. TGF‐β1 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‐β1. 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‐β1‐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‐β1, although Smad2 activation was not affected, and the knockdown of Spred2 enhanced the activation of ERK1,2 signal by TGF‐β1. The increment of uPA expression induced by TGF‐β1 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‐β1 treatment were unable to display the EMT, since the overexpression of Spred2 abolished the TGF‐β1‐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‐β1 stimulus on cell migration. Taken together, the data in the present study suggests that Spred2 is a regulator of TGF‐β1‐induced malignance in transformed keratinocytes.