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Eur J Cancer. 2012 Jul;48(10):1550-7. doi: 10.1016/j.ejca.2011.06.043. Epub 2011 Jul 26.

SMAD3 is essential for transforming growth factor-β1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes.

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1
Laboratory for Experimental Hematology, Institute for Medical Research, University of Belgrade, Dr. Subotica 4, PO Box 102, 11129 Belgrade, Serbia.

Abstract

Transforming growth factor-β1 (TGF-β1) stimulates the extracellular matrix degrading proteases expression and cell migration in order to enhance cancer cells malignancy. In the present study, we analysed the role of TGF-β1-induced Smad3 activation in the urokinase type plasminogen activator (uPA) production, as well as in cell migration and E-cadherin downregulation in transformed PDV keratinocyte cell line. TGF-β1 signalling was interfered by the chemical inhibitor of the TGF-β1-receptor 1 (ALK5), SB505124, and the specific Smad3 inhibitor, SiS3. Our results showed that TGF-β1 stimulates uPA expression directly through ALK5 activation. The inhibition of Smad3 strongly reduced the capacity of TGF-β1 to stimulate uPA expression, in parallel decreasing the uPA inhibitor plasminogen activator inhibitor type 1 (PAI-1) expression. In addition, the transient expression of dominant negative Smad3 mutant inhibited the TGF-β1-induced uPA promoter transactivation. Moreover, Smad3-/- mouse embryonic fibroblasts were refractory to the induction of uPA by TGF-β1. The inhibition of both ALK5 and Smad3 dramatically blocked the TGF-β1-stimulated E-cadherin downregulation, F-actin reorganisation and migration of PDV cells. Taken together, our results suggest that the TGF-β1-induced activation of Smad3 is the critical step for the uPA upregulation and E-cadherin downregulation, which are the key events preceding the induction of cell migration by TGF-β1 in transformed cells.

PMID:
21798735
DOI:
10.1016/j.ejca.2011.06.043
[Indexed for MEDLINE]
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