Abstract
Overexpression of the transcription factor Snail in epithelial MDCK cells promotes the epithelial-mesenchymal transition (EMT) and the acquisition of an invasive phenotype. We report here that the expression of Snail is associated with an increase in the promoter activity and expression of the matrix metalloproteinase MMP-9. The effect of Snail silencing on MMP-9 expression corroborates this finding. Induced transcription of MMP-9 by Snail is driven by a mechanism dependent on the MAPK and phosphoinositide 3-kinase (PI3K) signalling pathways. Although other regions of the promoter were required for a complete stimulation by Snail, a minimal fragment (nucleotides -97 to +114) produces a response following an increased phosphorylation of Sp-1 and either Sp-1 or Ets-1 binding to the GC-box elements contained in this region. The expression of a dominant negative form of MEK decreased these complexes. A moderate increase in the binding of the nuclear factor kappaB (NFkappaB) to the upstream region (nucleotide -562) of the MMP-9 promoter was also observed in Snail-expressing cells. Interestingly, oncogenic H-Ras (RasV12) synergistically co-operates with Snail in the induction of MMP-9 transcription and expression. Altogether, these results indicate that MMP-9 transcription is activated in response to Snail expression and that it might explain, at least in part, the invasive properties of the Snail-expressing cells.
Highlights
The Snail family of transcription factors can induce the process of cellular invasion and Snail itself regulates epithelialmesenchymal transition (EMT) both during embryonic development and in epithelial cell lines (Batlle et al, 2000; Bolos et al, 2003; Cano et al, 2000)
A moderate increase in the binding of the nuclear factor κB (NFκB) to the upstream region of the matrix metalloproteinases (MMPs)-9 promoter was observed in Snail-expressing cells
Oncogenic H-Ras (RasV12) synergistically co-operates with Snail in the induction of matrix metalloproteinase-9 (MMP-9) transcription and expression. These results indicate that MMP-9 transcription is activated in response to Snail expression and that it might explain, at least in part, the invasive properties of the Snail-expressing cells
Summary
The Snail family of transcription factors can induce the process of cellular invasion and Snail itself regulates epithelialmesenchymal transition (EMT) both during embryonic development and in epithelial cell lines (Batlle et al, 2000; Bolos et al, 2003; Cano et al, 2000). The matrix metalloproteinases (MMPs) is one of the most extensive families of ECM-degrading enzymes involved in EMT (Chakraborti et al, 2003; Kerkela and Saarialho-Kere, 2003). Epidermal growth factor and amphiregulin stimulate the production of MMP-9 in the SKBr3 human breast cancer cell line (Kondapaka et al, 1997), as does heregulin-β1 (Yao et al, 2001).
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