p53 Mediates Epidermal Growth Factor (EGF) Induction of MMP-2 Transcription and Trophoblast Invasion

Trophoblast invasion is a highly restricted process, regulated by growth factors, hormones and cytokines. Trophoblast invasion is attainable due to proteolytic degradation of the epithelial basement membrane and the extracellular matrix by proteolytic enzymes like the matrix metalloproteinases (MMPs) particularly MMP-2. Epidermal growth factor (EGF), a major mediator of implantation, has been documented to induce MMP-2 and trophoblast invasion. The aim of this study was to investigate the transcriptional regulation of MMP-2 in EGF- stimulated invasive trophoblast cells, using JAR choriocarcinoma cell line and 6-8w 1st trimester trophoblasts. MMP-2 expression was induced by EGF within 1 hour. Gelshift and supershift assay were used to explore transcription factors involved in MMP-2 regulation. EGF induced binding activity and expression of phophorylated p53, AP-2α and −γ, C/EBPɛ and −λ to their responding sequences, found in the MMP-2 promoter. Additionally EGF induced binding activity to SP-1, but reduced the expression of SP-1 and SP-4. Inhibition of p53 by antisense reduced both basic and EGF- induced MMP-2 expression. In summary: MMP-2 transcriptional regulation by EGF in invasive trophoblasts is mediated through several binding sites and transcription factors including p53, AP-2α and −γ, C/EBPɛ and −λ and SP-1. p53 mediates both basic and EGF-induced MMP-2 transcription.