Slug is a downstream mediator of transforming growth factor-β1-induced matrix metalloproteinase-9 expression and invasion of oral cancer cells

Members of Snail family of transcription factors play an important role in oral cancer progression by inducing epithelial-mesenchymal transition, by promoting invasion and by increasing matrix metalloproteinase (MMP) expression. Although Snail (Snai1) is the best characterized and the most extensively studied member of this family, the role and regulation of Slug (Snai2) in oral cancer progression is less well understood. In this report, we show that transforming growth factor-β1 (TGF-β1) increases Slug levels in tert-immortalized oral keratinocytes and in malignant oral squamous cell carcinoma (OSCC) cells. Inhibiting ERK1/2 signaling, but not PI3-kinase signaling, blocked TGF-β1-induced Slug expression in the malignant UMSCC1 cells. To further examine the role of Slug in OSCC progression, we generated UMSCC1 cells with inducible expression of Slug protein. Induction of Slug in UMSCC1 cells did not repress E-cadherin levels or regulate individual movement of UMSCC1 cells. Instead, Slug enhanced cohort migration and Matrigel invasion by UMSCC1 cells. Slug increased MMP-9 levels and MMP-9-specific siRNA blocked Slug-induced Matrigel invasion. Interestingly, Slug-specific siRNA attenuated TGF-β1-induced MMP-9 expression and Matrigel invasion. These data demonstrate that TGF-β1 increases Slug via ERK1/2 signaling, and thereby contributes to OSCC progression.