TGFβ and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells.

The epithelial-mesenchymal transition (EMT) is associated with progression and metastasis of epithelial ovarian cancer (EOC). Snail and Slug (two members of the Snail family of transcription factors) down-regulate the expression of the adhesion molecule E-cadherin and thus function as positive regulators of EMT. Their expression is associated with a more invasive phenotype of EOC. However, how their expression in EOC cells is regulated needs to be further defined. Here, we show that transforming growth factor β (TGFβ) and epidermal growth factor (EGF) synergistically induce the expression of Slug and Snail at both mRNA and protein levels in an EOC cell line OVCA429 cells. Using specific chemical inhibitors, we demonstrate that Slug and Snail expression induced by TGFβ is mediated by TGFβ/ALK5 pathway, and EGF-induced expression of Slug and Snail is MEK1/2-dependent. Interestingly, TGFβ-induced Slug expression is also MEK1/2-dependent. Further, we demonstrate that combined TGFβ and EGF stimulation is more potent than either alone in repressing the expression of E-cadherin. Functionally, combined stimulation of TGFβ and EGF enhances the mobility of OVCA429 cells and induces the production of MMP2 by OVCA429 cells more potently than either alone. Taken together, our data demonstrate that TGFβ and EGF signaling pathways synergistically induce EMT and render EOC cells a more invasive phenotype.