Epidermal Growth Factor Induces Human Oviductal Epithelial Cell Invasion by Down-Regulating E-Cadherin Expression

Context: The loss of E-cadherin enhances cell invasiveness. There is increasing evidence that high-grade serous ovarian cancer may arise from oviductal epithelial cells rather than the ovarian surface epithelium. Despite the controversy over the cellular origins of this disease, the roles of epidermal growth factor (EGF) in human oviductal epithelial cells are largely unknown. Objective: We examined whether EGF could induce oviductal epithelial cell invasion by its down-regulation of E-cadherin. Methods: Matrigel-coated transwells were used for the invasion assay. Small interfering RNA was used to knock down the expression of EGF receptor (EGFR). Specific mRNA and protein levels were examined by quantitative RT-PCR and Western blot, respectively. Results: The expression of Pax8 confirmed the secretory type of the cultured human oviductal epithelial cell line OE-E6/E7. EGFR was expressed in OE-E6/E7 cells, and treatment with EGF down-regulated E-cadherin expression. The effect of EGF on the down-regulation of E-cadherin was abolished by small interfering RNA-mediated depletion of EGFR. EGF treatment led to the activation of ERK1/2, p38, and Akt. Snail and Slug are transcriptional repressors of E-cadherin. Interestingly, our results show that EGF induced Slug but not Snail expression. Moreover, the inhibition of EGF-induced ERK1/2, p38, and Akt activation by pharmacological inhibitors attenuated EGF-induced Slug expression and the down-regulation of E-cadherin, as well as subsequent cell invasion. Conclusions: EGF induces human oviductal epithelial cell invasion through the activation of ERK1/2, p38, and Akt, the up-regulation of Slug, and the down-regulation of E-cadherin. (J Clin Endocrinol Metab 97: E1380-E1389, 2012)