Sorafenib controls the epithelial-mesenchymal transition of ovarian cancer cells via EGF and the CD44-HA signaling pathway in a cell type-dependent manner

摘要

Cluster of differentiation (CD) 44 and epidermal growth factor (EGF) are closely involved in cellular migration and have been used as stem cell markers. Although the hyaluronan (HA)-binding CD44 is responsible for enhanced cellular motility, the mechanism underlying its actions in various cell types and clinical conditions have yet to be elucidated. In the present study, the multikinase inhibitor sorafenib was used to investigate the diverse effects of EGF stimulation on epithelial-mesenchymal transition (EMT) in ovarian cancer cells using immunoblotting and reverse transcription-polymerase chain reaction. In addition, the association between EGF and CD44/HA signaling pathways in the control of mesenchymal phenotype was determined by gene silencing with small interfering RNA transfection. EGF stimulation of ovarian cancer cells increased cellular migration, mesenchymal transition, CD44 expression and the activation of matrix metalloproteinase (MMP)-2 and MMP-9. Sorafenib effectively suppressed the loss of epithelial characteristics in EGF-treated SK-OV-3 ovarian cancer cells, via targeting the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Although treatment of Caov-3 ovarian cancer cells with sorafenib blocked the expression of mesenchymal phenotypes following EGF stimulation, EGF-activated Caov-3 cells exhibited reduced MAPK/ERK signaling. Furthermore, EGF-activated Caov-3 cells increased the expression of hyaluronan synthase 2 and HA-CD44 ligation in EGF-exposed Caov-3 cells, which resulted in the activation of the Ras/Raf/MEK signaling pathway, amplification of migratory activity and the expression of mesenchymal markers, including N-cadherin and vimentin. Furthermore, silencing EGFR in SK-OV-3 cells and CD44 in Caov-3 cells suppressed their migratory activity, through inhibition of the MAPK/ERK pathway. The present results suggested that EGF-mediated signaling may regulate metastasis and invasion of ovarian cancer cells, in a cancer cell type-dependent manner.