Exon 4 deletion variant of epidermal growth factor receptor enhances invasiveness and cisplatin resistance in epithelial ovarian cancer

Abstract

Recently, de4 EGFR, a variant of epidermal growth factor receptor (EGFR) with exon 4 deletion, was identified in glioblastoma and ovarian cancer. However, its biological function on ovarian cancer is still not clear. In this study, the expression profile of de4 EGFR and its contribution to epithelial ovarian cancer cells proliferation, invasiveness and drug resistance were studied. Our results showed that 48.6% (35/72) of epithelial ovarian cancer tissues had de4 EGFR expression and the expression ratio positively correlated with clinical stages. Compared with EGFR transfectants, de4 EGFR transfectants exhibited significantly higher level of invasiveness in vitro. Mechanistically, de4 EGFR significantly upregulated the extracellular regulated protein kinase, AKT, focal adhesion kinase (FAK) and Src phosphorylation and matrix metalloproteinase-9 expression while downregulated the expression of E-cadherin. Additionally, knockdown of FAK obviously suppressed de4 EGFR-induced invasiveness. Interestingly, de4 EGFR transfectants displayed significantly lower sensitivity to cisplatin than EGFR transfectants, which could be ascribed to the upregulation of Bcl-2 and downregulation of BAD in the de4 EGFR transfectants. Collectively, these results demonstrate that de4 EGFR plays an important role in the invasiveness and cisplatin resistance in epithelial ovarian cancer cells and may provide a new potential therapeutic target for epithelial ovarian cancer.