VEGFR-2 silencing by small interference RNA (siRNA) suppresses LPA-induced epithelial ovarian cancer (EOC) invasion

Abstract

Background The VEGF–VEGF receptor (VEGFR) signaling axis has emerged as a promising target for cancer therapy, attributing to its vital role in tumor angiogenesis and growth. We have previously reported the regulation of epithelial ovarian cancer (EOC) invasion and migration by VEGF and the implication of VEGF-VEGFR-2 axis in lysophosphatidic acid (LPA)-induced EOC invasion. However, the expression profile of VEGF and VEGFRs in EOC, their association with tumor aggressiveness, and their regulation by LPA remain unclear. Objectives and methods In this study, we examined the expression of VEGFR-1, VEGFR-2, neuropilin-1 (NRP-1), NRP-2, VEGF 121, and VEGF 165 in established EOC cell lines and assessed their correlation with cell invasiveness. Moreover, using an ovarian cancer tissue qPCR array, we analyzed VEGFR-2 expression across a panel of 48 tissues with different disease stages and histological grades. We also tested the effect of LPA on VEGF and VEGFR-2 expression and examined whether blocking VEGFR-2 by RNA interference (RNAi) affects LPA-induced EOC invasion. Results We show that VEGF and VEGFR-2 expression correlates with cell invasiveness and VEGFR-2 expression in ovarian cancer tissues correlate with tumor grade. In addition, LPA, at 20 μM, significantly induced the expression of VEGF 121, VEGF 165, and VEGFR-2 in SKOV3 and DOV13 cells ( P < 0.05). VEGFR-2 small interference RNA (siRNA) transfection remarkably decreased LPA's invasion-promoting effect ( P < 0.001) in SKOV3 cells without significantly decreasing SKOV3 cells' basal invasiveness. In DOV13 cells, VEGFR-2 silencing significantly decreases both the basal level cell invasion and LPA's invasion promoting effect ( P < 0.001). Conclusion These results suggest that decreasing VEGFR-2 expression by RNAi may prove to be an effective method to reduce the metastatic potential of EOC cells exposed to elevated levels of LPA.