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


OBJECTIVE
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 muM, 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).


CONCLUSIONS
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.
Wang
Feng-qiang
FQ
Department of Obstetrics, Gynecology, and Reproductive Sciences, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.
Barfield
Elaine
E
Dutta
Sonia
S
Pua
Tarah
T
Fishman
David A
DA
D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D039942:Neuropilin-1 / Q000096:biosynthesis; D039943:Neuropilin-2 / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D008246:Lysophospholipids; D039943:Neuropilin-2; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C032881:lysophosphatidic acid