期刊
GYNECOLOGIC ONCOLOGY
卷 145, 期 1, 页码 167-175出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2017.01.022
关键词
Protease activated receptor 2; Tissue factor-factor Vila complex; Ovarian cancer; Microparticles; Vascular endothelial growth factor
资金
- Clinical and Translational Science Award (CTSA) program of the National Center for Advancing Translational Science (NCATS) [NIH T32 HL007899, UL1TR000427]
- University of Wisconsin Carbone Cancer Center Cancer Center Support [P30 CA014520]
- University of Wisconsin Carbone Cancer Center Investigator-initiated Pilot Project
Objective. Enhanced tissue factor (TF) expression in epithelial ovarian cancer (EOC) is associated with aggressive disease. Our objective was to evaluate the role of the TF-factor Vila-protease-activated receptor-2 (PAR-2) pathway in human EOC. Methods. TCGA RNAseq data from EOC databases were analyzed for PAR expression. Cell and microparticle (MP) associated TF protein expression (Western blot) and MP-associated coagulant activity were determined in human EOC (SKOV-3, OVCAR-3 and CaOV-3) and control cell lines. PAR-I and PAR-2 protein expressions were similarly examined. The PAR dependence of VEGF-A release (ELISA) and chemotactic migration in response to FVIIa and cellular proliferation in response to thrombin was evaluated with small molecule antagonists. Results. Relative mRNA expression consistently demonstrated PAR-2 > PAR-I >> PAR-3/4 in multiple EOC datasets. Human EOC cell line lysates confirmed expression of TF, PAR-I and PAR-2 proteins. MPs isolated from EOC cell lines demonstrated markedly enhanced (4-10 fold) TF coagulant activity relative to control cell lines. FVIIa induced a dose-dependent increase in VEGF-A release (2.5-3 fold) from EOC cell lines that was abrogated by the PAR-2 antagonist ENMD-1068. FVIIa treatment of CaOV-3 and OVCAR-3 cells resulted in increased chemotactic migration that was abolished by ENMD-1068. Thrombin induced dose-dependent EOC cell line proliferation was completely reversed by the PAR-I antagonist vorapaxar. Small molecule antagonists had no effect on these phenotypes without protease present. Conclusions. Enhanced activity of the TF-FVIIa-PAR-2 axis may contribute to the EOC progression via PAR-2 dependent signaling that supports an angiogenic and invasive phenotype and local thrombin generation supporting PAR-I dependent proliferation. (C) 2017 Elsevier Inc. All rights reserved.
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