Abstract 2068: Cyclooxygenase-1 gene expression contributes to multiple oncogenic pathways in high grade serous ovarian cancer

Abstract

Abstract Ovarian cancer is the most lethal gynecologic malignancy. Most women diagnosed with high grade serous ovarian cancer present with advanced disease characterized by widespread peritoneal carcinomatosis. Recent epidemiological results indicate that cyclooxygenase (COX) inhibitors aspirin and other non-steroidal anti-inflammatory drugs are a promising preventive strategy to reduce the risk of developing ovarian cancer. COX-1 and COX-2 catalyze the rate-limiting step in the biosynthesis of prostaglandins and thromboxanes, which contribute to tumorigenesis by promoting proliferation, escape from apoptosis, and angiogenesis. Emerging evidence from our group and others suggests that COX-1 is an important molecular target in ovarian cancer, distinguishing ovarian cancer from most other solid tumors, where COX-2 is the dominant isoform. However, the precise roles of COX-1 and COX-2 in human ovarian cancer remain controversial. Therefore, the aim of this study was to gain additional insight into COX-1 gene expression and function in human ovarian cancer. First, we extracted RNA-seq V2 mRNA expression data for COX-1 and COX-2 in the PANCAN12 tumor panel of The Cancer Genome Atlas. COX-1 mRNA levels were significantly higher than those of COX-2 in high grade serous ovarian tumors, and higher than COX-1 expression in 11 other solid tumor types. We confirmed these findings in a tissue microarray generated from 209 ovarian cancer patients. COX-1 protein was highly expressed in a large subset of serous tumors, with significantly lower COX-2 expression present. In contrast, there was markedly lower COX-1 expression in endometrioid, mucinous and clear cell ovarian tumors compared to COX-2. Second, stable COX-1 knockdown in serous-representative OVCAR-3 cells significantly reduced cell viability compared to control cells. Pathway analysis from RNA-seq data revealed that COX-1 knockdown induced a coordinated transcriptional response consistent with reduced cell proliferation (eg. reduced cyclin D1 and increased p21 expression), cell migration/invasion (eg. reduced TGF-β signaling and expression of MMPs), angiogenesis (eg. reduced VEGF expression), epithelial-mesenchymal transition (eg. increased E-cadherin expression and reduced BMP signaling), and NF-κB signaling. Gene expression changes were validated by western blot. In SKOV-3 ovarian cancer cells stably overexpressing COX-1, opposite effects on cell viability and on these genes/pathways were observed. Our findings confirm that COX-1 is over-expressed in serous ovarian cancer, and likely plays a key role in tumor progression. Exploiting high COX-1 expression in ovarian cancer with COX-1-targeted molecules has the potential to improve the treatment and detection of this deadly disease. Citation Format: Andrew J. Wilson, Brian D. Lehmann, Jeanette Saskowski, MD Jashim Uddin, Cristina Daniel, Brenda C. Crews, Qi Liu, Shilin Zhao, Deok-Soo Son, Jennifer A. Pietenpol, Lawrence J. Marnett, Dineo Khabele. Cyclooxygenase-1 gene expression contributes to multiple oncogenic pathways in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2068. doi:10.1158/1538-7445.AM2015-2068