Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

Abstract

// Andrew J. Wilson 1 , Oluwole Fadare 2 , Alicia Beeghly-Fadiel 3, 4 , Deok-Soo Son 5 , Qi Liu 6, 7 , Shilin Zhao 7 , Jeanette Saskowski 1 , Md. Jashim Uddin 8, 9 , Cristina Daniel 8, 9 , Brenda Crews 8, 9 , Brian D. Lehmann 4, 8 , Jennifer A. Pietenpol 4, 8 , Marta A. Crispens 1, 4 , Lawrence J. Marnett 4, 8, 9 , Dineo Khabele 1, 4 1 Department of Obstetrics & Gynecology, Vanderbilt University Medical Center, Nashville, TN 2 Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA 3 Department of Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN 4 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 5 Department of Biochemistry & Cancer Biology, Meharry Medical College, Nashville, TN 6 Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 7 Vanderbilt Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 8 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 9 Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN Correspondence to: Dineo Khabele, e-mail: [e-mail] Keywords: high-grade serous ovarian cancer, cyclooxygenase-1, cell migration/invasion, pro-tumorigenic pathways Received: February 25, 2015      Accepted: April 21, 2015      Published: May 04, 2015 ABSTRACT Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors.