COX2 is Induced in the Ovarian Epithelium During Ovulatory Wound Repair and Promotes Cell Survival.

The ovarian surface epithelium (OSE) is a monolayer of cells surrounding the ovary that is ruptured during ovulation. After ovulation, the wound is repaired, however, this process is poorly understood. In epithelial tissues, wound repair is mediated by an epithelial-to-mesenchymal transition (EMT). Transforming Growth Factor Beta-1 (TGF beta 1) is a cytokine commonly known to induce an EMT and is present throughout the ovarian microenvironment. We, therefore, hypothesized that TGF beta 1 induces an EMT in OSE cells and activates signaling pathways important for wound repair. Treating primary cultures of mouse OSE cells with TGF beta 1 induced an EMT mediated by TGF beta RI signaling. The transcription factor Snail was the only EMT-associated transcription factor increased by TGF beta 1 and, when overexpressed, was shown to increase OSE cell migration. A polymerase chain reaction array of TGF beta signaling targets determined Cyclooxygenase-2 (Cox2) to be most highly induced by TGF beta 1. Constitutive Cox2 expression modestly increased migration and robustly enhanced cell survival, under stress conditions similar to those observed during wound repair. The increase in Snail and Cox2 expression with TGF beta 1 was reproduced in human OSE cultures, suggesting these responses are conserved between mouse and human. Finally, the induction of Cox2 expression in OSE cells during ovulatory wound repair was shown in vivo, suggesting TGF beta 1 increases Cox2 to promote wound repair by enhancing cell survival. These data support that TGF beta 1 promotes ovulatory wound repair by induction of an EMT and activation of a COX2-mediated prosurvival pathway. Understanding ovulatory wound repair may give insight into why ovulation is the primary non-hereditary risk factor for ovarian cancer.