Wnt5A and TGFβ1 Converges through YAP1 Activity and Integrin Alpha v Up-Regulation Promoting Epithelial to Mesenchymal Transition in Ovarian Cancer Cells and Mesothelial Cell Activation

In this paper, we investigate whether Wnt5A is associated with the TGF-β1/SMAD2/3 and Hippo-YAP1/TAZ-TEAD pathways, implicated in epithelial to mesenchymal transition (EMT) in epithelial ovarian Cancer. We used 3D and 2D cultures of human epithelial ovarian Cancer cell lines SKOV-3, OVCAR-3, CAOV-4, and different subtypes of human serous ovarian Cancer compared to normal ovary specimens. Wnt5A showed a positive correlation with TAZ and TGFβ1 in high- and low-grade serous ovarian Cancer specimens compared to borderline serous and normal ovaries. Silencing Wnt5A by siRNAs significantly decreased SMAD2/3 activation and YAP1 expression and nuclear shuttling in ovarian Cancer (OvCa) cells. Furthermore, Wnt5A was required for TGFβ1-induced cell migration and invasion. In addition, inhibition of YAP1 transcriptional activity by Verteporfin (VP) altered OvCa cell migration and invasion through decreased Wnt5A expression and inhibition of SMAD2/3 activation, which was reverted in the presence of exogenous Wnt5A. We found that the activation of TGFβ1 and YAP1 nuclear shuttling was promoted by Wnt5A-induced Integrin alpha v. Lastly, Wnt5A was implicated in activating human primary omental mesothelial cells and subsequent invasion of ovarian Cancer cells. Together, we propose that Wnt5A could be a critical mediator of EMT-associated pathways.

TGFβ1/Smad signaling; Wnt5A; epithelial to mesenchymal transition; hippo-YAP1/TAZ signaling; integrin alpha v; mesothelial cell activation; ovarian cancer.