Wnt۵A orchestrates multiple epithelial to mesenchymal-associated signaling pathways through up-regulation of integrin alpha v in epithelial ovarian cancer

Wnt۵A is a non-canonical signaling member of the Wnt family which is involved in epithelial to mesenchymal transition (EMT) in embryonic development and cancer. However, the molecular mechanism of Wnt۵A-induced EMT in epithelial ovarian cancer (EOC) remains largely unknown. Here we investigated whether Wnt۵A crosstalk with TGF۱/Smad and YAP/TAZ pathways in epithelial ovarian cancer-associated EMT. For this, we used human ovarian cancer cell lines SKOV-۳, OVCAR-۳, CAOV-۴, and human serous ovarian cancer specimens. We show here significantly higher expression levels of TGF۱ signaling components, Wnt۵A/ROR۱/ROR۲, and YAP/TAZ in human high grade serous ovarian cancer (HGSOC) specimens related to other histological serous subtypes and normal ovary. Moreover, Wnt۵A showed a positive correlation with TAZ and TGF۱ in metastatic serous subtypes specimens. Next, we demonstrated that the silencing of Wnt۵A in ovarian cancer cells in ۲D and ۳D cultures led to significantly decreased levels of Smad۲/۳ activation, and Wnt۵A was required for TGF۱-induced migration and invasion of ovarian cancer cells. Moreover, we found that inhibition of YAP transcriptional activity by Verteporfin (VP) alters ovarian cancer cell migration and invasion by two mechanisms: ۱) through suppression of Wnt۵A expression, and ۲) via the inhibition of Smad۲/۳ activation which was reverted upon recombinant human Wnt۵A addition. Moreover, we found that Wnt۵A induce up-regulation of integrin alpha v expression and activity which was involved in the activation of the TGFb۱ pathway and YAP/TAZ transcriptional activity. Together, our work showed that Wnt۵A orchestrates the EMT-associated signaling pathway through the up-regulation of integrin alpha v in epithelial ovarian cancer.

کلیدواژه ها:

EMT ، Wnt۵A ، TGF۱/Smad signaling ، YAP/TAZ signaling ، integrin alpha V