MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer

Abstract

Cancer stem-like cells (CSCs) have been suggested to be respon-sible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE! is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE! plays a key role in regulating CSC properties and tu-mor resistance to carboplatin via a microRNA-dependent mechanism. We found that WEE! expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE!. The overexpression of miR-424/503 suppressed CSC activity by in-hibiting WEE! expression, but this effect was reversed on the restoration of WEE! expression. Furthermore, we demon-strated that NANOG modulates the miR-424/503-WEE! axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/ 503-WEE! axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503-mediated WEE! inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seed-ing in the intraperitoneal mouse models of ovarian cancer. We identified a novel NANOG-miR-424/503-WEE! pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.