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

• Главные авторы: Jin Gu Cho (Автор), Sung-wook Kim (Автор), Aram Lee (Автор), Ha-neul Jeong (Автор), Eunsik Yun (Автор), Jihea Choi (Автор), Su Jin Jeong (Автор), Woochul Chang (Автор), Sumin Oh (Автор), Kyung Hyun Yoo (Автор), Jung Bok Lee (Автор), Sukjoon Yoon (Автор), Myeong-Sok Lee (Автор), Jong Hoon Park (Автор), Min Hyung Jung (Автор), So-Woon Kim (Автор), Ki Hyung Kim (Автор), Dong Soo Suh (Автор), Kyung Un Choi (Автор), Jungmin Choi (Автор), Jongmin Kim (Автор), Byung Su Kwon (Автор)
• Формат: ‌
• Опубликовано: Elsevier, 2022-09-01T00:00:00Z.
• Предметы: article
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Итог

Cancer stem-like cells (CSCs) have been suggested to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE1 plays a key role in regulating CSC properties and tumor resistance to carboplatin via a microRNA-dependent mechanism. We found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but this effect was reversed on the restoration of WEE1 expression. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503-mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer. We identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.

Примечание

2162-2531
10.1016/j.omtn.2022.08.028