MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian canceropen access
- Authors
- Cho, Jin Gu; Kim, Sung-wook; Lee, Aram; Jeong, Ha-neul; Yun, Eunsik; Choi, Jihea; Jeong, Su Jin; Chang, Woochul; Oh, Sumin; Yoo, Kyung Hyun; Lee, Jung Bok; Yoon, Sukjoon; Lee, Myeong-Sok; Park, Jong Hoon; Jung, Min Hyung; Kim, So-Woon; Kim, Ki Hyung; Suh, Dong Soo; Choi, Kyung Un; Choi, Jungmin; Kim, Jongmin; Kwon, Byung Su
- Issue Date
- Sep-2022
- Publisher
- CELL PRESS
- Keywords
- atorvastatin; carboplatin; chemoresistance; microRNA-424; microRNA-503; MT: Non-coding RNAs; NANOG; ovarian cancer; ovarian cancer spheroids; ovarian cancer stem-like cell; WEE1
- Citation
- MOLECULAR THERAPY-NUCLEIC ACIDS, v.29, pp 803 - 822
- Pages
- 20
- Journal Title
- MOLECULAR THERAPY-NUCLEIC ACIDS
- Volume
- 29
- Start Page
- 803
- End Page
- 822
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/152487
- DOI
- 10.1016/j.omtn.2022.08.028
- ISSN
- 2162-2531
- 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.
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