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

Authors
Cho, Jin GuKim, Sung-wookLee, AramJeong, Ha-neulYun, EunsikChoi, JiheaJeong, Su JinChang, WoochulOh, SuminYoo, Kyung HyunLee, Jung BokYoon, SukjoonLee, Myeong-SokPark, Jong HoonJung, Min HyungKim, So-WoonKim, Ki HyungSuh, Dong SooChoi, Kyung UnChoi, JungminKim, JongminKwon, 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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