한빛사논문
- 조회616
Jin Gu Cho1,2#, Sung-wook Kim3#, Aram Lee1,2#, Ha-neul Jeong1#, Eunsik Yun1, Jihea Choi1, Su Jin Jeong4, Woochul Chang5, Sumin Oh1,2, Kyung Hyun Yoo1,2, Jung Bok Lee1,2, Sukjoon Yoon1,2, MyeongSok Lee1,2, Jong Hoon Park1,2, Min Hyung Jung3, So-Woon Kim6, Ki Hyung Kim7, Dong Soo Suh7, Kyung Un Choi8, Jungmin Choi9, Jongmin Kim1,2*, Byung Su Kwon3*
1Division of Biological Sciences, Sookmyung Women’s University, Seoul, 04310, Korea
2Research Institute for Women’s Health, Sookmyung Women’s University, Seoul, 04310, Korea
3Department of Obstetrics and Gynecology, Kyung Hee University Medical Center, 23, Seoul, 02447, Korea
4Kyung Hee University Medical Center, Medical Science Research Institute, Statistics Support Part, Seoul, 02447, Korea
5Department of Biology Education, College of Education, Pusan National University, Busan, 46241, Korea
6Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, 02447, Korea
7Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan, 49241, Korea
8Department of Pathology, Pusan National University Hospital, Busan National University School of Medicine, Busan, 49241, Korea
9Department of Biomedical Sciences, Korea University College of Medicine, Seoul, 02841, Korea
#These authors contributed equally.
*Corresponding author.
Abstract
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. While 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 upon 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.
논문정보
- Research article
- 2022년 08월 (BRIC 등록일 2022-08-30)
- 국내 연구진
- 의약학 > 종양의학
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