@article{ea6d4fcb0a6b4ad5b71315359cd7a039,
title = "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 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.",
keywords = "MT: Non-coding RNAs, NANOG, WEE1, atorvastatin, carboplatin, chemoresistance, microRNA-424, microRNA-503, ovarian cancer, ovarian cancer spheroids, ovarian cancer stem-like cell",
author = "Cho, {Jin Gu} and Kim, {Sung wook} and Aram Lee and Jeong, {Ha neul} and Eunsik Yun and Jihea Choi and Jeong, {Su Jin} and Woochul Chang and Sumin Oh and Yoo, {Kyung Hyun} and Lee, {Jung Bok} and Sukjoon Yoon and Lee, {Myeong Sok} and Park, {Jong Hoon} and Jung, {Min Hyung} and Kim, {So Woon} and Kim, {Ki Hyung} and Suh, {Dong Soo} and Choi, {Kyung Un} and Jungmin Choi and Jongmin Kim and Kwon, {Byung Su}",
note = "Funding Information: We thank Dr. Kyung-Hee Chun (Yonsei University, Korea) and Dr. Sung Hee Baek (Seoul National University, Korea) for kindly providing us with the pcDNA-3X Flag-WEE1 plasmid DNA and pcDNA-Flag-NANOG, respectively. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea ( NRF ) supported by the Ministry of Education (NRF-2016R1A5A1011974 to J.K. and B.S.K.; NRF-2022R1A2C1003866 to J.K.). Funding Information: We thank Dr. Kyung-Hee Chun (Yonsei University, Korea) and Dr. Sung Hee Baek (Seoul National University, Korea) for kindly providing us with the pcDNA-3X Flag-WEE1 plasmid DNA and pcDNA-Flag-NANOG, respectively. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) supported by the Ministry of Education(NRF-2016R1A5A1011974 to J.K. and B.S.K.; NRF-2022R1A2C1003866 to J.K.). J.K. and B.S.K. designed and supervised the study. J.G.C. S.-W.K. A.L. H.-N.J. E.Y. J.C. S.-W.K. K.H.K. D.S.S. and K.U.C. carried out experiments and analyzed the data. K.H.Y. S.O. and J.C. analyzed computational data. S.J.J. performed the statistical analysis. J.K. B.S.K. J.G.C. S.-W.K. A.L. and H.-N.J. wrote the manuscript. A.L. and S.-W.K. prepared the figures. W.C. J.B.L. S.Y. M.-S.L. J.H.P. M.H.J. S.-W.K. K.H.K. D.S.S. and K.U.C. contributed to the discussion. All authors have read and approved the article. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = sep,
day = "13",
doi = "10.1016/j.omtn.2022.08.028",
language = "English",
volume = "29",
pages = "803--822",
journal = "Molecular Therapy - Nucleic Acids",
issn = "2162-2531",
publisher = "Nature Publishing Group",
}
