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

Jin Gu Cho; Sung-Wook Kim; Aram Lee; Ha-Neul Jeong; Eunsik Yun; Jihea Choi; Su Jin Jeong; Woochul Chang; Sumin Oh; Kyung Hyun Yoo; Jung Bok Lee; Sukjoon Yoon; Myeong-Sok Lee; Jong Hoon Park; Min Hyung Jung; So-Woon Kim; Ki Hyung Kim; Dong Soo Suh; Kyung Un Choi; Jungmin Choi; Jongmin Kim; Byung Su Kwon

doi:10.1016/j.omtn.2022.08.028

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

Mol Ther Nucleic Acids. 2022 Aug 24:29:803-822. doi: 10.1016/j.omtn.2022.08.028. eCollection 2022 Sep 13.

Authors

Jin Gu Cho^{1

2}, Sung-Wook Kim³, Aram Lee^{1

2}, Ha-Neul Jeong¹, Eunsik Yun¹, Jihea Choi¹, Su Jin Jeong⁴, Woochul Chang⁵, Sumin Oh^{1

2}, Kyung Hyun Yoo^{1

2}, Jung Bok Lee^{1

2}, Sukjoon Yoon^{1

2}, Myeong-Sok Lee^{1

2}, Jong Hoon Park^{1

2}, Min Hyung Jung³, So-Woon Kim⁶, Ki Hyung Kim⁷, Dong Soo Suh⁷, Kyung Un Choi⁸, Jungmin Choi⁹, Jongmin Kim^{1

2}, Byung Su Kwon³

Affiliations

¹ Division of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.
² Research Institute for Women's Health, Sookmyung Women's University, Seoul 04310, Korea.
³ Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Korea.
⁴ Kyung Hee University Medical Center, Medical Science Research Institute, Statistics Support Part, Seoul 02447, Korea.
⁵ Department of Biology Education, College of Education, Pusan National University, Busan 46241, Korea.
⁶ Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul 02447, Korea.
⁷ Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan 49241, Korea.
⁸ Department of Pathology, Pusan National University Hospital, Busan National University School of Medicine, Busan 49241, Korea.
⁹ Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.

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.