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

Molecular Therapy: Nucleic Acids (Sep 2022)

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

Affiliations

Jin Gu Cho: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Sung-wook Kim: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Korea
Aram Lee: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Ha-neul Jeong: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea
Eunsik Yun: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea
Jihea Choi: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea
Su Jin Jeong: Kyung Hee University Medical Center, Medical Science Research Institute, Statistics Support Part, Seoul 02447, Korea
Woochul Chang: Department of Biology Education, College of Education, Pusan National University, Busan 46241, Korea
Sumin Oh: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Kyung Hyun Yoo: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Jung Bok Lee: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Sukjoon Yoon: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Myeong-Sok Lee: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Jong Hoon Park: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea
Min Hyung Jung: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Korea
So-Woon Kim: Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul 02447, Korea
Ki Hyung Kim: Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan 49241, Korea
Dong Soo Suh: Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan 49241, Korea
Kyung Un Choi: Department of Pathology, Pusan National University Hospital, Busan National University School of Medicine, Busan 49241, Korea
Jungmin Choi: Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea
Jongmin Kim: Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea; Research Institute for Women’s Health, Sookmyung Women’s University, Seoul 04310, Korea; Corresponding author Jongmin Kim, Division of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea.
Byung Su Kwon: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Korea; Corresponding author Byung Su Kwon, Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Korea.

Journal volume & issue: Vol. 29
pp. 803 – 822

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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