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 ChoiJongmin Kim, Byung Su Kwon

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)803-822
Number of pages20
JournalMolecular Therapy - Nucleic Acids
Volume29
DOIs
Publication statusPublished - 2022 Sep 13

Keywords

  • MT: Non-coding RNAs
  • NANOG
  • WEE1
  • atorvastatin
  • carboplatin
  • chemoresistance
  • microRNA-424
  • microRNA-503
  • ovarian cancer
  • ovarian cancer spheroids
  • ovarian cancer stem-like cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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