The miR–181a–SFRP4 Axis Regulates Wnt Activation to Drive Stemness and Platinum Resistance in Ovarian Cancer
- 11 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (8), 2044-2055
- https://doi.org/10.1158/0008-5472.can-20-2041
Abstract
Wnt signaling is a major driver of stemness and chemo-resistance in ovarian cancer, yet the genetic drivers that stimulate its expression remain largely unknown. Unlike other cancers, mutations in the Wnt pathway are not reported in high-grade serous ovarian cancer (HGSOC). Hence, a key challenge that must be addressed in order to develop effective targeted therapies is to identify non-mutational drivers of Wnt activation. Using a miRNA sensor-based approach, we have identified miR-181a as a novel driver of Wnt/β-catenin signaling. miR-181ahigh primary HGSOC cells exhibited increased Wnt/β-catenin signaling, which was associated with increased stem-cell frequency and platinum resistance. Consistent with these findings, inhibition of β-catenin decreased stem-like properties in miR-181ahigh cell populations and downregulated miR-181a. The Wnt inhibitor SFRP4 was identified as a novel target of miR-181a. Overall, our results demonstrate that miR-181a is a non-mutational activator of Wnt signaling which drives stemness and chemoresistance in HGSOC, suggesting that the miR-181a-SFRP4 axis can be evaluated as a novel biomarker for β-catenin-targeted therapy in this disease.Keywords
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Funding Information
- Case Comprehensive Cancer Center (P30CA043703)
- Rogel Cancer Center at the University of Michigan (P30CA046592)
- National Cancer Institute (R01CA197780)
- Department of Defense (OC150553)
- CWRU Pharmacology Department MTTP Training grant (T32GM008803-11A1)
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