The miR–181a–SFRP4 Axis Regulates Wnt Activation to Drive Stemness and Platinum Resistance in Ovarian Cancer
Abstract
Wnt signaling is a major driver of stemness and chemoresistance 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 to develop effective targeted therapies is to identify nonmutational drivers of Wnt activation. Using an 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 nonmutational activator of Wnt signaling that 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 11, 2021
- Source ID
- 10.1158/0008-5472.can-20-2041
Entities
People
- Alexis Fleming
- Analisa DiFeo
- Anil Belur Nagaraj
- Arshia Surti
- Elmar Nurmemmedov
- Luca Beltrame
- Matthew Knarr
- Michaël Kahn
- Olga Kovalenko
- Peronne Joseph
- R. Shae Connor
- Sergio Marchini
- Sreeja Sekhar
Organizations
- Case Comprehensive Cancer Center
- Case Western Reserve University
- City of Hope National Medical Center
- Erlanger Health System
- Mayo Clinic
- National Cancer Institute
- United States Department of Defense
- University of Michigan
- University of Michigan Rogel Cancer Center
- University of Pennsylvania