The miR-181a-SFRP4 axis regulates Wnt activation to drive stemness and platinum resistance in ovarian cancer.
california; jwci; pacific neurosciences; psjhc
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.
Women & Children
Obstetrics & Gynecology
Belur Nagaraj, Anil; Knarr, Matthew; Sekhar, Sreeja; Connor, R Shae; Joseph, Peronne; Kovalenko, Olga; Fleming, Alexis; Surti, Arshia; Nurmemmedov, Elmar; Beltrame, Luca; Marchini, Sergio; Kahn, Michael; and DiFeo, Analisa, "The miR-181a-SFRP4 axis regulates Wnt activation to drive stemness and platinum resistance in ovarian cancer." (2021). Articles, Abstracts, and Reports. 4448.