RESUMO
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/ß-catenin signaling. miR-181ahigh primary HGSOC cells exhibited increased Wnt/ß-catenin signaling, which was associated with increased stem-cell frequency and platinum resistance. Consistent with these findings, inhibition of ß-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 ß-catenin-targeted therapy in this disease. SIGNIFICANCE: These results demonstrate that miR-181a is an activator of Wnt signaling that drives stemness and chemoresistance in HGSOC and may be targeted therapeutically in recurrent disease.
Assuntos
MicroRNAs/fisiologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , MicroRNAs/metabolismo , Terapia de Alvo Molecular , Mutação , Gradação de Tumores , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas/genética , Células Tumorais Cultivadas , Via de Sinalização Wnt/genética , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismoRESUMO
The effectiveness of simulation training for enhancing operative skills is well established. Here we describe the construction of a simple, low-cost model for teaching the loop electrosurgical excision procedure. Composed of common materials such as polyvinyl chloride pipe and sausages, the simulation model, shown in the accompanying figure, can be easily reproduced by other training programs. In addition, we also present an instructional video that utilizes this model to review loop electrosurgical excision procedure techniques, highlighting important steps in the procedure and briefly addressing challenging situations and common mistakes as well as strategies to prevent them. The video and model can be used in conjunction with a simulation skills laboratory to teach the procedure to students, residents, and new practitioners.
