Extracellular vesicles carrying miR-6836 derived from resistant tumor cells transfer cisplatin resistance of epithelial ovarian cancer via DLG2-YAP1 signaling pathway

Abstract

AbstractChemotherapy resistance is a significant cause for poor prognosis of epithelial ovarian cancer (EOC). However, the molecular mechanism of chemo-resistance remains unclear, and developing available therapies and effective biomarkers for resistant EOC is in urgent demand. Stemness of cancer cells directly results in chemo-resistance. Exosomal miRNAs rebuild tumor microenvironment (TME) and act as widely used clinical liquid biopsy markers. In our study, high throughput screenings and comprehensive analysis were performed to screen for miRNAs, which were both up-regulated in resistant EOC tissues and related to stemness, and miR-6836 was identified accordingly. Clinically, high miR-6836 expression was closely correlated with poor chemotherapy response and survival for EOC patients. Functionally, miR-6836 promoted EOC cell cisplatin resistance by increasing stemness and suppressing apoptosis. Mechanistically, miR-6836 directly targeted DLG2 to enhance Yap1 nuclear translocation, and was regulated by TEAD1 forming the positive feedback loop: miR-6836-DLG2-Yap1-TEAD1. Furthermore, miR-6836 could be packaged into secreted exosomes in cisplatin-resistant EOC cells and exosomal miR-6836 was able to be delivered into cisplatin-sensitive EOC cells and reverse their cisplatin response. Our study revealed the molecular mechanisms of chemotherapy resistance, and identified miR-6836 as the possible therapeutic target and effective biopsy marker for resistant EOC.