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


ABSTRACT: Background: Chemotherapy 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. Methods: 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. Results: 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. Conclusion: 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.

SUBMITTER: Zou Y 

PROVIDER: S-EPMC10321283 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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

Zou Yazhu Y   Zhao Zitong Z   Wang Jingjing J   Ma Liying L   Liu Yi Y   Sun Li L   Song Yongmei Y  

International journal of biological sciences 20230612 10


<b>Background:</b> Chemotherapy 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. <b>Methods:</b> In our study, high thro  ...[more]

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