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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.
- Source :
-
International journal of biological sciences [Int J Biol Sci] 2023 Jun 12; Vol. 19 (10), pp. 3099-3114. Date of Electronic Publication: 2023 Jun 12 (Print Publication: 2023). - Publication Year :
- 2023
-
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.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Humans
Female
Cisplatin pharmacology
Cisplatin therapeutic use
Carcinoma, Ovarian Epithelial drug therapy
Carcinoma, Ovarian Epithelial genetics
Signal Transduction genetics
Adaptor Proteins, Signal Transducing metabolism
Transcription Factors genetics
Transcription Factors metabolism
Drug Resistance, Neoplasm genetics
Cell Line, Tumor
Tumor Microenvironment
Tumor Suppressor Proteins metabolism
Guanylate Kinases metabolism
Ovarian Neoplasms drug therapy
Ovarian Neoplasms genetics
Ovarian Neoplasms metabolism
MicroRNAs metabolism
Exosomes genetics
Exosomes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1449-2288
- Volume :
- 19
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- International journal of biological sciences
- Publication Type :
- Academic Journal
- Accession number :
- 37416779
- Full Text :
- https://doi.org/10.7150/ijbs.83264