Introduction/Background Ovarian cancer (OVCA) develop resistance to cisplatin during treatment. Exosome is associated with chemoresistance in various cancers, whereas such a role in OVCA is not yet clear.

Methodology The exosomes were extracted by ultracentrifugation. High-Throughput sequencing was used to measure miRNA levels in exosomes isolated by A2780 and cisplatin-resistant A2780-DDP. Integrated with public databases, exosomal miRNAs associated with cisplatin-resistance, prognosis were identified using computational studies, including 113 machine learning-based integrative procedures and other comprehensive algorithms. The crucial miR-148a-3p were selected for further investigation based on comprehensive bioinformatics approaches. Gain- or loss-functional assays were performed to define the function of miR-148a-3p, including Quantitative real-time PCR, Western Blot, CCK8, colony formation, transwell, wound healing, flow cytometry, and dual-luciferase reporter assays. The plasma exosomes and surgical tissues were collected to detect the expression level.

Results The exosomes were characterized by measuring protein markers, performing nanoparticle tracking analyses and transmission electron microscopy. 126 differentially expressed and 12 prognostic exosomal miRNAs were observed. The prognostic exosomal miRNAs-related cluster and signature were established and validated, indicating their clinical and biological significance. Comprehensive bioinformatics approaches demonstrated crucial role of miR-148a-3p in prognosis and cisplatin-resistance. Low expression of miR-148a-3p was observed in cell and tissues, especially cisplatin-resistant samples. Nevertheless, miR-148a-3p was overexpressed in plasma exosome and cisplatin-resistant cell exosomes. We confirmed the findings in both publicly available expression profiling (a series of datasets) and the samples we collected. We found that miR-148a-3p suppressed proliferation, migration, invasion, cisplatin-resistance, and induced apoptosis, indicating the role of tumor suppressor for miR-148a-3p. Ulteriorly, the inhibition of exosome release induced miR-148a-3p intracellular accumulation, the opposite was observed in the stimulative of exosome.

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Abstract #256 Figure 1

The schematic representation of the molecular mechanism miR-148a-3p in ovarian cancer

Conclusion Our data elucidated an unappreciated mechanism of miR-148a-3p in tumor suppressing and cisplatin resistance for OVCA. We uncovered that exosome exclusion of miR-148a-3p to promotes malignancy and cisplatin resistance of OVCA.

Disclosures The authors declare that they have no competing interests.