Exosomal miR-130a-3p confers cisplatin resistance in esophageal cancer by regulating ferroptosis via the suppression of METTL14-mediated m6A RNA methylation of FSP1.

Exosomal microRNA (miRNA)s have been proven to affect recipient cell chemoresistance in several cancers. This research attempted to uncover the role of exosomal miRNA and the regulatory mechanism in cisplatin resistance of esophageal cancer (EC). Cisplatin-resistant EC cells (KYSE-150-CisR and TE-1-CisR) were established by the parental cells (KYSE-150 and TE-1) treated with a gradual increase of cisplatin concentration. Exosomes from both cisplatin-resistant EC cells and the parental one were obtained with ultracentrifugation (CisR-exo and CisS-exo), and identified by transmission electron microscopy and nanoparticle tracking analysis. The effect of CisR-exo on the cisplatin resistance of EC was assessed by in vitro (and in vivo functional experiments.Intracellular reactive oxygen species and iron were determined by the corresponding kits. The m6A dot blot assay and methylated RIP-qPCR was conducted to analyze the m6A modification level. Dual-luciferase reporter assay was performed to confirm the intermolecular interaction. Increased levels of miR-130a-3p were observed in both KYSE-150CisR and TE-1CisR cells, as well as their derived CisR-exos when compared with the parental cells and CisS-exos. Exosomal miR-130a-3p from cisplatin-resistant EC cells conferred cisplatin resistance to EC in vitro and in vivo, which might be mediated by the suppression of ferroptosis. Mechanically, KYSE-150CisR derived exosomal miR-130a-3p interacted with METTL14 to inhibit FSP1 (a ferroptosis suppressor) m6A modification of recipient cells. Overexpressing METTL14 restrained the cisplatin resistance disseminated by CisR-exos in KYSE-150 cells. Cisplatin-resistant EC cell-isolated exosomal miR-130a-3p suppressed the m6A modification of FSP1 to modulate ferroptosis, enhancing cisplatin resistance.