Extracellular transfer of HuR promotes acquired cisplatin resistance in esophageal cancer cells.

Cisplatin (DDP) resistance is a key factor hindering esophageal cancer (ESCA) treatment. Exosomes have been reported to confer resistance to DDP in various tumor cells. However, the effects of ESCA cell-derived exosomes and exosomal human antigen R (HuR) on DDP resistance in cancer cells have not been elucidated. In this study, isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. CCK-8 and flow cytometry were employed to assess the functional role of exosomes in ESCA DDP-resistant cells and their parental cells. Bioinformatics analysis was performed to identify molecules that were positively associated with HuR and validated using dual-luciferase reporter analysis and RNA immunoprecipitation assays. We found that exosomes from ESCA cells enhance the resistance of drug-resistant cells to DDP. Importantly, HuR protein, but not mRNA, was directly transferred into DDP-resistant cells via exosomes, thereby increasing the level of HuR protein. Mechanistically, HuR positively correlated with Lamin B2 (LMNB2) in ESCA cells, and ESCA DDP-resistant cells transfected with siRNA targeting LMNB2 exhibited reduced cell viability and elevated apoptosis rates. Moreover, the role of ESCA cell-derived exosomes in the transmission of DDP resistance in vivo was validated using a nude mouse model. Collectively, our results revealed that exosomes exposed to ESCA cells induced greater drug resistance in DDP-resistant ESCA cells via HuR delivery. Targeting HuR or its positively related target LMNB2 may present new therapeutic opportunities for treating patients with DDP-resistant ESCA.