Exosome‐mediated transfer of long noncoding RNA H19 induces doxorubicin resistance in breast cancer

Development of the acquired resistance is one major obstacle during chemotherapy for cancer patients. Exosomes mediate intercellular communication and cause environmental changes in tumor progression by transmitting active molecules. In this study, the role of long noncoding RNA H19 within exosomes is elucidated in terms of regulating doxorubicin (DOX) resistance of breast cancer. As a result, increased H19 expression was observed in DOX‐resistant breast cancer cells in comparison with the corresponding parental cells. Suppression of H19 significantly lowered DOX resistance by decreasing cell viability, lowering colony‐forming ability, and inducing apoptosis. Moreover, extracellular H19 could be moved to sensitive cells via being incorporated into exosomes. Treating sensitive cells with exosomes from resistant cells increased the chemoresistance of DOX, while downregulation of H19 in sensitive cells abated this effect. Taken together, H19 could be delivered by exosomes to sensitive cells, leading to the dissemination of DOX resistance. Our finding highlights the potential of exosomal H19 as a molecular target to reduce DOX resistance. H19 knockdown induces DOX sensitivity in DOX‐resistant breast cancer cells. (A) qRT‐PCR analysis was performed to examine the knockdown efficiency of three siRNAs in MCF‐7/DOX and MDA‐MB‐231/DOX. (B and C) CCK‐8 assay was used to determine the effects of H19 depletion on cell viability and IC50 values in MCF‐7/DOX and MDA‐MB‐231/DOX cells after treatment with various concentrations of DOX. (D and E) Colony forming ability was detected in si‐NC‐ and or si‐H19#2‐transfected MCF‐7/DOX and MDA‐MB‐231/DOX cells upon DOX treatment. (F and G) MCF‐7/DOX and MDA‐MB‐231/DOX cells transfected with si‐NC or si‐H19#2 were treated with DOX for 48 hr, followed by flow cytometry analysis of apoptotic rate.