miR-26a Reverses Multidrug Resistance in Osteosarcoma by Targeting MCL1

This is the authors' abstract. We don't add key points for this paper.

The multidrug resistance (MDR) acquired in human osteosarcoma is a huge obstacle for effective chemotherapy. Recently, microRNA-26a (miR-26a) has been associated with the pathogenesis and progression of osteosarcoma. However, whether it regulates MDR in osteosarcoma is unknown. We show here that miR-26a expression declines in chemoresistant osteosarcoma after neoadjuvant chemotherapy, and its expression correlates with clinical outcome. In addition, compared with sensitive parental cells, miR-26a expression also declines in osteosarcoma MDR cells, together suggesting a negative correlation between miR-26a expression and MDR development in osteosarcoma. We also show that the enforced expression of miR-26a reverses MDR in osteosarcoma cells, and conversely, miR-26a knockdown confers MDR in chemosensitive osteosarcoma cells treated with doxorubicin, methotrexate, or cisplatin. Mechanistically, miR-26a directly targets the pro-survival protein myeloid cell leukemia 1 (MCL1), and in turn, the enforced expression of MCL1 markedly antagonizes miR-26a-decreased MDR in osteosarcoma MDR cells, therefore demonstrating that miR-26a reverses MDR in osteosarcoma by targeting MCL1. Lastly, miR-26a reverses resistance to doxorubicin in osteosarcoma MDR cells xenografted in nude mice. Collectively, these results reveal a negative role and the underlying mechanism of miR-26a in the regulation of MDR in human osteosarcoma, implying a potential tactic of manipulating miR-26a for overcoming MDR in osteosarcoma chemotherapy.