Abstract
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.
Highlights
Osteosarcoma is the most common type of primary bone malignancy in children and adolescents, which remains the leading cause of cancer-related death in adolescents across the world (Luetke et al, 2014; Isakoff et al, 2015; Bray et al, 2018)
Given miR-26a downregulation in chemoresistant osteosarcoma, we speculated that the correlation of miR-26a with these clinical features might be associated with altered chemotherapy response
We found that, compared with chemosensitive counterparts KHOS (Figures 1D,F—left half) and U2OS (Figures 1E,F—right half), miR-26a expression was all decreased in those clones of osteosarcoma cells with multidrug resistance (MDR), which was developed by continuous culture with stepwise increases in the concentration of paclitaxel for over 8 months (Yang et al, 2009)
Summary
Osteosarcoma is the most common type of primary bone malignancy in children and adolescents, which remains the leading cause of cancer-related death in adolescents across the world (Luetke et al, 2014; Isakoff et al, 2015; Bray et al, 2018). MiR-26a Reverses Multidrug Resistance in Osteosarcoma poor and the chance of long-term survival is less than 20% despite aggressive therapies (Sakamoto and Iwamoto, 2008). Due to the development of multidrug resistance (MDR) either through an intrinsic or acquired manner, chemoresistance becomes the major cause of recurrences and failure of current therapy (Hattinger et al, 2015; Li et al, 2015). Its downregulation is associated with metastatic potential and poor prognosis of osteosarcoma patients (Song et al, 2014). These results suggest that miR-26a possesses several anti-osteosarcoma activities, whereas whether it regulates MDR in osteosarcoma and the mechanisms are unclear. By investigating clinical osteosarcoma samples and MDR osteosarcoma cell lines, we show that MiR-26a functions to reverse MDR in human osteosarcoma, wherein the targeted expression of myeloid cell leukemia 1 (MCL1) represents a critical mechanism
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