Xueli Zhou, Panpan Wei , Xinju Wang, Jianguo Zhang and Yulin Shi *
Aims: This study aimed to evaluate the roles and molecular targets of miRNA-141-3p in the cisplatin sensitivity of osteosarcoma.
Background: Osteosarcoma is one of the most common-type bone tumors, occurring mainly in children and adolescent. Cancer cells display dysregulated cellular metabolism, such as the abnormally elevated glutamine metabolism.
Objective: Non-coding RNA miRNA-141-3p has been reported to act as a tumor suppressor in osteosarcoma. Currently, the precise molecular mechanisms for the miR-141-3p-mediated chemosensitivity through regulating glutamine metabolism remain unclear.
Methods: We collected thirty-paired OS tumors and their adjacent normal tissues. The osteosarcoma cell lines [Saos-2] and normal osteoblast cells, hFOB1.19 were used for in vitro experiments. RT-qPCR and Western blot were applied for gene expression detections. Targets of miR-141-3p was predicted from starBase. The MTT and flow cytometric assays were performed to determine cell growth and apoptosis rates. The cellular glutamine metabolism was monitored by glutamine uptake assay and the glutaminase [GLS] activity assay.
Results: We report miR-141-3p were significantly downregulated in osteosarcoma tissues and cells. Overexpression of miR-141-3p suppressed OS cell growth and sensitized OS cells to cisplatin. In addition, glutamine metabolism was significantly increased in osteosarcoma. We characterized that GLS played oncogenic roles in osteosarcoma and validated GLS was a direct target of miR-141-3p in OS cells. Specifically, rescue experiments consistently demonstrated the miR-141-3p-promoted cisplatin sensitivity was through direct targeting GLS.
Conclusion: Overall, our findings revealed new molecular mechanisms of the miR-141-3p-modulated cisplatin sensitization through targeting the GLS-glutamine metabolism pathway. This study will contribute to developing new therapeutic approaches for the treatments of chemoresistant osteosarcoma.
Osteosarcoma, Cisplatin resistance, miR-141-3p, Glutaminase, glutamine, metabolism
Department of Spinal Surgery, Changyi People's Hospital. Changyi, Weifang City, Shandong Province, Department of Anesthesiology, Changyi People's Hospital. Changyi, Weifang City, Shandong Province, Medical center of Changyi People's Hospital. Changyi, Weifang City, Shandong Province, Department of Anesthesiology, Changyi People's Hospital. Changyi, Weifang City, Shandong Province, Department of Spinal Surgery, Weifang People's Hospital. Weifang City, Shandong Province