A Chemotherapy-Driven Increase in Mcl-1 Mediates the Effect of miR-375 on Cisplatin Resistance in Osteosarcoma Cells
A Chemotherapy-Driven Increase in Mcl-1 Mediates the Effect of miR-375 on Cisplatin Resistance in Osteosarcoma Cells
复制标题
化疗驱动的 Mcl-1 增加介导 miR-375 对骨肉瘤细胞顺铂耐药性的影响。
DOI：
10.2147/ott.s231125
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Huang, Ju-fang
中科院分区：
文献类型：
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作者：
Liu, An-song;Yu, Hai-yang;Huang, Ju-fang
骨肉瘤（OS）是最难治疗的癌症之一，由于其对化疗的抵抗力。Mcl-1在促进化疗耐药性中所起的重要作用已在多种癌症中观察到，包括OS，而潜在的机制仍不清楚。方法检测42例卵巢癌患者辅助化疗前后标本中Mcl-1的表达，并分析其与临床病理特征的关系。进行功能丧失和获得研究以分析Mcl-1调节对OS细胞中的化疗敏感性的影响，以及涉及Mcl-1失调的机制。结果化疗后OS组织中Mcl-1的表达显著上调，Mcl-1高表达与总生存率和复发率相关。此外，我们证明了化疗驱动的Mcl-1增加通过促进肿瘤增殖和抑制DNA损伤来降低化疗敏感性。此外，发现Mcl-1是OS细胞中miR-375的直接靶点。Mcl-1的敲低表型模仿miR-375的下调，而miR-375的过表达挽救了由Mcl-1介导的顺铂诱导的DNA损伤的作用。结论化疗诱导的Mcl-1表达增加在卵巢癌化疗耐药中起重要作用，干预miR-375/Mcl-1轴可能为提高卵巢癌化疗敏感性提供新的策略。
Background Osteosarcoma (OS) is one of the most difficult cancers to treat due to its resistance to chemotherapy. The essential role played by Mcl-1 in promoting chemoresistance has been observed in a variety of cancers, including OS, while the underlying mechanism remains unclear. Methods We investigated the expression of Mcl-1 in 42 paired OS specimens obtained before and after adjuvant chemotherapy, and its correlation with clinicopathological characteristics. Loss and gain of function studies were performed to analyze the effects of Mcl-1 modulations on the chemosensitivity, and the mechanism involved in the deregulation of Mcl-1 in OS cells. Results In OS specimens, the expression of Mcl-1 was significantly upregulated after chemotherapy, and high Mcl-1 expression was associated with poorer overall survival and an increased recurrence rate. Furthermore, we demonstrated that chemotherapy-driven increased Mcl-1 decreased chemosensitivity by promoting tumour proliferation and inhibiting DNA damage. Moreover, Mcl-1 was found to be a direct target of miR-375 in OS cells. The knockdown of Mcl-1 phenocopied miR-375 downregulation, and the overexpression of miR-375 rescued the effects of cisplatin-induced DNA damage mediated by Mcl-1. Conclusion Our data indicated that chemotherapy-driven increase in the expression of Mcl-1 plays a critical role in chemoresistance, and the intervention of the miR-375/Mcl-1 axis may offer a novel strategy to enhance chemosensitivity in OS treatment.