A Chemotherapy-Driven Increase in Mcl-1 Mediates the Effect of miR-375 on Cisplatin Resistance in Osteosarcoma Cells

An-song Liu,1 Hai-yang Yu,1 Yan-lin Yang,2 Fu-yao Xue,1 Xia Chen,3 Yun Zhang,3 Zi-yu Zhou,1 Bin Zhang,1 Lan Li,4 Chuan-zheng Sun,5 Peng Huang,6 Ju-fang Huang1 1Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, People’s Republic of China; 2Department of Oncology, Affiliated Nanhua Hospital, University of South China, Hengyang, People’s Republic of China; 3Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 4Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 5Emergency Department, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 6Department of General Surgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Peng HuangDepartment of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha 410008, People’s Republic of ChinaTel +86 15273124136Email xiangyahp@csu.edu.cnJu-fang HuangDepartment of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, No. 172 Tongzipo Road, Changsha 410013, Hunan, People’s Republic of ChinaTel +86 15873108338Email huangjufang@csu.edu.cnBackground: 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.Keywords: osteosarcoma, Mcl-1, chemotherapy resistance, miR-375, cisplatin