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

Authors Liu A, Yu H, Yang Y, Xue F, Chen X, Zhang Y, Zhou Z, Zhang B, Li L, Sun C, Huang P, Huang J

Received 15 September 2019

Accepted for publication 13 December 2019

Published 31 December 2019 Volume 2019:12 Pages 11667—11677

DOI https://doi.org/10.2147/OTT.S231125

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Sanjay Singh


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 China

Correspondence: Peng Huang
Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha 410008, People’s Republic of China
Tel +86 15273124136
Email xiangyahp@csu.edu.cn
Ju-fang Huang
Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, No. 172 Tongzipo Road, Changsha 410013, Hunan, People’s Republic of China
Tel +86 15873108338
Email huangjufang@csu.edu.cn

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.

Keywords: osteosarcoma, Mcl-1, chemotherapy resistance, miR-375, cisplatin

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