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06 December 2018 : Laboratory Research  

miR-29 Family Inhibits Resistance to Methotrexate and Promotes Cell Apoptosis by Targeting COL3A1 and MCL1 in Osteosarcoma

Wei Xu12BCDE, Zhikun Li2BDF, Xiaodong Zhu2CDF, Ruijun Xu2AE, Youjia Xu1AEG*

DOI: 10.12659/MSM.911972

Med Sci Monit 2018; 24: LBR8812-8821

Abstract

BACKGROUND: MicroRNAs (miRNAs) play a crucial role in regulating diverse biological processes, including drug resistance. We investigated the potential roles of the miR-29 family in methotrexate (MTX) resistance in osteosarcoma.

MATERIAL AND METHODS: Two MTX-resistant osteosarcoma cell lines, MG-63/MTX and U2OS/MTX, were generated by continuous exposure to stepwise increasing concentrations of MTX. miR-29abc, COL3A1, and MCL1 mRNA expression levels were determined using quantitative real-time PCR (qRT-PCR). Protein expression levels of COL3A1 and MCL1 were detected by Western blot. Cell viability, IC50 value, and cell apoptosis were assessed by CCK-8 assay and flow cytometry, respectively. The target relationship between the miR-29 family and COL3A1 or MCL1 was confirmed by luciferase reporter assay.

RESULTS: miR-29a, miR-29b, and miR-29c were significantly downregulated in MG-63/MTX and U2OS/MTX cells and in chemotherapy poor-response osteosarcoma tissues. Overexpression of the miR-29 family sensitized MG-63/MTX and U2OS/MTX cells to MTX and obviously promoted cell apoptosis compared with negative control. COL3A1 and MCL1 were identified to be target genes of the miR-29 family, and transfection with miR-29abc mimics in MG-63/MTX and U2OS/MTX cells decreased COL3A1 and MCL1 mRNA and protein expression. Meanwhile, overexpression of COL3A1 and MCL1 partly neutralized the effects of the miR-29 family on MTX resistance and cell apoptosis.

CONCLUSIONS: Taken together, our findings suggested a tumor-suppressor role of the miR-29 family in control of MTX resistance and cell apoptosis through regulating COL3A1 or MCL1. Targeting the miR-29 family might provide new strategies to overcome the high-dosage MTX-induced cytotoxicity in osteosarcoma treatment.

Keywords: Methotrexate

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750