MiR-20a-5p represses multi-drug resistance in osteosarcoma by targeting the KIF26B gene.

Youguang Pu,Wenjing Cai,Shanbao Cai,Fangfang Zhao,Haiyan Wang,Qiyi Yi

doi:10.1186/s12935-016-0340-3

Abstract

BackgroundChemoresistance hinders curative cancer chemotherapy in osteosarcoma (OS), resulting in only an approximately 20 % survival rate in patients with metastatic disease at diagnosis. Identifying the mechanisms responsible for regulating chemotherapy resistance is crucial for improving OS treatment.MethodsThis study was performed in two human OS cell lines (the multi-chemosensitive OS cell line G-292 and the multi-chemoresistant OS cell line SJSA-1). The levels of miR-20a-5p and KIF26B mRNA expression were determined by quantitative real-time PCR. KIF26B protein levels were determined by western blot analysis. Cell viability was assessed by MTT assay. Apoptosis was evaluated by flow cytometry.ResultsWe found that miR-20a-5p was more highly expressed in G-292 cells than in SJSA-1 cells. Forced expression of miR-20a-5p counteracted OS cell chemoresistance in both cell culture and tumor xenografts in nude mice. One of miR-20a-5p’s targets, kinesin family member 26B (KIF26B), was found to mediate the miR-20a-5p-induced reduction in OS chemoresistance by modulating the activities of the MAPK/ERK and cAMP/PKA signaling pathways.ConclusionsIn addition to providing mechanistic insights, our study revealed that miR-20a-5p and KIF26B contribute to OS chemoresistance and determined the roles of these genes in this process, which may be critical for characterizing drug responsiveness and overcoming chemoresistance in OS patients.

Highlights

Chemoresistance hinders curative cancer chemotherapy in osteosarcoma (OS), resulting in only an approximately 20 % survival rate in patients with metastatic disease at diagnosis
We report that miR-20a-5p was downregulated in a multi-drug-resistant (MDR) human OS cell line (SJSA-1) and describe the mechanism of OS chemoresistance mediated by miR-20a-5p
Expression of the DNA methylation‐regulated miR‐20a gene positively correlates with the multi‐chemoresistance of OS cells The doses at which 50 % of cells were killed by the drugs Dox, Etop, MTX, CDDP and Carb following individual 72 h treatments were determined in the following seven OS cell lines: G-292, SJSA-1, MG63.2, MG63, Saos.2, U2OS, and MNNG/HOS

Summary

Introduction

Chemoresistance hinders curative cancer chemotherapy in osteosarcoma (OS), resulting in only an approximately 20 % survival rate in patients with metastatic disease at diagnosis. Identifying the mechanisms responsible for regulating chemotherapy resistance is crucial for improving OS treatment. Multi-drug chemotherapy regimens that were pioneered in the 1970s and early 80s have dramatically improved the survival rate, and the necessity. The regulation of post-transcriptional and translational events has been well documented to play a key role in tumor chemoresistance [7,8,9,10,11,12]. MicroRNAs (miRNAs or miRs) can regulate translation and play pivotal roles in modulating various biological processes, including multi-drug resistance in cancer cells. Over 30 % of human protein-encoding genes are predicted to be post-transcriptionally regulated by miRs [13,14,15]. Given the major roles of miRNAs in regulating protein expression in general, understanding how miRNAs contribute to OS chemoresistance is necessary

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