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Int J Biol Sci 2017; 13(8):1038-1050. doi:10.7150/ijbs.19476

Research Paper

DNA Methylation Mediated Downregulation of miR-449c Controls Osteosarcoma Cell Cycle Progression by Directly Targeting Oncogene c-Myc

Qing Li1*, Hua Li1*, Xueling Zhao1, Bing Wang1, Lin Zhang1, Caiguo Zhang2✉, Fan Zhang1✉

1. Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China;
2. Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
* These authors contributed equally to this work.

Abstract

MicroRNAs (miRNAs) are critical regulators of gene expression, and they have broad roles in the pathogenesis of different diseases including cancer. Limited studies and expression profiles of miRNAs are available in human osteosarcoma cells. By applying a miRNA microarray analysis, we observed a number of miRNAs with abnormal expression in cancerous tissues from osteosarcoma patients. Of particular interest in this study was miR-449c, which was significantly downregulated in osteosarcoma cells and patients, and its expression was negatively correlated with tumor size and tumor MSTS stages. Ectopic expression of miR-449c significantly inhibited osteosarcoma cell proliferation and colony formation ability, and caused cell cycle arrest at the G1 phase. Further analysis identified that miR-449c was able to directly target the oncogene c-Myc and negatively regulated its expression. Overexpression of c-Myc partially reversed miR-449c-mimic-inhibited cell proliferation and colony formation. Moreover, DNA hypermethylation was observed in two CpG islands adjacent to the genomic locus of miR-449c in osteosarcoma cells. Conversely, treatment with the DNA methylation inhibitor AZA caused induction of miR-449c. In conclusion, our results support a model that DNA methylation mediates downregulation of miR-449c, diminishing miR-449c mediated inhibition of c-Myc and thus leading to the activation of downstream targets, eventually contributing to osteosarcoma tumorigenesis.

Keywords: microRNA, miR-449c, DNA methylation, cell cycle, osteosarcoma.

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How to cite this article:
Li Q, Li H, Zhao X, Wang B, Zhang L, Zhang C, Zhang F. DNA Methylation Mediated Downregulation of miR-449c Controls Osteosarcoma Cell Cycle Progression by Directly Targeting Oncogene c-Myc. Int J Biol Sci 2017; 13(8):1038-1050. doi:10.7150/ijbs.19476. Available from http://www.ijbs.com/v13p1038.htm