Int J Biol Sci 2017; 13(5):561-573. doi:10.7150/ijbs.19032

Research Paper

DNA Methylation Mediated Down-Regulation of miR-370 Regulates Cell Growth through Activation of the Wnt/β-Catenin Signaling Pathway in Human Osteosarcoma Cells

Wentao Zhang1, 2*, Ning Duan2*, Qian Zhang3, Tao Song2, Zhong Li2, Caiguo Zhang4✉, Xun Chen2✉, Kunzheng Wang1✉

1. Department of Orthopedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710005, Shaanxi, China;
2. Department of Orthopaedics, Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine Xi'an 710054, Shaanxi, China;
3. The second department of surgery room, Shaanxi Provincial Tumor Hospital, Xi'an 710061, Shaanxi, China;
4. Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora 80045, CO, USA.
* These authors contribute equally to this work.

Abstract

MicroRNA-370 (miR-370) has been observed to act as a tumor suppressor through the targeting of different proteins in a variety of tumors. Our previous study indicated that miR-370 was able to target forkhead box protein M1 (FOXM1) to inhibit cell growth and metastasis in human osteosarcoma cells. In this study, we reported that FOXM1 interacted with β-catenin in vitro and in vivo. Similar to FOXM1, critical components of the Wnt signaling pathway, including β-catenin, c-Myc, and Cyclin D1, were also highly expressed in different human osteosarcoma cells lines. Pharmacological inhibition of FOXM1 or β-catenin but not of c-Myc was associated with the increased expression of miR-370. Ectopic expression of miR-370 inhibited the downstream signaling of β-catenin. Moreover, osteosarcoma cells treated with 5-AZA-2'-deoxycytidine (AZA), a DNA methylation inhibitor, exhibited increased levels of miR-370 and decreased levels of β-catenin downstream targets, which resulted in inhibition of cell proliferation and colony formation ability. In conclusion, our results supported a model in which the DNA methylation-mediated down-regulation of miR-370 reduced its inhibitory effect on FOXM1, thereby promoting FOXM1-β-catenin interaction and activating the Wnt/β-Catenin signaling pathway in human osteosarcoma cells.

Keywords: miR-370, methylation, FOXM1, Wnt/β-Catenin, c-Myc and Cyclin D1.

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How to cite this article:
Zhang W, Duan N, Zhang Q, Song T, Li Z, Zhang C, Chen X, Wang K. DNA Methylation Mediated Down-Regulation of miR-370 Regulates Cell Growth through Activation of the Wnt/β-Catenin Signaling Pathway in Human Osteosarcoma Cells. Int J Biol Sci 2017; 13(5):561-573. doi:10.7150/ijbs.19032. Available from http://www.ijbs.com/v13p0561.htm