Induction of the mesenchymal to epithelial transition by demethylation-activated microRNA-125b is involved in the anti-migration/invasion effects of arsenic trioxide on human chondrosarcoma.

Xing Bao,Shidong Wang,Kuisheng Liu,Tingting Ren,Wei Guo,Yi Huang,Fan Zhang,Bingxin Zheng

doi:10.1186/s13046-016-0407-y

Abstract

BackgroundIn addition to treating acute promyelocytic leukemia, arsenic trioxide (ATO) suppresses other solid tumors, including chondrosarcoma. However, the effects of ATO on metastasis in chondrosarcoma cells, and the underlying molecular mechanisms remain unclear.MethodsThe effects of ATO on the migratory and invasive capacities of chondrosarcoma cells were investigated by Wound healing, Transwell and EMT assays. The expression of miR-125b in human chondrosarcoma tissues and cell lines was detected by real-time PCR analysis. Bisulfite sequencing analysis (BSP) was used to detect the effects of ATO on the expression of miR-125b. The gain-of-function and loss-of-function experiments were performed on chondrosarcoma cell lines to investigate the effects of miR-125b on chondrosarcoma invasion, and to determine whether signal transducer and activator of transcription 3(Stat3) mediates these effects. Dual-luciferase reporter assay was used to identify whether Stat3 is a direct target of miR-125b.ResultsMiR-125b was significantly downregulated in human metastatic chondrosarcoma tissues and cell lines but not in non-metastatic chondrosarcoma tissues. ATO up-regulates the expression of miR-125b by the demethylation of DNA. ATO induces MET and attenuates the invasive capacities of chondrosarcoma cells through miR-125b. Stat3 was verified as a direct target of miR-125b, which is involved in ATO regulating EMT-associated traits.ConclusionsThese findings, for the first time, provides evidence that the miR-125b-mediated inhibition of Stat3 is involved in the ATO-induced attenuation of metastasis in chondrosarcoma cells.

Highlights

In addition to treating acute promyelocytic leukemia, arsenic trioxide (ATO) suppresses other solid tumors, including chondrosarcoma
We demonstrated that miR-125b inhibited the epithelialmesenchymal transition (EMT) process in chondrosarcoma cells by targeting signal transducer and activator of transcription 3 (Stat3); constitutive activation of Stat3 is a key player in tumor angiogenesis and metastasis
The results showed that there is no significant difference between the adjacent normal tissues and the nonmetastatic chondrosarcoma tissues in the expression level of miR-125b

Summary

Introduction

In addition to treating acute promyelocytic leukemia, arsenic trioxide (ATO) suppresses other solid tumors, including chondrosarcoma. The effects of ATO on metastasis in chondrosarcoma cells, and the underlying molecular mechanisms remain unclear. Current practices for the treatment of chondrosarcoma include wide-margin surgical resection and chemotherapy and are less than satisfactory because of high recurrence rates and metastasis [1,2,3]. The mechanisms underlying metastasis and recurrence remain obscure. A continued search for molecular markers that predict metastasis and the recurrence of chondrosarcoma is essential. Emerging evidence suggests that the epithelialmesenchymal transition (EMT) contributes to tumor metastasis and recurrence in chondrosarcoma and other tumors [4, 5]. Several lines of evidence have demonstrated the significance of the EMT in chondrosarcoma progression, the molecular mechanisms that regulate EMT remain unclear

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