Abstract
// Xin Xiao 1, * , Wei Wang 2, * , Xiaokang Li 1, * , Yuqian Li 3 , Di Yang 1 , Chao Shen 1 , Peng Gao 1 , Jie Wu 1 , Shuo Guo 1 and Zheng Guo 1 1 Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, P.R. China 2 Department of Immunology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P.R. China 3 Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China * These authors contributed equally to this work Correspondence to: Zheng Guo, email: guozheng@fmmu.edu.cn Keywords: osteosarcoma; metastasis; miR-495; HSP90AA1; PI3K/Akt/mTOR pathway Received: November 03, 2017 Accepted: January 03, 2018 Published: January 08, 2018 ABSTRACT MiR-495 is a tumor-suppressive microRNA that participates in tumor progression in human cancers. However, its expression and biological function in osteosarcoma remains unknown. In this study, we firstly found that miR-495 is markedly downregulated in both osteosarcoma tissues and cell lines. Then we demonstrated that miR-495 suppresses the invasion and metastasis of osteosarcoma cells in vitro through inhibiting epithelial to mesenchymal transition. Function of miR-495 in vivo was also examined in mice xenograft model and we found it significantly inhibiting the lung-metastasis of osteosarcoma cells. We also demonstrated that HSP90AA1 is a direct target of miR-495 using luciferase reporter assay and Western blot analysis. Furthermore, knockdown of HSP90AA1 can restore the increased cell invasion and migration in miR-495-knockdown cells and over expression of HSP90AA1 can neutralize the impaired metastatic ability of miR-495 mimic-treated cells. This metastasis-suppressive role of miR-495 in osteosarcoma is achieved by HSP90AA1-mediated PI3K/Akt/mTOR signaling pathway. Overall, our findings proved for the first time that miR-495 acts as a tumor suppressor in osteosarcoma and inhibits cell migration and invasion by targeting HSP90AA1, thus offering a promising therapeutic target for osteosarcoma treatment.
Highlights
Osteosarcoma is the most frequent primary malignancy bone tumor and occurs mainly in adolescents and young adults [1]
Function of miR-495 in vivo was examined in mice xenograft model and we found it significantly inhibiting the lung-metastasis of osteosarcoma cells
MiR-495 is downregulated in osteosarcoma tissues and cell lines
Summary
Osteosarcoma is the most frequent primary malignancy bone tumor and occurs mainly in adolescents and young adults [1]. Identification of the biological process and molecular mechanism involved in the metastasis of osteosarcoma is of significant value for improving the patients’ prognosis. Accumulating evidence has indicated that miRNAs participate in a broad range of biological processes, such as proliferation, apoptosis, invasion and metastasis of different kind of tumors [8]. MiR-495, as a tumor-suppressive miRNA in most cases, has been shown to be under-expressed and to repress various target genes to inhibit the malignant processes of several types of tumor [9, 10]. There are different views on the role of miR-495 in regulating tumor invasion and migration. In breast [14], bladder [15] and gastric [16] cancer cells, this miRNA promotes tumor invasion and migration. To explore how miR-495 participates in osteosarcoma progression, especially its effect on the invasion and migration of osteosarcoma cells, aiming at discovering novel targets for treatment becomes our goal of study
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