MicroRNA-761 targets FGFR1 to suppress the malignancy of osteosarcoma by deactivating PI3K/Akt pathway
Authors Lv Z, Ma J, Wang J, Lu J
Received 11 March 2019
Accepted for publication 15 August 2019
Published 15 October 2019 Volume 2019:12 Pages 8501—8513
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Geoffrey Pietersz
Zhongzhe Lv,1 Jinming Ma,2 Jianchuan Wang,1 Jianmin Lu1
1Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Liaoning 116001, People’s Republic of China; 2School of Graduate Studies, Zunyi Medical University, Guizhou 563000, People’s Republic of China
Correspondence: Jianmin Lu
Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Road, Zhongshan District, Liaoning 116001, People’s Republic of China
Tel +86 181 467 5683
Purpose: MicroRNA-761 (miR-761) has been reported to be deregulated in many types of human cancers and play important roles in cancer genesis and progression. However, the biological roles of miR-761 in osteosarcoma (OS) and the underlying mechanisms remain largely unknown.
Methods: The expression of miR-761 in OS tissues and cell lines was analyzed using RT-qPCR. A series of gain-of-function tests were performed, and status of malignancy was evaluated on basis of proliferation, migration, invasion, and apoptosis using different assays to determine the regulatory roles of miR-761 in OS cells in vivo and in vitro. Notably, the mechanisms underlying the action of miR-761 in the pathogenesis of OS were investigated using bioinformatic analysis, luciferase reporter assay, RT-qPCR and Western blotting.
Results: The results showed that miR-761 expression was decreased in OS tissues and cell lines and is closely correlated with clinical stage and distant metastasis in OS patients. Patients with OS having low miR-761 expression showed worse prognosis compared to OS patients with high miR-761 expression. Restoring the miR-761 expression level decreased OS cell proliferation, migration, and invasion in vitro; promoted cell apoptosis in vitro; and impaired tumor growth in vivo. In addition, fibroblast growth factor receptor 1 (FGFR1) was found as a direct target gene of miR-761 in OS cells. Furthermore, silencing FGFR1 expression stimulated the tumor-suppressing roles of miR-761 upregulation in OS cells, whereas the activity of miR-761 overexpression in OS cells was abolished by the restoration of FGFR1 expression. Moreover, restoration of miR-761 expression deactivated the PI3K/Akt pathway in vitro and in vivo.
Conclusion: These results suggest that miR-761 plays anti-cancer roles in OS by directly targeting FGFR1 and deactivating the PI3K/Akt pathway. The newly identified miR-761/FGFR1/PI3K/Akt pathway partially illustrates the mechanism of OS pathogenesis and presents a novel candidate therapeutic target for antitumor therapy.
Keywords: microRNA-761, osteosarcoma, fibroblast growth factor receptor 1, PI3K/Akt pathway, pathogenesis
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