title: miR-199a-3p negatively regulates the progression of osteosarcoma through targeting AXL.
abstract: Dysregulation of micro-RNAs has been shown to contribute to multiple tumorigenic processes, as well as to correlate with tumor progression and prognosis. miR-199a has been shown to be dysregulated in many different tumor types; however, the association between miR-199a and the clinicopathological features of osteosarcoma is unknown, and the target gene for miR-199a and the regulatory mechanism are also unknown. In this study, we demonstrated that miR-199a-3p is expressed at low levels in osteosarcoma cells, which may inhibit the migration and invasion of these tumor cells. The downregulation of miR-199a-3p expression is significantly correlated with the recurrence and lung metastasis of patients with osteosarcoma. Using multivariate Cox regression analysis, low level of expression of miR-199a-3p was shown to be an independent predictor for worse prognosis in osteosarcoma. Furthermore, we showed that miR-199a-3p mimics can decrease the expression of the mRNA and protein of the receptor tyrosine kinase AXL, and miR-199a-3p targets directly the 3'-UTR of AXL mRNA, suggesting that miR-199a-3p may downregulate the expression of the AXL gene to inhibit the progression of osteosarcoma. In patients' osteosarcoma samples, we also showed a statistically significant inverse relation between the levels of miR-199a-3p and AXL, which is consistent with the results in osteosarcoma cell lines. Interestingly, miR-199a-3p mimics reduced the level of phosphorylation of AKT. Together with the previous data, we conclude that miR-199a-3p negatively contributes to the progression of osteosarcoma by downregulating the expression of AXL mRNA and protein. By this mechanism, a regulatory pathway comprised of miR-199a-3p and AXL may exist in osteosarcoma cells, which may as a result regulate the progression of osteosarcoma through the AKT pathway.
authors.affiliation: Department of Pathology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Tian
authors.affiliation: Department of Musculoskeletal Oncology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Xianbiao
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Pathology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Ju
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Pathology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Canqiao
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Musculoskeletal Oncology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Bicheng
authors.initials: B
authors.lastname: Yong
authors.affiliation: Department of Pathology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Musculoskeletal Oncology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pathology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
authors.forename: Tingsheng
authors.initials: T
authors.lastname: Peng
keywords: AXL; Osteosarcoma; invasion; miR-199a-3p; migration; prognosis