Tian Rui, Xie Xianbiao, Han Ju, Luo Canqiao, Yong Bicheng, Peng Huizhi, Shen Jingnan, Peng Tingsheng
Department of Pathology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
Department of Musculoskeletal Oncology, First Affiliated Hospital of Sun Yat-sen University Guangzhou, P. R. China.
Am J Cancer Res. 2014 Nov 19;4(6):738-50. eCollection 2014.
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.
微小RNA的失调已被证明与多种肿瘤发生过程有关，并且与肿瘤进展和预后相关。miR-199a在许多不同肿瘤类型中已被证明存在失调；然而，miR-199a与骨肉瘤临床病理特征之间的关联尚不清楚，miR-199a的靶基因及其调控机制也不清楚。在本研究中，我们证明miR-199a-3p在骨肉瘤细胞中低表达，这可能抑制这些肿瘤细胞的迁移和侵袭。miR-199a-3p表达下调与骨肉瘤患者的复发和肺转移显著相关。使用多变量Cox回归分析，miR-199a-3p低表达被证明是骨肉瘤预后较差的独立预测因子。此外，我们表明miR-199a-3p模拟物可降低受体酪氨酸激酶AXL的mRNA和蛋白表达，并且miR-199a-3p直接靶向AXL mRNA的3'-UTR，提示miR-199a-3p可能通过下调AXL基因表达来抑制骨肉瘤进展。在患者的骨肉瘤样本中，我们还发现miR-199a-3p水平与AXL之间存在统计学上显著的负相关关系，这与骨肉瘤细胞系中的结果一致。有趣的是，miR-199a-3p模拟物降低了AKT的磷酸化水平。结合先前的数据，我们得出结论，miR-199a-3p通过下调AXL mRNA和蛋白表达对骨肉瘤进展起负向作用。通过这种机制，骨肉瘤细胞中可能存在由miR-199a-3p和AXL组成的调控通路，其可能通过AKT通路调节骨肉瘤的进展。
