Xiao Jie, Yu Weifeng, Hu Kongzu, Li Maoqiang, Chen Jianwei, Li Zhanchun
Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China.
Department of Orthopaedic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.
Oncol Rep. 2017 Apr;37(4):2513-2521. doi: 10.3892/or.2017.5484. Epub 2017 Mar 2.
MicroRNAs (miRNAs) play critical roles in human cancers including osteosarcoma (OS). miR-92a has been found to be a cancer-related miRNA in many cancer types and it is upregulated in OS cell lines. However, the expression and biological function of miR-92a in OS have not been investigated. In this study, we showed that miR-92a expression was increased in OS tissues, and its high expression was correlated with clinical stage, T classification and histological differentiation. Furthermore, patients with high expression of miR-92a had a significantly poorer survival rate. Functionally, miR-92a overexpression promoted the proliferation and cell cycle progression, and inhibited apoptosis in MG-63 cells. While inhibition of miR-92a showed contrary effects with reduced proliferation, cell cycle arrest at G1 phase and increased apoptosis in U2OS cells. Moreover, we confirmed that miR-92a inhibition reversed the tumor growth of OS cells in nude mice. Phosphatase and tensin homolog (PTEN), a well-known tumor suppressor, was confirmed to be the direct downstream target of miR-92a in OS. Notably, miR-92a consequently regulated the expression of the downstream targets of PTEN/AKT signaling pathway including p-Akt(Ser473), mTOR, p-p27(Thr157) and p-MDM2(Ser166). Furthermore, PTEN knockdown abrogated the functional effects of miR-92a silencing on the proliferation, apoptosis and cell cycle progression in OS cells. Thus, miR-92a that exerts an oncogenic role by targeting PTEN/AKT pathway in OS potentially acts as a biomarker and drug-target.
微小RNA（miRNA）在包括骨肉瘤（OS）在内的人类癌症中发挥着关键作用。miR-92a已被发现在多种癌症类型中是一种与癌症相关的miRNA，并且在OS细胞系中表达上调。然而，miR-92a在OS中的表达和生物学功能尚未得到研究。在本研究中，我们发现miR-92a在OS组织中的表达增加，其高表达与临床分期、T分级和组织学分化相关。此外，miR-92a高表达的患者生存率明显较差。在功能上，miR-92a过表达促进了MG-63细胞的增殖和细胞周期进程，并抑制了其凋亡。而抑制miR-92a则产生相反的效果，U2OS细胞的增殖减少、细胞周期停滞在G1期且凋亡增加。此外，我们证实抑制miR-92a可逆转OS细胞在裸鼠中的肿瘤生长。磷酸酶和张力蛋白同源物（PTEN）是一种著名的肿瘤抑制因子，在OS中被证实是miR-92a的直接下游靶点。值得注意的是，miR-92a进而调节了PTEN/AKT信号通路下游靶点的表达，包括p-Akt（Ser473）、mTOR、p-p27（Thr157）和p-MDM2（Ser166）。此外，PTEN基因敲低消除了miR-92a沉默对OS细胞增殖、凋亡和细胞周期进程的功能影响。因此，miR-92a通过靶向OS中的PTEN/AKT途径发挥致癌作用，可能作为一种生物标志物和药物靶点。
