MicroRNA-199a-5p promotes tumour growth by dual-targeting PIAS3 and p27 in human osteosarcoma.
MicroRNA-199a-5p promotes tumour growth by dual-targeting PIAS3 and p27 in human osteosarcoma.
复制标题
MicroRNA-199a-5p 通过双靶向 PIAS3 和 p27 促进人骨肉瘤中的肿瘤生长。
DOI：
10.1038/srep41456
复制
发表时间：
2017-01-25
影响因子：
4.6
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Wang C;Ba X;Guo Y;Sun D;Jiang H;Li W;Huang Z;Zhou G;Wu S;Zhang J;Chen J
骨肉瘤（OS）是最常见的原发性骨恶性肿瘤，仍然是青少年癌症相关死亡的主要原因。有证据表明microRNAs（miRNAs）与OS的临床和生物学特征相关，但miR-199 a-5 p在OS发生发展中的作用尚不清楚。在这项研究中，我们研究了miR-199 a-5 p在体外和体内的功能。结果显示，miR-199 a-5 p在OS患者组织和细胞中显著上调。miR-199 a-5 p的抑制导致细胞增殖和肿瘤生长的显著降低。我们进一步证明miR-199 a-5 p可以直接与PIAS 3和p27 mRNA的3′ UTR结合，并介导PIAS 3和p27蛋白水平的降低，从而刺激OS细胞中STAT 3的活化和细胞周期的进展。PIAS 3和p27的拯救实验进一步揭示了PIAS 3和p27是miR-199 a-5 p的功能靶点。此外，在OS异种移植模型中使用miR-199 a-5 p靶向抑制剂增强PIAS 3和p27的表达被证明是OS临床治疗的有前景的方法。我们的研究结果表明，miR-199 a-5 p靶向PIAS 3和p27的途径是一种可能的机制，有助于OS中的肿瘤生长。
Osteosarcoma (OS) is the most common primary bone malignancy and remains a leading cause of cancer-related deaths in adolescents. Emerging evidence indicates that microRNAs (miRNAs) are correlated with clinical and biological characteristics of OS. However, the involvement of miR-199a-5p in OS development remains unclear. In this study, we examined the function of miR-199a-5p in vitro and in vivo. The results showed that miR-199a-5p was significantly up-regulated in OS patient tissues and cells. The inhibition of miR-199a-5p led to a significant decrease in cell proliferation and tumour growth. We further demonstrated that miR-199a-5p could directly bind to the 3′UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3 and p27, thereby stimulating STAT3 activation and cell cycle progression in OS cells. Rescue experiments of PIAS3 and p27 further revealed that PIAS3 and p27 were functional targets of miR-199a-5p. Moreover, enhancing the expressions of both PIAS3 and p27 using miR-199a-5p-targeted inhibitors in an OS xenograft model was shown to be a promising approach for OS clinical therapy. Our findings indicate that the pathway of miR-199a-5p targeting both PIAS3 and p27 is a possible mechanism that contributes to tumour growth in OS.