Wu Liang, Zhang Yiming, Huang Zhongyue, Gu Huijie, Zhou Kaifeng, Yin Xiaofan, Xu Jun
Minhang Hosptial, Fudan University, Shanghai, China.
Front Pharmacol. 2019 Feb 21;10:137. doi: 10.3389/fphar.2019.00137. eCollection 2019.
Osteosarcoma (OS) is the most common bone cancer worldwide. There is evidence that microRNA-409 (miR-409-3p) is involved in tumorigenesis and cancer progression, however, its possible role in OS requires clarification. In the present study, we evaluated the expression level, clinical significance, and mode of action of miR-409-3p in OS. The miR-409-3p levels were diminished in the OS cells and tissues compared with associated adjacent non-tumor tissues and a non-cancer osteoplastic cell line. Low miR-409-3p expression levels were associated with clinical stage and distant metastasis in patients with OS. Resumption of miR-409-3p expression attenuated OS cell proliferation and invasion. Additionally, based on informatics analyses, we predicted that zinc-finger E-box-binding homeobox-1 (ZEB1) is a possible target of miR-409-3p. This hypothesis was confirmed using luciferase reporter assays, reverse transcription-quantitative real-time polymerase chain reaction, and Western blot analyses. The findings of the current study indicated that ZEB1 was up-regulated in the OS tissues and cell lines, and that this up-regulation was inversely proportional to miR-409-3p expression levels. Furthermore, down-regulation of ZEB1 decreased OS cell invasion and proliferation, illustrating that the tumor suppressive role of miR-409-3p in OS cells may be exerted negative regulation of ZEB1. Taken together, our observations highlight the potential role of miR-409-3p as a tumor suppressor in OS partially through down-regulation of ZEB1 and suggest that miR-409-3p has potential applications in OS treatment.
骨肉瘤（OS）是全球最常见的骨癌。有证据表明，微小RNA-409（miR-409-3p）参与肿瘤发生和癌症进展，然而，其在骨肉瘤中可能发挥的作用尚需阐明。在本研究中，我们评估了miR-409-3p在骨肉瘤中的表达水平、临床意义及作用方式。与相关的邻近非肿瘤组织和非癌性成骨细胞系相比，骨肉瘤细胞和组织中的miR-409-3p水平降低。miR-409-3p低表达水平与骨肉瘤患者的临床分期和远处转移相关。恢复miR-409-3p表达可减弱骨肉瘤细胞的增殖和侵袭。此外，基于信息学分析，我们预测锌指E盒结合同源框-1（ZEB1）是miR-409-3p的一个可能靶点。使用荧光素酶报告基因检测、逆转录-定量实时聚合酶链反应和蛋白质免疫印迹分析证实了这一假设。本研究结果表明，ZEB1在骨肉瘤组织和细胞系中上调，且这种上调与miR-409-3p表达水平呈负相关。此外，ZEB1的下调降低了骨肉瘤细胞的侵袭和增殖，说明miR-409-3p在骨肉瘤细胞中的肿瘤抑制作用可能是通过对ZEB1的负调控来实现的。综上所述，我们的观察结果突出了miR-409-3p作为骨肉瘤肿瘤抑制因子的潜在作用，其部分是通过下调ZEB1实现的，并表明miR-409-3p在骨肉瘤治疗中具有潜在应用价值。
