miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma
miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma
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DOI：
10.1093/carcin/bgt184
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发表时间：
2013-10-01
期刊：
影响因子：
4.7
通讯作者：
Yousef, G. M.
中科院分区：
文献类型：
--
作者：
Khella, H. W. Z.;Bakhet, M.;Yousef, G. M.
microRNA（miRNAs）在肿瘤的进展和转移中起着至关重要的作用。我们和其他研究人员最近发现，与原发性肾细胞癌相比，转移性肾细胞癌中的一些miRNAs表达异常。在这里，我们研究了三种在转移性肿瘤中显著下调的miRNA：miR-192，miR-194和miR-215。功能获得分析表明，在肾细胞癌细胞系模型中，它们的表达的恢复降低了细胞迁移和侵袭，而这些miRNA的敲低导致细胞迁移和侵袭能力的增强。我们确定了这些miRNA在肿瘤侵袭性中具有潜在作用的三个靶点：小鼠双微体2、胸苷酸合成酶和Smad相互作用蛋白1/锌指E-box结合同源框2。我们观察到这些miRNA的收敛效应（同一分子可以被所有三种miRNA靶向）和发散效应（同一miRNA可以控制多个靶点）。我们使用三种独立的方法实验验证了这些miRNAtarget相互作用。首先，我们观察到miRNA过表达显著降低了其靶基因的mRNA和蛋白水平。在第二个实验中，我们观察到在miRNA过表达后，含有靶的3 'UTR的载体的荧光素酶信号显著降低。最后，我们显示了患者标本中miRNA变化与其靶点表达水平之间存在负相关性。我们还研究了miR-215在肾细胞癌中的预后意义。miR-215的低表达与无病生存时间显著缩短相关。这些发现在癌症基因组图谱的独立数据集上得到了验证。这些结果可以为miRNAs作为预后标志物和治疗靶点的临床应用铺平道路。
MicroRNAs (miRNAs) play a crucial role in tumor progression and metastasis. We, and others, recently identified a number of miRNAs that are dysregulated in metastatic renal cell carcinoma compared with primary renal cell carcinoma. Here, we investigated three miRNAs that are significantly downregulated in metastatic tumors: miR-192, miR-194 and miR-215. Gain-of-function analyses showed that restoration of their expression decreases cell migration and invasion in renal cell carcinoma cell line models, whereas knockdown of these miRNAs resulted in enhancing cellular migration and invasion abilities. We identified three targets of these miRNAs with potential role in tumor aggressiveness: murine double minute 2, thymidylate synthase, and Smad Interacting protein 1/zinc finger E-box binding homeobox 2. We observed a convergent effect (the same molecule can be targeted by all three miRNAs) and a divergent effect (the same miRNA can control multiple targets) for these miRNAs. We experimentally validated these miRNAtarget interactions using three independent approaches. First, we observed that miRNA overexpression significantly reduces the mRNA and protein levels of their targets. In the second, we observed significant reduction of the luciferase signal of a vector containing the 3'UTR of the target upon miRNA overexpression. Finally, we show the presence of inverse correlation between miRNA changes and the expression levels of their targets in patient specimens. We also examined the prognostic significance of miR-215 in renal cell carcinoma. Lower expression of miR-215 is associated with significantly reduced disease-free survival time. These findings were validated on an independent data set from The Cancer Genome Atlas. These results can pave the way to the clinical use of miRNAs as prognostic markers and therapeutic targets.