miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression
miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression
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miR-141通过控制EphA2表达是肾细胞癌增殖和转移的关键调节因子
DOI：
10.1158/1078-0432.ccr-13-3224
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发表时间：
2014-05-15
影响因子：
11.5
通讯作者：
Zhang, Xiaoping
中科院分区：
文献类型：
--
作者：
Chen, Xuanyu;Wang, Xuegang;Zhang, Xiaoping
目的：虽然microRNAs(MiRNA)已被发现是肿瘤发生的重要调节因子，但我们对其在肾细胞癌(RCC)中的作用了解有限。在这里，我们试图识别作为肾癌发生的关键调节因子的人类miRNAs。实验设计：我们对肾透明细胞癌(CcRCC)及其邻近正常组织进行了基于微阵列的miRNA图谱分析，然后探讨了在体外和体内miR-141的作用，miR-141是在ccRCC组织中下调最显著的。结果：与正常组织相比，CcRCC中共有74个miRNAs表达异常。MIR-141在92.6%(63/68)的肾细胞癌组织中表达明显下调，有望成为鉴别肾细胞癌与正常组织的生物标志物，其受试者工作特征曲线下面积为0.93。在体外和人肾细胞癌原位移植中，miR-141的过表达通过阻止细胞处于G0-G1期而强烈地损害了ccRCC细胞的迁移和侵袭特性，并抑制了细胞增殖。值得注意的是，miR-141的抗肿瘤活性是通过其对促红细胞生成素(EphA2)产生的肝细胞(EphA2)的逆转调节而介导的，EphA2继而传递一系列信号转导来减弱粘着斑激酶(FAK)、AKT和MMP2/9的功能。此外，在人肾癌标本中，miR-141与EphA2的表达存在特异性和负相关。最后，miR-141可以从ccRCC供体细胞分泌，并在ccRCC受体细胞中适度摄取和发挥功能。结论：MIR-141通过调控EphA2/p-FAK/p-AKT/MMPs信号通路，是区分肾细胞癌和正常组织的潜在生物标志物，也是肾细胞癌细胞增殖和转移的重要抑制因子。临床癌症资源；20(10)；2617-30。©2014 AACR。
Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0–G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells. Conclusion: miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade. Clin Cancer Res; 20(10); 2617–30. ©2014 AACR.