MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14)
MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14)
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MicroRNA-451 通过靶向 ras 相关蛋白 14 (RAB14) 作为人类非小细胞肺癌的肿瘤抑制因子
DOI：
10.1038/onc.2010.642
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发表时间：
2011-06-01
期刊：
影响因子：
8
通讯作者：
Chen, L-B
中科院分区：
文献类型：
--
作者：
Wang, R.;Wang, Z-X;Chen, L-B
越来越多的证据表明，microRNAs （miRNAs）是重要的基因调控因子，在包括肿瘤发生在内的多种生物过程中发挥着关键作用。在这项研究中，我们利用miRNA微阵列平台分析了非小细胞肺癌（NSCLC）中miRNA的表达谱，并鉴定了40个差异表达的miRNA。我们发现miRNA (miR)-451在NSCLC组织中下调最多。发现miR-451的表达水平与肿瘤分化、病理分期及淋巴结转移有显著相关性。此外，低miR-451表达水平也与NSCLC患者的总生存期缩短相关（P< 0.001）。异位miR-451表达通过增强细胞凋亡，显著抑制裸鼠NSCLC细胞的体外增殖、集落形成及肿瘤的发生，这可能与Akt信号通路失活有关。有趣的是，异位miR-451表达可以显著抑制RAB14蛋白表达，降低含有RAB14 3 ' -未翻译区（UTR）的荧光素酶报告蛋白活性。此外，RNA干扰沉默RAB14基因可以重现miR-451的抑瘤功能，而恢复RAB14表达可以部分减弱miR-451在NSCLC细胞中的抑瘤功能。此外，我们还发现RAB14蛋白的强阳性免疫反应性与miR-451的下调显著相关（P= 0.01）。这些发现表明，miR-451部分通过下调RAB14来调节NSCLC细胞的存活。因此，靶向miR-451/RAB14相互作用可能成为治疗NSCLC患者的一种新的治疗应用。
Accumulating evidence suggests that microRNAs (miRNAs) are important gene regulators, which can have critical roles in diverse biological processes including tumorigenesis. In this study, we analyzed the miRNA expression profiles in non-small cell lung carcinoma (NSCLC) by use of a miRNA microarray platform and identified 40 differentially expressed miRNAs. We showed that miRNA (miR)-451 was the most downregulated in NSCLC tissues. The expression level of miR-451 was found to be significantly correlated with tumor differentiation, pathological stage and lymph-node metastasis. Moreover, low miR-451 expression level was also correlated with shorter overall survival of NSCLC patients (P< 0.001). Ectopic miR-451 expression significantly suppressed the in vitro proliferation and colony formation of NSCLC cells and the development of tumors in nude mice by enhancing apoptosis, which might be associated with inactivation of Akt signaling pathway. Interestingly, ectopic miR-451 expression could significantly inhibit RAB14 protein expression and decrease a luciferase-reporter activity containing the RAB14 3′-untranslated region (UTR). In addition,, RNA interference silencing of RAB14 gene could recapitulate the tumor suppressor function of miR-451, whereas restoration of RAB14 expression could partially attenuate the tumor suppressor function of miR-451 in NSCLC cells. Furthermore, we also showed that strong positive immunoreactivity of RAB14 protein was significantly associated with downregulation of miR-451 (P= 0.01). These findings suggest that miR-451 regulates survival of NSCLC cells partially through the downregulation of RAB14. Therefore, targeting with the miR-451/RAB14 interaction might serve as a novel therapeutic application to treat NSCLC patients.