miR-218 Suppresses Nasopharyngeal Cancer Progression through Downregulation of Survivin and the SLIT2-ROBO1 Pathway
miR-218 Suppresses Nasopharyngeal Cancer Progression through Downregulation of Survivin and the SLIT2-ROBO1 Pathway
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DOI：
10.1158/0008-5472.can-10-2754
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Liu, Fei-Fei
中科院分区：
文献类型：
--
作者：
Alajez, Nehad M.;Lenarduzzi, Michelle;Liu, Fei-Fei
鼻咽癌（NPC）是一种与EB病毒相关的恶性肿瘤，最常见于东亚和非洲。在这里，我们报告了microRNA miR-218在原发性NPC组织和细胞系中的频繁下调，它在NPC进展中起着关键作用。miR-218的抑制与SLIT 2和SLIT 3的表观遗传沉默相关，SLIT 2和SLIT 3是先前参与肿瘤血管生成的ROBO受体的配体。miR-218的外源性表达在体外对NPC细胞产生了显著的毒性，并在体内延迟了肿瘤的生长。我们使用了一种综合的三模态方法来鉴定miR-218在NPC、宫颈和乳腺细胞系中的靶点。miR-218与编码ROBO 1、生存素（BIRC 5）和连接蛋白43（GJA 1）的mRNA的3 '非翻译区（UTR）之间的直接相互作用在基于内切酶的转录报告基因测定中得到验证。机制研究揭示了负反馈环，其中miR-218通过SLIT-ROBO途径调节NPC细胞迁移。miR-218对NPC存活和迁移的多效性作用通过分别增强miR-218抗性的、工程化的生存素和ROBO 1亚型的表达而被拯救。在NPC的临床标本（n = 71）中，ROBO 1过表达与总体（P = 0.04，HR = 2.4）和淋巴结无复发生存率（P = 0.008，HR = 6.0）显著相关。我们的研究结果定义了NPC中miR-218的综合肿瘤抑制功能，并进一步表明恢复NPC中miR-218的表达可能对其临床治疗有用。Cancer Res; 71（6）; 2381-91.（C）2011年《非洲标准化评论》。
Nasopharayngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Here we report frequent downregulation of the microRNA miR-218 in primary NPC tissues and cell lines where it plays a critical role in NPC progression. Suppression of miR-218 was associated with epigenetic silencing of SLIT2 and SLIT3, ligands of ROBO receptors that have been previously implicated in tumor angiogenesis. Exogenous expression of miR-218 caused significant toxicity in NPC cells in vitro and delayed tumor growth in vivo. We used an integrated trimodality approach to identify targets of miR-218 in NPC, cervical, and breast cell lines. Direct interaction between miR-218 and the 3'-untranslated regions (UTR) of mRNAs encoding ROBO1, survivin (BIRC5), and connexin43 (GJA1) was validated in a luciferase-based transcription reporter assay. Mechanistic investigations revealed a negative feedback loop wherein miR-218 regulates NPC cell migration via the SLIT-ROBO pathway. Pleotropic effects of miR-218 on NPC survival and migration were rescued by enforced expression of miR-218-resistant, engineered isoforms of survivin and ROBO1, respectively. In clinical specimens of NPC (n = 71), ROBO1 overexpression was significantly associated with worse overall (P = 0.04, HR = 2.4) and nodal relapse-free survival (P = 0.008, HR = 6.0). Our findings define an integrative tumor suppressor function for miR-218 in NPC and further suggest that restoring miR-218 expression in NPC might be useful for its clinical management. Cancer Res; 71(6); 2381-91. (C)2011 AACR.