Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling.
Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling.
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DOI：
10.1038/onc.2016.414
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发表时间：
2017-05-04
期刊：
影响因子：
8
通讯作者：
Jiang BH
中科院分区：
文献类型：
--
作者：
Shi ZM;Wang L;Shen H;Jiang CF;Ge X;Li DM;Wen YY;Sun HR;Pan MH;Li W;Shu YQ;Liu LZ;Peiper SC;He J;Jiang BH
上皮间质转化（EMT）已被认为是肺癌细胞迁移和侵袭的关键因素，但其潜在机制尚未完全阐明。最近，新的证据表明，miRNA在控制EMT和EMT相关性状如迁移、侵袭和化疗抗性中起着至关重要的作用。在此，我们发现肺癌组织中miR-218的表达水平与癌旁组织相比显著下调，并且miR-218的表达水平与组织学分级和淋巴结转移显著相关。miR-218的过表达抑制了细胞的迁移和侵袭以及EMT过程。特别重要的是，miR-218通过抑制局部侵袭和远处定殖参与肺癌细胞的体内转移过程。我们将Slug和ZEB2确定为miR-218的直接功能靶点。在癌组织样品中观察到miR-218水平和Slug/ZEB2水平之间的负相关。此外，miR-218在H1299中的过表达通过抑制Slug和ZEB 2增加了细胞对顺铂治疗的化学敏感性。这些发现强调了miR-218在调节EMT相关性状和肺癌转移中的重要作用，部分通过调节Slug/ZEB2信号传导，并通过靶向miR-218在NSCLC中提供了潜在的治疗策略。
Epithelial–mesenchymal transition (EMT) has been recognized as a key element of cell migration and invasion in lung cancer; however, the underlying mechanisms are not fully elucidated. Recently, emerging evidence suggest that miRNAs have crucial roles in control of EMT and EMT-associated traits such as migration, invasion and chemoresistance. Here, we found that miR-218 expression levels were significantly downregulated in lung cancer tissues compared with adjacent non-cancerous tissues, and the levels of miR-218 were significantly associated with histological grades and lymph node metastasis. Overexpression of miR-218 inhibited cell migration and invasion as well as the EMT process. Of particular importance, miR-218 was involved in the metastatic process of lung cancer cells in vivo by suppressing local invasion and distant colonization. We identified Slug and ZEB2 as direct functional targets of miR-218. Inverse correlations were observed between miR-218 levels and Slug/ZEB2 levels in cancer tissue samples. In addition, overexpression of miR-218 in H1299 increased chemosensitivity of cells to cisplatin treatment through suppression of Slug and ZEB2. These findings highlight an important role of miR-218 in the regulation of EMT-related traits and metastasis of lung cancer in part by modulation of Slug/ZEB2 signaling, and provide a potential therapeutic strategy by targeting miR-218 in NSCLC.