Downregulation of miR-153 contributes to epithelial-mesenchymal transition and tumor metastasis in human epithelial cancer
Downregulation of miR-153 contributes to epithelial-mesenchymal transition and tumor metastasis in human epithelial cancer
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miR-153的下调有助于人上皮癌的上皮间质转化和肿瘤转移
DOI：
10.1093/carcin/bgs374
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发表时间：
2013-03-01
期刊：
影响因子：
4.7
通讯作者：
Zhang, Zhiyuan
中科院分区：
文献类型：
--
作者：
Xu, Qin;Sun, Qiang;Zhang, Zhiyuan
上皮间质转化（EMT）是上皮癌侵袭和转移的关键步骤。本研究的目的是调查和验证调节 EMT 的未识别的 micro RNA (miRNA)，并揭示它们在上皮癌患者中的临床相关性。通过在天然上皮-间质表型细胞系对和转化生长因子诱导的 EMT 细胞模型中应用 miRNA 阵列筛选，我们发现 miR-153 在经历 EMT 的细胞中显着下调。 miR-153 的抑制与 EMT 表型以及上皮癌细胞的侵袭能力之间存在密切关联。间充质样细胞中 miR-153 的异位表达导致上皮形态改变，细胞侵袭能力下降。相反，在上皮样细胞中转染 miR-153 抑制剂会导致间充质表型发生变化。 miR-153的体内异位表达显着抑制肿瘤细胞转移形成。双荧光素酶报告基因检测的数据首次表明 SNAI1 和 ZEB2 是 miR-153 的直接靶标。口腔癌患者样本中 miR-153 与 SNA1 和 ZEB2 水平之间也观察到负相关。此外，miR-153的低表达水平被发现与口腔癌患者的转移和不良预后显着相关。这些数据表明，miR-153 是一种通过靶向 SNAI1 和 ZEB2 的新型 EMT 调节因子，并表明其在减少癌症转移方面的潜在治疗价值。
The epithelial-mesenchymal transition (EMT) is a crucial step in epithelial cancer invasion and metastasis. The aims of this study were to investigate and validate unidentified micro RNAs (miRNAs) that regulate EMT and to reveal their clinical relevance in epithelial cancer patients. By applying miRNA array screening in a natural epithelial-mesenchymal phenotype cell line pair and in a transforming growth factor -induced EMT cell model, we found miR-153 was markedly downregulated in the cells that underwent an EMT. A close association was confirmed between inhibition of miR-153 and the EMT phenotype, as well as the invasive ability of epithelial cancer cells. Ectopic expression of miR-153 in mesenchymal-like cells resulted in an epithelial morphology change with decreased cellular invasive ability. On the contrary, transfection of a miR-153 inhibitor in epithelial-like cells led to a mesenchymal phenotype change. In vivo ectopic expression of miR-153 significantly inhibited tumor cell metastasis formation. Data from the dual-luciferase reporter gene assay showed, for the first time, that SNAI1 and ZEB2 were direct targets of miR-153. Inverse correlations were also observed between miR-153 and SNA1 and ZEB2 levels in oral cancer patients' samples. Furthermore, low expression level of miR-153 was found to be significantly related to metastasis and poor prognosis in oral cancer patients. These data demonstrate that miR-153 is a novel regulator of EMT by targeting SNAI1 and ZEB2 and indicate its potential therapeutic value for reducing cancer metastasis.