EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN
EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN
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EBV-miR-BART7-3p通过抑制抑癌基因PTEN促进鼻咽癌细胞EMT和转移
DOI：
10.1038/onc.2014.341
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发表时间：
2015-04-23
期刊：
影响因子：
8
通讯作者：
Li, X.
中科院分区：
文献类型：
--
作者：
Cai, L-M;Lyu, X-M;Li, X.
上皮-间质转化（EMT）是肿瘤进展和转移的关键。尽管已经鉴定出多种细胞miRNA来调节癌症中的EMT和转移，但病毒miRNA在癌症进展中的作用仍然在很大程度上未知。鼻咽癌（Nasopharyngealcarcinoma，NPC）是一种与EB病毒（Epstein-Barr virus，EBV）相关的恶性肿瘤，其典型特征是早期转移。在本研究中，我们发现了一种病毒miRNA，EBV-miR-BART 7 - 3 p，参与NPC细胞的EMT和转移。我们初步观察到EBV-miR-BART 7 - 3 p在NPC中高表达，并与NPC的淋巴结转移和临床分期呈正相关。随后，我们证明了EBV-miR-BART 7 - 3 p在体外增强细胞迁移/侵袭，在体内增强癌症转移，特别是在NPC细胞中以上皮标记物的丧失和间充质特征的获得为特征的EMT。此外，机制研究揭示EBV-miR-BART 7 - 3 p靶向主要的人类肿瘤抑制因子PTEN，调节PI 3 K/Akt/GSK-3β信号传导并最终导致Snail和β-catenin的高表达和核积累，这有利于EMT。PTEN的敲除可以表型复制EBV-miR-BART 7 - 3 p的作用，而PTEN的重新表达导致表型逆转。此外，这些发现得到了EBV阳性细胞模型的观察结果的支持，其中内源性EBV-miR-BART 7 - 3 p的沉默通过逆转PI 3 K/Akt、Snail和β-连环蛋白表达部分减弱了细胞迁移/侵袭并改变了EMT蛋白表达模式。因此，本研究提示了EBV-miR-BART 7 - 3 p调节NPC细胞EMT和转移的新机制，以及EBV-miR-BART 7 - 3 p作为潜在生物标志物或治疗靶点的临床意义。
The epithelial-mesenchymal transition (EMT) is crucial to cancer progression and metastasis. Although multiple cellular miRNAs have been identified to regulate the EMT and metastasis in cancers, the role of viral miRNAs in cancer progression remains largely unknown. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy typically characterized by its early metastasis. In the present study, we have discovered the involvement of a viral miRNA, EBV-miR-BART7-3p, in the EMT and metastasis of NPC cells. Initially, we observed that EBV-miR-BART7-3p was highly expressed in NPC and positively correlated with lymph node metastasis and clinical stage of NPC. Subsequently, we demonstrated that EBV-miR-BART7-3p enhanced cell migration/invasion in vitro, cancer metastasis in vivo, and particularly the EMT characterized by loss of epithelial markers and gain of mesenchymal features in NPC cells. Furthermore, mechanistic studies disclosed that EBV-miR-BART7-3p targeted a major human tumor suppressor PTEN, modulating PI3K/Akt/GSK-3β signaling and eventually leading to the high expression and nuclear accumulation of Snail and β-catenin, which favor EMT. Knockdown of PTEN could phenocopy the effect of EBV-miR-BART7-3p, whereas re-expression of PTEN resulted in a phenotypic reversion. Moreover, these findings were supported by an observation of an EBV-positive cell model in which silencing of endogenous EBV-miR-BART7-3p partially attenuated cell migration/invasion and altered EMT protein expression pattern via reverting PI3K/Akt, Snail and β-catenin expression. Thus, this study suggests a novel mechanism by which EBV-miR-BART7-3p modulates the EMT and metastasis of NPC cells, and a clinical implication of EBV-miR-BART7-3p as a potential biomarker or therapeutic target.