EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN

L. M. Cai, X. M. Lyu, W. R. Luo, X. F. Cui, Y. F. Ye, C. C. Yuan, Q. X. Peng, D. H. Wu, T. F. Liu, E. Wang, F. M. Marincola, K. T. Yao, W. Y. Fang, H. B. Cai, X. Li

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Abstract

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 migrationinvasion 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 PI3KAktGSK-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 migrationinvasion and altered EMT protein expression pattern via reverting PI3KAkt, 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.

Original languageEnglish
Pages (from-to)2156-2166
Number of pages11
JournalOncogene
Volume34
Issue number17
DOIs
Publication statusPublished - 23 Apr 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Cai, L. M., Lyu, X. M., Luo, W. R., Cui, X. F., Ye, Y. F., Yuan, C. C., Peng, Q. X., Wu, D. H., Liu, T. F., Wang, E., Marincola, F. M., Yao, K. T., Fang, W. Y., Cai, H. B., & Li, X. (2015). EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN. Oncogene, 34(17), 2156-2166. https://doi.org/10.1038/onc.2014.341