EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN
- 27 October 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 34 (17), 2156-2166
- https://doi.org/10.1038/onc.2014.341
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 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.Keywords
This publication has 64 references indexed in Scilit:
- miR-149 Inhibits Non-Small-Cell Lung Cancer Cells EMT by Targeting FOXM1Biochemistry Research International, 2013
- Functional Cooperation between Snail1 and Twist in the Regulation of ZEB1 Expression during Epithelial to Mesenchymal TransitionJournal of Biological Chemistry, 2011
- Epithelial-Mesenchymal Transitions in Development and DiseaseCell, 2009
- An Epstein-Barr virus–encoded microRNA targets PUMA to promote host cell survivalThe Journal of Experimental Medicine, 2008
- Viruses associated with human cancerBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2008
- Epstein-Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5Nucleic Acids Research, 2007
- Modulation of LMP1 protein expression by EBV-encoded microRNAsProceedings of the National Academy of Sciences of the United States of America, 2007
- Expression of Viral MicroRNAs in Epstein-Barr Virus-Associated Gastric CarcinomaJournal of Virology, 2007
- The global health burden of infection‐associated cancers in the year 2002International Journal of Cancer, 2006
- Epstein–Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathwayOncogene, 2004