EBV microRNA BART2-5p promotes metastasis in nasopharyngeal carcinoma via suppressing RND3

Abstract

 Nasopharyngeal carcinoma(NPC) is a EBV related malignancy which is highly prevalent in South China. Distant metastasis is the major cause of treatment failure. Here, an EBV encoded microRNA BART2-5p was found to be highly abundant in patients’ serum and the copy number of which was positively correlated with metastasis. Multivariate analysis suggested high level of BART2-5p was an independent unfavorable prognostic factor for progression free survival. Further investigation showed ectopic expression of BART2-5p could promote EBV(-) NPC cells migration and invasion in vitro, whereas knock down of BART2-5p in EBV(+) NPC cells showed undermined capability of migration and invasion. For in vivo study, NPC cells with ectopic expression of BART2-5p developed more metastatic nodules in the lung in tail vein injection model and extensive metastasis in multiple organs in spleen injection model. Mechanistically, RND3, a negative regulator of Rho signaling, was predicted as the target of BART2-5p by bioinformatic analysis and validated by luciferase reporter and RIP assay. Knock down of RND3 could phenocopy the effect of BART2-5p and reconstitution of RND3 in BART2-5p expressing cells rescued the phenotype. By suppressing RND3, BART2-5p activated Rho signaling, which resulted in myosin light chain phosphorylation and actin reorganization. Overall, these findings suggested a novel role of EBV-BART2-5p in promoting NPC metastasis and its potential value as a prognostic indicator or therapeutic target.