Epstein-Barr Virus miRNA BART2-5p Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing RND3.

Abstract

Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-related malignancy. Recently, we found that the EBV-encoded miRNA <i>BART2-5p</i> was increased in the serum of patients with preclinical nasopharyngeal carcinoma and that the copy number positively correlated with disease progression. In this study, we established its role in nasopharyngeal carcinoma progression and explored underlying mechanisms and clinical significance. <i>BART2-5p</i> was an independent unfavorable prognostic factor for progression-free survival and its circulating abundance positively associated with distant metastasis. Ectopic expression of <i>BART2-5p</i> promoted migration and invasion of EBV-negative nasopharyngeal carcinoma cells, whereas genetic downregulation of <i>BART2-5p</i> in EBV-positive nasopharyngeal carcinoma cells decreased aggressiveness. Mechanistically, <i>BART2-5p</i> targeted <i>RND3</i>, a negative regulator of Rho signaling. Downregulation of <i>RND3</i> phenocopied the effect of <i>BART2-5p</i> and reconstitution of <i>RND3</i> rescued the phenotype. By suppressing <i>RND3, BART2-5p</i> activated Rho signaling to enhance cell motility. These findings suggest a novel role for EBV miRNA <i>BART2-5p</i> in promoting nasopharyngeal carcinoma metastasis and its potential value as a prognostic indicator or therapeutic target. SIGNIFICANCE: This study shows that EBV-encoded BART2-5p miRNA suppresses expression of the RND3 Rho family GTPase, consequently promoting ROCK signaling, cell motility, and metastatic behavior of NPC cells.