EBV-Derived miR-BART20-3p Influences Proliferation and Migration in EBV-Positive Gastric Cancer Models by Suppressing PPARα

Epstein&ndash:Barr virus (EBV) is the first oncogenic DNA virus known to encode microRNAs (miRNAs) and has been implicated in the pathogenesis of multiple malignancies, including a distinct subset of gastric cancers (EBV-associated gastric cancer, EBVaGC). However, the functional roles of individual EBV-encoded miRNAs in EBVaGC remain poorly defined. In this study, we integrate bioinformatic and experimental analyses to uncover a novel oncogenic axis driven by EBV-encoded miR-BART20-3p. Analysis of public transcriptomic datasets revealed that peroxisome proliferator-activated receptor &alpha: (PPAR&alpha:) is significantly downregulated in EBVaGC compared with EBV-negative gastric tumors. We confirmed that both PPAR&alpha: mRNA and protein are reduced in EBVaGC cell lines and primary tumor specimens, and that this reduction inversely correlates with miR-BART20-3p levels. A dual-luciferase reporter assay demonstrated that miR-BART20-3p directly binds the PPAR&alpha: 3&prime:-UTR. Functionally, miR-BART20-3p overexpression in AGS cells enhanced proliferation and migration, whereas inhibition of miR-BART20-3p in EBV-infected AGS cells attenuated these phenotypes. Mechanistic studies employing PPAR&alpha:-specific siRNA together with qRT-PCR and ELISA reveal that suppression of PPAR&alpha: or overexpression of miR-BART20-3p leads to upregulation of interleukin 6 (IL-6), indicating disruption of the PPAR&alpha:&ndash:IL-6 regulatory axis. Collectively, EBV-encoded miR-BART20-3p promotes EBVaGC progression by directly targeting PPAR&alpha:, and thereby derepressing IL-6 expression. This miRNA&ndash:PPAR&alpha:&ndash:IL-6 pathway may serve as both a mechanistic biomarker and a novel therapeutic target in EBVaGC.