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

TL;DR

This study shows that a virus-encoded microRNA, miR-BART20-3p, promotes the growth and spread of a specific type of stomach cancer by targeting a protein called PPARα and increasing IL-6 levels.

Contribution

The study identifies a new oncogenic pathway involving EBV-encoded miR-BART20-3p, PPARα, and IL-6 in EBV-associated gastric cancer.

Findings

miR-BART20-3p directly targets PPARα in EBV-positive gastric cancer cells.

Suppression of PPARα or overexpression of miR-BART20-3p increases IL-6 levels.

miR-BART20-3p promotes cancer cell proliferation and migration in EBV-positive models.

Abstract

Epstein–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 α (PPARα) is significantly downregulated in EBVaGC compared with EBV-negative gastric tumors. We confirmed that both PPARα 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 PPARα 3′-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 PPARα-specific siRNA together with qRT-PCR and ELISA reveal that suppression of PPARα or overexpression of miR-BART20-3p leads to upregulation of interleukin 6 (IL-6), indicating disruption of the PPARα–IL-6 regulatory axis. Collectively, EBV-encoded miR-BART20-3p promotes EBVaGC progression by directly targeting PPARα, and thereby derepressing IL-6 expression. This miRNA–PPARα–IL-6 pathway may serve as both a mechanistic biomarker and a novel therapeutic target in EBVaGC.

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