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  • Epstein–Barr Virus-Encoded MicroRNAs in Gastric Cancer: Linking Viral Epigenetic Regulation to Tumor Progression and Clinical Outcome

  • Mohammad Shayestehpour,1,*
    1. Department of Bacteriology and Virology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.


  • Introduction: Epstein–Barr virus (EBV) is an oncogenic herpesvirus implicated in a distinct molecular subtype of gastric cancer known as EBV-associated gastric cancer (EBVaGC). Unlike many oncogenic viruses, EBV can persist in tumor cells with limited expression of viral proteins while maintaining a substantial regulatory output through non-coding RNAs, particularly viral microRNAs (miRNAs). Among these, miRNAs encoded within the BamHI-A rightward transcript (BART) region are abundantly expressed in EBVaGC and may modify host-cell signaling, apoptosis, immune responses, and metastatic behavior. Increasing evidence suggests that these small regulatory molecules are not merely by-products of viral latency but may actively participate in the biological processes underlying gastric tumor development. This evidence-based synthesis aimed to characterize the contribution of EBV-encoded miRNAs to gastric carcinogenesis and evaluate their potential relevance as biomarkers of tumor behavior and clinical outcome.
  • Methods: Peer-reviewed studies indexed in PubMed and published in established biomedical journals were evaluated, with emphasis on investigations examining EBV-encoded miRNAs in primary gastric cancer tissues, EBV-positive gastric cancer cell models, and clinical specimens. Evidence concerning miRNA expression, molecular targets, cancer-related signaling pathways, tumor invasion or metastasis, and survival outcomes was synthesized. Particular attention was given to BART-family miRNAs for which both molecular and clinical evidence was available. Findings from experimental studies were integrated with published clinical and prognostic data to develop a cancer-focused interpretation of the role of EBV miRNAs in EBVaGC.
  • Results: The available evidence indicates that EBV-encoded BART miRNAs constitute an active regulatory component of EBVaGC. Early molecular studies demonstrated expression of BART miRNAs in EBV-positive gastric carcinoma tissues, supporting their involvement in gastric tumor biology. More comprehensive profiling subsequently identified multiple abundant viral miRNAs, with BART4, BART11, BART2, BART6, BART9, and BART18 among the prominent species detected in EBVaGC. BART9 has been implicated in epithelial–mesenchymal transition (EMT), while experimental depletion of BART9 was associated with increased E-cadherin expression and reduced proliferative and invasive characteristics of EBV-positive gastric cancer cells. Other BART miRNAs appear to influence apoptosis and tumor-cell survival. For example, BART4-5p has been experimentally linked to suppression of the pro-apoptotic protein BID. Furthermore, BART10-3p and BART22 have been associated with lymph-node metastasis and poorer 5-year overall survival and were shown to enhance migration and invasion through modulation of APC/DKK1 and activation of canonical Wnt signaling. BART2-5p and BART11-5p have additionally been reported to promote gastric cancer cell proliferation and migration while reducing apoptosis through regulation of RB and p21. At the clinical level, elevated EBV-miRNA expression has also been associated with unfavorable survival outcomes across EBV-associated epithelial malignancies; a published meta-analysis of 11 eligible studies, including four in the quantitative analysis, reported a pooled hazard ratio of 3.168 (95% CI, 2.020–4.969) for increased EBV-miRNA expression.
  • Conclusion: Current evidence supports a biologically meaningful role for EBV-encoded miRNAs in EBV-associated gastric cancer. Rather than functioning solely as markers of viral persistence, selected BART miRNAs appear capable of reshaping cellular pathways involved in apoptosis, proliferation, EMT, invasion, and metastatic progression. Their detectability in tumor tissues and association with clinical outcomes further highlight their potential translational value as molecular biomarkers. However, the heterogeneity of EBV-miRNA expression among tumors and the predominantly retrospective or experimental nature of available studies limit immediate clinical implementation. Prospective investigations integrating viral miRNA profiles with tumor genomics, immune characteristics, and treatment response may clarify whether EBV miRNAs can serve as reliable biomarkers for risk stratification and whether specific viral miRNA–host interactions represent actionable therapeutic vulnerabilities in gastric cancer.
  • Keywords: Epstein–Barr virus; EBV-associated gastric cancer; Viral microRNA; BART miRNAs; Gastric carcinogenes

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