2. Academic Validation
  3. SFK Inhibition Suppresses EBV-Encoded BART miRNAs and Induces Apoptosis in EBV-Positive Gastric Epithelial Cells

SFK Inhibition Suppresses EBV-Encoded BART miRNAs and Induces Apoptosis in EBV-Positive Gastric Epithelial Cells

  • Cancers (Basel). 2026 Mar 26;18(7):1082. doi: 10.3390/cancers18071082.
Yuxin Liu 1 2,  Zolzaya Tumurgan 1 3,  Aung Phyo Wai 1,  Moushumi Akter 1,  Afifah Fatimah Azzahra Ahmad Wadi 1,  Yoichi Mizukami 4,  Masami Wada 1,  Shunpei Okada 1,  Daisuke Niino 5,  Takayuki Murata 6,  Hisashi Iizasa 1,  Hironori Yoshiyama 1
Affiliations

Affiliations

  • 1 Department of Microbiology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo 693-8504, Shimane, Japan.
  • 2 Department of Microbiology and Molecular Genetics, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
  • 3 PuREC Co., Ltd., 89-1 Enya-cho, Izumo City 693-0021, Shimane, Japan .
  • 4 Center for Gene Research, Yamaguchi University, Ube 755-8505, Yamaguchi, Japan.
  • 5 Department of Pathology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo 693-8504, Shimane, Japan.
  • 6 Department of Virology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Aichi, Japan.
PMID: 41976305 DOI: 10.3390/cancers18071082
Abstract

Background/Objectives: Epstein-Barr virus (EBV) is associated with a subset of gastric carcinomas characterized by latency programs that promote survival of infected cells. EBV-encoded BamH I A rightward transcript (BART) MicroRNAs contribute to Apoptosis resistance in infected epithelial cells. This study investigated whether dasatinib, a Src family kinase (SFK) inhibitor, selectively targets EBV-positive gastric epithelial cells and examined the molecular mechanisms underlying this effect. Methods: EBV-positive and EBV-negative gastric epithelial cell models were analyzed to evaluate cell viability, Apoptosis induction, signaling pathways, and viral gene regulation. BART miRNA expression was quantified by RT-qPCR, and promoter activity was examined using luciferase reporter assays. Downstream target gene expression was analyzed at both the transcript and protein levels. Recombinant EBV lacking BZLF1 or LMP2A was used to assess the contributions of lytic activation and LMP2A-associated signaling. Results: Dasatinib preferentially reduced viability and induced Apoptosis in EBV-positive gastric epithelial cells compared with EBV-negative counterparts. Treatment suppressed phosphorylation of Src and ERK and reduced expression of the anti-apoptotic proteins Bcl-xL and MCL1. Apoptosis was also observed in cells infected with LMP2A-deficient EBV, suggesting that the effect cannot be fully explained by inhibition of LMP2A-associated signaling. Dasatinib inhibited BART miRNA promoter activity and reduced pri-, pre-, and mature miR-BART levels, accompanied by increased expression of pro-apoptotic target genes including CASZ1a, OCT1, ARID2, TP53INP1, and DAB2. In parallel, dasatinib suppressed BZLF1 promoter activity without evidence of lytic reactivation. Conclusions: Dasatinib promotes Apoptosis in EBV-positive gastric epithelial cells in association with coordinated suppression of SFK signaling and EBV-encoded BART miRNA expression, accompanied by derepression of pro-apoptotic cellular genes. These findings reveal a previously underappreciated vulnerability of EBV-positive epithelial cells and suggest that targeting host kinase signaling pathways that regulate viral MicroRNAs may represent a potential therapeutic strategy for EBV-associated malignancies.

Keywords

BamH I A rightward transcripts; Dasatinib; Epstein–Barr virus; Src family kinase; apoptosis; gastric cancer; microRNA.

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