Epstein-Barr virus-encoded microRNA-BART17-5p suppresses cell proliferation and metastasis by targeting CERK
- 1Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- 2Department of paediatrics, the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- 3Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
Abstract
Epstein-Barr virus (EBV) is an oncogenic DNA virus that is etiologically associated with multiple malignancies, including nasopharyngeal carcinoma, gastric carcinoma, and lymphomas. Although EBV encodes numerous viral microRNAs (miRNAs), the pathogenic functions of individual miRNAs remain incompletely characterized. In this study, we identify EBV-encoded miR-BART17-5p as a tumor-suppressive miRNA that directly targets ceramide kinase (CERK). CERK expression is significantly downregulated in EBV-associated gastric cancer (EBVaGC) tissues and EBV-positive AGS-EBV cells and inversely correlates with miR-BART17-5p levels. Mechanistic analyses further demonstrate that miR-BART17-5p directly targets the 3′ untranslated region (3′UTR) of CERK, thereby regulating its expression. Overexpression of miR-BART17-5p mimics or knockdown of CERK in AGS cells significantly suppresses tumor -associated phenotypes, including cell proliferation, migration, and invasion. Conversely, inhibition of miR-BART17-5p in AGS-EBV cells rescues these phenotypes. Similar results were obtained in SNU719 cells. Mechanistically, miR-BART17-5p inhibits the PI3K/AKT signaling by targeting CERK. Restoration of CERK expression reactivates PI3K/AKT signaling and reverses the inhibitory effects on cell proliferation, migration, and invasion in AGS cells. To evaluate the therapeutic potential of miR-BART17-5p, systemic administration of engineered cholesterol-conjugated miR-BART17-5p agomirs significantly suppresses tumor growth in xenograft models. Collectively, our findings reveal a previously unrecognized EBV-host interaction whereby miR-BART17-5p constrains cancer progression through modulation of CERK/PI3K/AKT signaling activation, highlighting its potential as a preclinical therapeutic strategy for cancer. Author summary: Epstein-Barr virus (EBV) is a common virus that infects most people worldwide and is linked to several types of cancer, including cancers of the stomach, nose, and blood system. Although this virus produces many small regulatory molecules, microRNAs, the roles of many of these molecules in cancer development remain unclear. In this study, we investigated the function of one viral microRNA, known as miR-BART17-5p, and its impact on cancer progression. We found that miR-BART17-5p acts as a natural brake on cancer growth by reducing the activity of a host protein, ceramide kinase (CERK), which normally promotes signals that support cell growth and spread. When levels of miR-BART17-5p were increased, cells grew more slowly and were less able to move and invade surrounding tissues. In contrast, blocking this microRNA restored aggressive cancer behaviors. We also showed that restoring miR-BART17-5p in animal models using a chemically modified mimic significantly reduced tumor growth. Our findings reveal an unexpected way in which a virus can restrain cancer development by regulating host cell signaling. This work improves our understanding of virus-host interactions and suggests that viral microRNAs may be developed as candidate molecules for future therapeutic development in cancers associated with EBV.
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BibTeX
@article{wu2026epsteinbarr,
title = {{Epstein-Barr virus-encoded microRNA-BART17-5p suppresses cell proliferation and metastasis by targeting CERK}},
author = {Peilin Wu and Xiazhen Xu and Qiong Wu and Lu Zhang and Fan Xin and Xiaowei Zheng and Xu Lin and Wannan Chen},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014519},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014519},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epstein-Barr virus-encoded microRNA-BART17-5p suppresses cell proliferation and metastasis by targeting CERK
AU - Peilin Wu
AU - Xiazhen Xu
AU - Qiong Wu
AU - Lu Zhang
AU - Fan Xin
AU - Xiaowei Zheng
AU - Xu Lin
AU - Wannan Chen
PY - 2026
DA - 2026/09/15
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014519
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014519
AB - Epstein-Barr virus (EBV) is an oncogenic DNA virus that is etiologically associated with multiple malignancies, including nasopharyngeal carcinoma, gastric carcinoma, and lymphomas. Although EBV encodes numerous viral microRNAs (miRNAs), the pathogenic functions of individual miRNAs remain incompletely characterized. In this study, we identify EBV-encoded miR-BART17-5p as a tumor-suppressive miRNA that directly targets ceramide kinase (CERK). CERK expression is significantly downregulated in EBV-associated gastric cancer (EBVaGC) tissues and EBV-positive AGS-EBV cells and inversely correlates with miR-BART17-5p levels. Mechanistic analyses further demonstrate that miR-BART17-5p directly targets the 3′ untranslated region (3′UTR) of CERK, thereby regulating its expression. Overexpression of miR-BART17-5p mimics or knockdown of CERK in AGS cells significantly suppresses tumor -associated phenotypes, including cell proliferation, migration, and invasion. Conversely, inhibition of miR-BART17-5p in AGS-EBV cells rescues these phenotypes. Similar results were obtained in SNU719 cells. Mechanistically, miR-BART17-5p inhibits the PI3K/AKT signaling by targeting CERK. Restoration of CERK expression reactivates PI3K/AKT signaling and reverses the inhibitory effects on cell proliferation, migration, and invasion in AGS cells. To evaluate the therapeutic potential of miR-BART17-5p, systemic administration of engineered cholesterol-conjugated miR-BART17-5p agomirs significantly suppresses tumor growth in xenograft models. Collectively, our findings reveal a previously unrecognized EBV-host interaction whereby miR-BART17-5p constrains cancer progression through modulation of CERK/PI3K/AKT signaling activation, highlighting its potential as a preclinical therapeutic strategy for cancer. Author summary: Epstein-Barr virus (EBV) is a common virus that infects most people worldwide and is linked to several types of cancer, including cancers of the stomach, nose, and blood system. Although this virus produces many small regulatory molecules, microRNAs, the roles of many of these molecules in cancer development remain unclear. In this study, we investigated the function of one viral microRNA, known as miR-BART17-5p, and its impact on cancer progression. We found that miR-BART17-5p acts as a natural brake on cancer growth by reducing the activity of a host protein, ceramide kinase (CERK), which normally promotes signals that support cell growth and spread. When levels of miR-BART17-5p were increased, cells grew more slowly and were less able to move and invade surrounding tissues. In contrast, blocking this microRNA restored aggressive cancer behaviors. We also showed that restoring miR-BART17-5p in animal models using a chemically modified mimic significantly reduced tumor growth. Our findings reveal an unexpected way in which a virus can restrain cancer development by regulating host cell signaling. This work improves our understanding of virus-host interactions and suggests that viral microRNAs may be developed as candidate molecules for future therapeutic development in cancers associated with EBV.
SN - 1553-7374
ER -