Epigenetic Activation of ANGPTL4 Drives EBV‐Negative Gastric Cancer via Neutrophil Recruitment and NET Release via Stabilizing ANXA5
- 1Department of Stomatology Hubei Provincial Clinical Research Center For Umbilical Cord Blood Hematopoietic Stem Cells Taihe Hospital Hubei University of Medicine Shiyan Hubei China
- 2Hubei Key Laboratory of Embryonic Stem Cell Research School of Basic Medical Sciences Hubei University of Medicine Shiyan Hubei China
- 3Shiyan Key Laboratory of Comprehensive Prevention and Treatment of Oral Cancer Academy of Bio‐Medicine Research Hubei University of Medicine Shiyan China
Abstract
EBV‐positive (EBVaGC) and EBV‐negative (EBVnGC) gastric cancers exhibit distinct clinical outcomes, prognostic features, and immune infiltration landscapes; however, the molecular mechanisms driving these subtype differences, as well as the subtype‐specific epigenetic regulation and biological functions of ANGPTL4 within the immune microenvironment, remain unclear. Here, through integrated analysis of multi‐omics data, we discovered that EBV infection induces marked hypermethylation at the ANGPTL4 promoter, leading to transcriptional silencing of ANGPTL4 in EBVaGC. Conversely, hypomethylation‐mediated ANGPTL4 overexpression is clinically associated with poor prognosis and distant metastasis in EBVnGC. Mechanistically, the C‐terminal secreted form (cANGPTL4) promotes GC progression by enhancing proliferation, epithelial‐mesenchymal transition (EMT), and neutrophil recruitment. Clinically, ANGPTL4 expression is positively correlated with neutrophil infiltration and neutrophil extracellular traps (NETs) levels in GC. Spatial transcriptomics and immunohistochemistry (IHC) analyses confirmed the spatial colocalization of ANGPTL4 with tumor‐infiltrating neutrophils. cANGPTL4 mediates tumor‐associated neutrophil (TAN) recruitment via the NF‐κB/CXCL8 axis and directly binds and stabilizes neutrophil‐derived ANXA5 to facilitate NET release, thereby driving GC progression. In conclusion, ANGPTL4 represents a potential intervention target for EBVnGC. Targeting ANGPTL4 may exert dual anti‐tumor effects by directly suppressing GC proliferation, EMT, and metastasis, and by remodeling the immunosuppressive microenvironment via attenuating TANs infiltration and NET release.
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BibTeX
@article{li2026epigenetic,
title = {{Epigenetic Activation of ANGPTL4 Drives EBV‐Negative Gastric Cancer via Neutrophil Recruitment and NET Release via Stabilizing ANXA5}},
author = {Dandan Li and Xinqi Li and Xiangyin Luo and Jiayi Wang and Yiwei Zha and Zeng Zhou and Yanyan Chen and Qi Wang and Lingyun Xia and Weidong Leng and Shanshan Qin},
journal = {Advanced Science},
year = {2026},
month = nov,
doi = {10.1002/advs.78595},
url = {https://doi.org/10.1002/advs.78595},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epigenetic Activation of ANGPTL4 Drives EBV‐Negative Gastric Cancer via Neutrophil Recruitment and NET Release via Stabilizing ANXA5
AU - Dandan Li
AU - Xinqi Li
AU - Xiangyin Luo
AU - Jiayi Wang
AU - Yiwei Zha
AU - Zeng Zhou
AU - Yanyan Chen
AU - Qi Wang
AU - Lingyun Xia
AU - Weidong Leng
AU - Shanshan Qin
PY - 2026
DA - 2026/11/05
JO - Advanced Science
DO - 10.1002/advs.78595
UR - https://doi.org/10.1002/advs.78595
AB - EBV‐positive (EBVaGC) and EBV‐negative (EBVnGC) gastric cancers exhibit distinct clinical outcomes, prognostic features, and immune infiltration landscapes; however, the molecular mechanisms driving these subtype differences, as well as the subtype‐specific epigenetic regulation and biological functions of ANGPTL4 within the immune microenvironment, remain unclear. Here, through integrated analysis of multi‐omics data, we discovered that EBV infection induces marked hypermethylation at the ANGPTL4 promoter, leading to transcriptional silencing of ANGPTL4 in EBVaGC. Conversely, hypomethylation‐mediated ANGPTL4 overexpression is clinically associated with poor prognosis and distant metastasis in EBVnGC. Mechanistically, the C‐terminal secreted form (cANGPTL4) promotes GC progression by enhancing proliferation, epithelial‐mesenchymal transition (EMT), and neutrophil recruitment. Clinically, ANGPTL4 expression is positively correlated with neutrophil infiltration and neutrophil extracellular traps (NETs) levels in GC. Spatial transcriptomics and immunohistochemistry (IHC) analyses confirmed the spatial colocalization of ANGPTL4 with tumor‐infiltrating neutrophils. cANGPTL4 mediates tumor‐associated neutrophil (TAN) recruitment via the NF‐κB/CXCL8 axis and directly binds and stabilizes neutrophil‐derived ANXA5 to facilitate NET release, thereby driving GC progression. In conclusion, ANGPTL4 represents a potential intervention target for EBVnGC. Targeting ANGPTL4 may exert dual anti‐tumor effects by directly suppressing GC proliferation, EMT, and metastasis, and by remodeling the immunosuppressive microenvironment via attenuating TANs infiltration and NET release.
SN - 2198-3844
ER -