DataSheet_1_EBV-Induced CXCL8 Upregulation Promotes Vasculogenic Mimicry in Gastric Carcinoma via NF-κB Signaling.docx

Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC via NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.

EB病毒（Epstein–Barr virus, EBV）相关胃癌（Epstein–Barr virus-associated gastric carcinoma, EBVaGC）是一类独特的肿瘤亚型，与EB病毒阴性胃癌相比，其肿瘤微环境特征更为显著。然而，EBV在胃癌发生发展中的确切作用仍未明确。本研究发现，EBV可上调趋化因子配体8（CXCL8）的表达，且CXCL8可显著促进胃癌（gastric carcinoma, GC）细胞的血管生成拟态（vasculogenic mimicry, VM）形成。与此研究结果一致的是，CXCL8过表达可增强AGS及BGC823细胞的增殖与迁移能力，而通过小干扰RNA（siRNA）敲低CXCL8则可抑制AGS-EBV细胞的增殖与迁移。此外，CXCL8诱导的血管生成拟态形成依赖于核因子κB（NF-κB）信号通路的激活，该过程可被NF-κB抑制剂BAY 11-7082与BMS345541阻断。进一步研究显示，EB病毒编码的长链非编码RNA（lncRNA）RPMS1可激活NF-κB信号级联反应，这正是EBV诱导血管生成拟态形成的核心分子机制。EBVaGC的异种移植瘤及临床样本均存在组织学层面的血管生成拟态，且该现象与CXCL8过表达呈正相关。最后，CXCL8的表达水平与胃癌患者的总生存期呈正相关。综上，EBV上调的CXCL8表达可通过激活NF-κB信号通路促进胃癌细胞的血管生成拟态形成，CXCL8或可成为EBVaGC的新型抗肿瘤治疗靶点。