EB病毒编码的microRNA-BART17-5p通过靶向CERK抑制细胞增殖和转移

文献信息

中文摘要

EB病毒（EBV）是一种致癌DNA病毒，在病因学上与多种恶性肿瘤相关，包括鼻咽癌、胃癌和淋巴瘤。尽管EBV编码大量病毒microRNA（miRNA），但单个miRNA的致病功能仍未被完全阐明。在本研究中，我们鉴定出EBV编码的miR-BART17-5p是一种肿瘤抑制性miRNA，直接靶向神经酰胺激酶（CERK）。在EBV相关胃癌（EBVaGC）组织和EBV阳性AGS-EBV细胞中，CERK表达显著下调，并与miR-BART17-5p水平呈负相关。机制分析进一步表明，miR-BART17-5p直接靶向CERK的3'非翻译区（3'UTR），从而调控其表达。在AGS细胞中过表达miR-BART17-5p模拟物或敲低CERK可显著抑制肿瘤相关表型，包括细胞增殖、迁移和侵袭。相反，在AGS-EBV细胞中抑制miR-BART17-5p可恢复这些表型。在SNU719细胞中也获得了类似结果。机制上，miR-BART17-5p通过靶向CERK抑制PI3K/AKT信号通路。恢复CERK表达可重新激活PI3K/AKT信号通路，并逆转对AGS细胞增殖、迁移和侵袭的抑制作用。为评估miR-BART17-5p的治疗潜力，全身给予工程化胆固醇偶联的miR-BART17-5p agomir可显著抑制异种移植模型中的肿瘤生长。总之，我们的发现揭示了一种此前未被认识的EBV-宿主相互作用，即miR-BART17-5p通过调节CERK/PI3K/AKT信号通路的激活来限制癌症进展，突显其作为癌症临床前治疗策略的潜力。

英文摘要

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.