Wu Qiong, Ye Guiying, Xu Xiazhen, Zeng Xianchang, Wu Biyun, Xin Fan, Zhang Lu, Lin Xu, Lin Xinjian, Chen Wannan
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, 1 Xue Fu North Road, Fuzhou 350122, China.
Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xue Fu North Road, Fuzhou 350122, China.
Microorganisms. 2025 Jun 28;13(7):1514. doi: 10.3390/microorganisms13071514.
Epstein-Barr virus (EBV) is the first oncogenic DNA virus known to encode microRNAs (miRNAs) and has been implicated in the pathogenesis of multiple malignancies, including a distinct subset of gastric cancers (EBV-associated gastric cancer, EBVaGC). However, the functional roles of individual EBV-encoded miRNAs in EBVaGC remain poorly defined. In this study, we integrate bioinformatic and experimental analyses to uncover a novel oncogenic axis driven by EBV-encoded miR-BART20-3p. Analysis of public transcriptomic datasets revealed that peroxisome proliferator-activated receptor α (PPARα) is significantly downregulated in EBVaGC compared with EBV-negative gastric tumors. We confirmed that both PPARα mRNA and protein are reduced in EBVaGC cell lines and primary tumor specimens, and that this reduction inversely correlates with miR-BART20-3p levels. A dual-luciferase reporter assay demonstrated that miR-BART20-3p directly binds the PPARα 3'-UTR. Functionally, miR-BART20-3p overexpression in AGS cells enhanced proliferation and migration, whereas inhibition of miR-BART20-3p in EBV-infected AGS cells attenuated these phenotypes. Mechanistic studies employing PPARα-specific siRNA together with qRT-PCR and ELISA reveal that suppression of PPARα or overexpression of miR-BART20-3p leads to upregulation of interleukin 6 (IL-6), indicating disruption of the PPARα-IL-6 regulatory axis. Collectively, EBV-encoded miR-BART20-3p promotes EBVaGC progression by directly targeting PPARα, and thereby derepressing IL-6 expression. This miRNA-PPARα-IL-6 pathway may serve as both a mechanistic biomarker and a novel therapeutic target in EBVaGC.
爱泼斯坦-巴尔病毒（EBV）是已知的第一种编码微小RNA（miRNA）的致癌DNA病毒，并且与多种恶性肿瘤的发病机制有关，包括一种独特的胃癌亚型（EBV相关胃癌，EBVaGC）。然而，单个EBV编码的miRNA在EBVaGC中的功能作用仍不清楚。在本研究中，我们整合了生物信息学和实验分析，以揭示由EBV编码的miR-BART20-3p驱动的新型致癌轴。对公共转录组数据集的分析显示，与EBV阴性胃肿瘤相比，过氧化物酶体增殖物激活受体α（PPARα）在EBVaGC中显著下调。我们证实，PPARα mRNA和蛋白在EBVaGC细胞系和原发性肿瘤标本中均减少，并且这种减少与miR-BART20-3p水平呈负相关。双荧光素酶报告基因检测表明，miR-BART20-3p直接结合PPARα 3'-UTR。在功能上，AGS细胞中miR-BART20-3p的过表达增强了增殖和迁移，而在EBV感染的AGS细胞中抑制miR-BART20-3p则减弱了这些表型。使用PPARα特异性siRNA以及qRT-PCR和ELISA的机制研究表明，抑制PPARα或过表达miR-BART20-3p会导致白细胞介素6（IL-6）上调，表明PPARα-IL-6调节轴被破坏。总体而言，EBV编码的miR-BART20-3p通过直接靶向PPARα促进EBVaGC进展，从而解除对IL-6表达的抑制。这种miRNA-PPARα-IL-6途径可能作为EBVaGC的机制性生物标志物和新型治疗靶点。
