EBV编码的miR-BART19-3p靶向ZFAND5驱动鼻咽癌恶性表型

文献信息

中文摘要

鼻咽癌（NPC）是一种与Epstein-Barr病毒（EBV）相关的上皮性恶性肿瘤，具有独特的地理分布以及高度局部侵袭和远处转移倾向。EBV编码的microRNA已成为NPC中宿主基因表达的重要病毒调控因子；然而，EBV-miR-BART19-3p的生物学功能仍不完全清楚。本研究分析了公共转录组和microRNA数据集，以识别NPC中失调的分子，并预测ZFAND5为EBV-miR-BART19-3p的潜在靶点。EBV-miR-BART19-3p在NPC组织和EBV阳性C666-1细胞中显著上调，而ZFAND5在mRNA和蛋白水平均下调。Kaplan-Meier分析进一步显示，在公共NPC队列中，较高的ZFAND5表达与更好的无病生存相关。双荧光素酶报告基因实验证实，EBV-miR-BART19-3p直接结合ZFAND5的3'-非翻译区。在功能上，EBV-miR-BART19-3p过表达增强了C666-1细胞增殖、集落形成、迁移和侵袭，同时抑制凋亡。相反，抑制EBV-miR-BART19-3p或过表达ZFAND5可抑制这些恶性表型并促进凋亡。重要的是，敲低ZFAND5部分逆转了抑制EBV-miR-BART19-3p所诱导的肿瘤抑制作用。生物信息学富集分析表明，NPC中的差异表达基因与免疫调节、趋化因子信号、细胞黏附、PI3K-Akt、Wnt和NF-kappaB信号相关。这些发现提示，EBV-miR-BART19-3p至少部分通过抑制ZFAND5促进EBV阳性NPC细胞的恶性表型，为EBV编码的microRNA与NPC进展之间提供了潜在的机制联系。

英文摘要

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy with distinct geographic distribution and a high propensity for local invasion and distant metastasis. EBV-encoded microRNAs have emerged as important viral regulators of host gene expression in NPC; however, the biological function of EBV-miR-BART19-3p remains incompletely understood. In this study, public transcriptomic and microRNA datasets were analyzed to identify dysregulated molecules in NPC, and ZFAND5 was predicted as a potential target of EBV-miR-BART19-3p. EBV-miR-BART19-3p was significantly upregulated in NPC tissues and EBV-positive C666-1 cells, whereas ZFAND5 was downregulated at both the mRNA and protein levels. Kaplan-Meier analysis further showed that higher ZFAND5 expression was associated with better disease-free survival in a public NPC cohort. Dual-luciferase reporter assays confirmed that EBV-miR-BART19-3p directly binds to the 3'-untranslated region of ZFAND5. Functionally, EBV-miR-BART19-3p overexpression enhanced C666-1 cell proliferation, colony formation, migration and invasion while suppressing apoptosis. Conversely, EBV-miR-BART19-3p inhibition or ZFAND5 overexpression suppressed these malignant phenotypes and promoted apoptosis. Importantly, ZFAND5 knockdown partially reversed the tumor-suppressive effects induced by EBV-miR-BART19-3p inhibition. Bioinformatic enrichment analysis indicated that differentially expressed genes in NPC were associated with immune regulation, chemokine signaling, cell adhesion, PI3K-Akt, Wnt and NF-kappaB signaling. These findings suggest that EBV-miR-BART19-3p promotes malignant phenotypes in EBV-positive NPC cells, at least in part, by repressing ZFAND5, providing a potential mechanistic link between EBV-encoded microRNAs and NPC progression.