EV转运的miR-7111-3p通过靶向APP调控的上皮-间质转化抑制鼻咽癌恶性表型和肿瘤生长

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中文摘要

背景与目的： 细胞外囊泡（EV）介导的微小RNA转移已成为驱动肿瘤进展的关键机制，但其在鼻咽癌（NPC）中的功能相关性仍不明确。本研究旨在阐明EV相关miR-7111-3p在NPC进展中的功能作用和分子机制。
方法： 在NPC患者血清样本和NPC细胞系中检测miR-7111-3p表达。通过体外功能获得和功能缺失实验以及异种移植模型评估功能效应。使用双荧光素酶报告基因实验验证miR-7111-3p对淀粉样前体蛋白（APP）的直接靶向作用。通过EV分离、表征和共培养实验评估EV介导的转移。
结果： miR-7111-3p在NPC血清和细胞系中显著下调。其过表达显著抑制NPC细胞增殖、迁移、侵袭和上皮-间质转化（EMT），而敲低则产生相反效应。APP被鉴定为miR-7111-3p的直接靶点，APP过表达逆转了miR-7111-3p诱导的抑制作用。来自miR-7111-3p缺陷NPC细胞的EV促进受体NP69细胞中APP表达、增殖和迁移，而抑制EV分泌减弱了这些效应。在体内，miR-7111-3p过表达减少异种移植肿瘤生长并下调APP表达。
结论： 这些发现确定了一个新的EV-miR-7111-3p-APP信号轴，该轴调控NPC中的EMT、恶性表型和肿瘤生长，突显了其作为治疗靶点的潜力。

英文摘要

BACKGROUND AND PURPOSE: Extracellular vesicle (EV)-mediated transfer of microRNAs has emerged as a critical mechanism driving tumor progression, yet its functional relevance in nasopharyngeal carcinoma (NPC) remains poorly defined. This study sought to elucidate the functional role and molecular mechanism of EV-associated miR-7111-3p in NPC progression.
METHODS: miR-7111-3p expression was measured in serum samples from NPC patients and in NPC cell lines. Functional effects were evaluated through gain- and loss-of-function assays in vitro and in xenograft models. Direct targeting of amyloid precursor protein (APP) by miR-7111-3p was validated using dual-luciferase reporter assays. EV-mediated transfer was assessed by EV isolation, characterization, and co-culture experiments.
RESULTS: miR-7111-3p was significantly downregulated in NPC serum and cell lines. Its overexpression markedly suppressed NPC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas its knockdown exerted the opposite effects. APP was identified as a direct target of miR-7111-3p, and APP overexpression reversed the inhibitory effects induced by miR-7111-3p. EVs derived from miR-7111-3p-deficient NPC cells promoted APP expression, proliferation and migration in recipient NP69 cells, whereas inhibition of EV secretion attenuated these effects. In vivo, miR-7111-3p overexpression reduced xenograft tumor growth and downregulated APP expression.
CONCLUSION: These findings identify a novel EV-miR-7111-3p-APP signaling axis that regulates EMT, malignant phenotypes and tumor growth in NPC, highlighting its potential as a therapeutic target.