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Abstract：
Dysregulation of long noncoding RNAs (lncRNAs) contributes to tumorigenesis by modulating specific cancer-related pathways, but the roles of N6-methyladenosine (m6A)-enriched lncRNAs and underlying mechanisms remain elusive in nasopharyngeal carcinoma (NPC). Here, we reanalyzed the previous genome-wide analysis of lncRNA profiles in 18 pairs of NPC and normal tissues as well as in ten paired samples from NPC with or without post-treatment metastases. We discerned that an oncogenic m6A-enriched lncRNA, LINC00839, which was substantially upregulated in NPC and correlated with poor clinical prognosis, promoted NPC growth and metastasis both in vitro and in vivo. Mechanistically, by using RNA pull-down assay combined with mass spectrometry, we found that LINC00839 interacted directly with the transcription factor, TATA-box binding protein associated factor (TAF15). Besides, chromatin immunoprecipitation and dual-luciferase report assays demonstrated that LINC00839 coordinated the recruitment of TAF15 to the promoter region of amine oxidase copper-containing 1 (AOC1), which encodes a secreted glycoprotein playing vital roles in various cancers, thereby activating AOC1 transcription in trans. In this study, potential effects of AOC1 in NPC progression were first proposed. Moreover, ectopic expression of AOC1 partially rescued the inhibitory effect of downregulation of LINC00839 in NPC. Furthermore, we showed that silencing vir-like m6A methyltransferase-associated (VIRMA) and insulin-like growth factor 2 mRNA-binding proteins 1 (IGF2BP1) attenuated the expression level and RNA stability of LINC00839 in an m6A-dependent manner. Taken together, our study unveils a novel oncogenic VIRMA/IGF2BP1-LINC00839-TAF15-AOC1 axis and highlights the significance and prognostic value of LINC00839 expression in NPC carcinogenesis.
摘要：
长链非编码RNA（lncRNAs）的失调通过调节特定的癌症相关途径促进肿瘤发生，但富含m6A的lncRNAs的作用和潜在机制在鼻咽癌（NPC）中仍然难以捉摸。这里,我们重新分析了18对NPC和正常组织的lncRNA谱，以及来自有或没有治疗后转移的NPC的10个配对样本。我们发现一种富含m6A的lncRNA，LINC00839在NPC中显著上调，与不良临床预后相关，在体外和体内都促进了NPC的生长和转移。机械上,通过使用RNA下拉分析结合质谱，我们发现LINC00839与转录因子直接相互作用，TATA盒结合蛋白相关因子(TAF15)。此外,ChIP和双荧光素酶报告测定表明，LINC00839协调TAF15募集到胺氧化酶含铜1（AOC1）的启动子区域，它编码一种分泌的糖蛋白，在各种癌症中起着至关重要的作用，从而激活AOC1的反式转录。在这项研究中,首次提出AOC1在NPC进展中的潜在作用。此外，AOC1的异位表达部分挽救了LINC00839在NPC中下调的抑制作用。此外，我们发现沉默vir样m6A甲基转移酶相关(VIRMA)和胰岛素样生长因子2mRNA结合蛋白1(IGF2BP1)以m6A依赖性方式减弱LINC00839的表达水平和RNA稳定性.一起来看,我们的研究揭示了一种新的致癌VIRMA/IGF2BP1-LINC00839-TAF15-AOC1轴，并强调LINC00839表达在鼻咽癌发生中的意义和预后价值。
