长间隔非编码RNA（lincRNA）在EBV感染细胞中表达差异，并在肿瘤进程中发挥重要作用。lincRNA在EBV驱动的自然杀伤T细胞淋巴瘤（NKTCL）的分子发病机制尚不清楚。我们使用439个淋巴瘤样本的高通量RNA测序数据研究了ncRNA谱，并筛选出LINC00486，其下调在EBV编码RNA（EBER）阳性的淋巴瘤，特别是NKTCL中，进一步通过定量实时聚合酶链反应得到验证。体外和体内研究均表明LINC00486通过抑制肿瘤细胞生长和诱导G0/G1细胞周期阻滞发挥肿瘤抑制功能。作用机制方面，LINC00486特异性地与NKRF相互作用，以撤销其与磷酸化p65的结合，激活NF-κB / TNF-α信号途径进而增强EBV的清除。在NKTCL中，上调的溶质载体家族1成员1（SLC1A1）介导谷氨酰胺依赖性和肿瘤进展，并与NKRF的表达呈负相关。NKRF特异性地结合到促进子上并通过染色质免疫共沉淀（ChIP）和荧光素酶检测表明转录下调SLC1A1的表达。总之，LINC00486在NKTCL中发挥肿瘤抑制作用，并抵御EBV感染。我们的研究提高了对NKTCL EBV驱动致癌机制的认识，并为抗癌治疗中EBV清除提供了临床依据。版权所有©2023 Elsevier B.V.发行。

Long intergenic noncoding RNAs (lincRNAs) are differentially expressed in EBV-infected cells and play an essential role in tumor progression. Molecular pathogenesis of lincRNAs in EBV-driven natural killer T cell lymphoma (NKTCL) remains unclear. Here we investigated the ncRNA profile using high-throughput RNA sequencing data of 439 lymphoma samples and screened out LINC00486, whose downregulation was further validated by quantitative real-time polymerase chain reaction in EBV-encoded RNA (EBER)-positive lymphoma, particularly NKTCL. Both in vitro and in vivo studies revealed the tumor suppressive function of LINC00486 through inhibiting tumor cell growth and inducing G0/G1 cell cycle arrest. As mechanism of action, LINC00486 specifically interacted with NKRF to abrogate its binding with phosphorylated p65, activated NF-κB/TNF-α signaling and subsequently enhanced EBV eradication. Solute carrier family 1 member 1 (SLC1A1), upregulated and mediated the glutamine-addiction and tumor progression in NKTCL, was negatively correlated with the expression of NKRF. NKRF specifically bound to the promoter and transcriptionally downregulated the expression of SLC1A1, as evidenced by Chromatin Immunoprecipitation (ChIP) and luciferase assay. Collectively, LINC00486 functioned as a tumor suppressor and counteracted EBV infection in NKTCL. Our study improved the knowledge of EBV-driven oncogenesis in NKTCL and provided the clinical rationale of EBV eradication in anti-cancer treatment.Copyright © 2023. Published by Elsevier B.V.