lncRNA LINC02446通过调控EBV-NK-LPDs中KLRs和IL-10的表达促进肿瘤进展和HLH的发生

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-04-21 DOI:10.1016/j.intimp.2025.114696

Yaxian Ma , Yuhan Bao , Jiachen Wang , Qing Yin , Min Liu , Zetong Hong , Qiaolin Huang , Miao Zheng

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引用次数: 0

摘要

导言：难治性爱泼斯坦-巴氏病毒相关NK细胞淋巴增生性疾病（EBV-NK-LPDs）易导致嗜血细胞淋巴组织细胞增多症（HLH），存活期短，预后差。虽然已采用多种疗法缓解症状，但造血干细胞移植被认为是唯一可能的治疗方法。目前迫切需要探索 EBV-NK-LPDs 的发病机制，并开发出更有效的治疗方法。方法在此，我们利用高通量 RNA 测序数据（n = 6，健康供者；n = 5，传染性单核细胞增多症；n = 10，慢性活动性爱泼斯坦-巴氏病毒病（CAEBV）-NK；n = 7，CAEBV-T）研究了长非编码 RNA（lncRNA）谱，筛选出 LINC02446，并通过实时定量聚合酶链反应进一步验证了其在 EBV-NK-LPDs 中的上调。我们进一步探讨了LINC02446与EBV-NK-LPDs患者临床特征的相关性。结果LINC02446在EBV-NK-LPDs患者的NK细胞中特异性高表达。LINC02446高表达的EBV-NK-LPDs患者表现出更高的EBV-DNA拷贝数和铁蛋白水平，以及更高的HLH发病率。LINC02446与KLRs家族密切相关，LINC02446可调控KLRs基因的表达。此外，LINC02446还能正向调节EBV-NK-LPDs细胞系中IL-10的表达，这揭示了LINC02446可能通过上调EBV-NK-LPDs中的IL-10而促进HLH的发生。结论这是首次研究发现LINC02446能调节EBV-NK-LPDs中KLRs家族和IL-10的表达，从而导致淋巴瘤进展和HLH的发生，显示了其作为EBV-NK-LPDs治疗靶点的潜力。

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The lncRNA LINC02446 promotes tumor progression and HLH occurrence by regulating the expression of KLRs and IL-10 in EBV-NK-LPDs

Introduction

Refractory Epstein-Barr virus-associated NK-cell lymphoproliferative diseases (EBV-NK-LPDs) are prone to hemophagocytic lymphohistiocytosis (HLH) with short survival and poor prognosis. Although various therapies have been used to relieve the symptoms, hematopoietic stem cell transplantation is considered the only potentially therapeutic approach. There is an urgent need to explore the pathogenesis of EBV-NK-LPDs and develop an effective better treatment.

Methods

Here, we investigated long non-coding RNA (lncRNA) profile using high-throughput RNA sequencing data (n = 6, healthy donors; n = 5, infectious mononucleosis; n = 10, chronic active Epstein-Barr virus disease (CAEBV)-NK; n = 7, CAEBV-T) and screened out LINC02446, whose upregulation was further validated by quantitative real-time polymerase chain reaction in EBV-NK-LPDs. We further explored the correlation between LINC02446 and the clinical characteristics of patients with EBV-NK-LPDs. Then, based on sequencing data, we performed in vitro experiments to investigate the function and mechanism of LINC02446 in EBV-NK-LPDs.

Results

LINC02446 was specifically highly expressed in NK cells of EBV-NK-LPDs patients. EBV-NK-LPDs patients with high expression of LINC02446 showed higher EBV-DNA copy number and ferritin levels, as well as a higher incidence of HLH. LINC02446 was closely related to the KLRs family and LINC02446 could regulate the expression of KLRs genes. In addition, LINC02446 positively regulated the expression of IL-10 in EBV-NK-LPDs cell lines, which revealed that LINC02446 may promote HLH by upregulating IL-10 in EBV-NK-LPDs.

Conclusions

This is the first study that LINC02446 regulates the expression of KLRs family and IL-10 in EBV-NK-LPDs, resulting in lymphoma progression and HLH occurrence, showing its potential as a therapeutic target for EBV-NK-LPDs.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.