LncRNA RP11-1100L3.8 Involves in the Pathogenesis of Multiple Myeloma by Regulating NR4A1.

IF 2 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Discovery medicine Pub Date : 2023-02-01 DOI:10.24976/Discov.Med.202335174.9

Youfan Feng, Xiaofang Wei, Yuan Fu, Fei Liu, QiaoLin Chen, Wenjie Zhang, Yangyang Zhao, Xiujuan Huang, Yang Chen, Qingfen Li, Li Zhao, Qike Zhang

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引用次数: 0

Abstract

Purpose: Although numerous studies have revealed that various long-non coding RNA (lncRNA) are implicated in multiple myeloma (MM) regulation, MM lncRNA profile and novel functional lncRNAs in MM need to be elucidated.

Methods: Herein, lncRNAs and mRNAs (messenger ribonucleic acids) patterns in MM were evaluated using RNA-sequencing (RNAseq). Differentially expressed (DE) genes were defined and a complex regulatory network based on validation and predication was shaped.

Results: LncRNA-seq data analysis identified 539 DE lncRNAs and RP11-1100L3.8 was the most up-regulated known lncRNA. Subsequently, the upregulation and clinical RP11-1100L3.8 utilization value was verified in an expanded cohort. Based on the results of Cis nearby-targets and co-expression analysis, 1 correlation pair RP11-1100L3.8-nuclear receptor subfamily 4 group A member 1 (NR4A1) was defined. It is worth noting that NR4A1 is one of the top 5 significantly up-regulated DE mRNAs in MM patients. Moreover, it was found that NR4A1 overexpression is associated with poor prognosis in MM patients, making it suitable as biomarker. Additionally, spearman correlation analysis revealed the positive association between RP11-1100L3.8 and NR4A1 in MM patients. Furthermore, the dominant NR4A1 interacted genes were predicated and it was found that the genes containing NR4A1 were remarkably enriched in phosphatidylinositol 3-kinase (PI3K)-AKT (protein kinase B) signaling pathway. In addition, in vitro experiment suggested that RP11-1100L3.8 downregulation decreased NR4A1 expression in U266 and RPMI 8226 MM cells. RP11-1100L3.8 inhibition declined proliferation and promoted apoptosis in MM cells, which were rescued by NR4A1 overexpression. Moreover, it was found that RP11-1100L3.8 inhibition impeded PI3K and AKT phosphorylation and rapamycin mammalian target in MM cells, which was rescued by NR4A1 overexpression.

Conclusions: This study identifies RP11-1100L3.8 as a potential MM biomarker, and it may be involved in MM pathophysiology by regulating NR4A1-mediated PI3K-AKT signaling pathway. This study provides a novel biomarker candidate for MM therapy.

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LncRNA RP11-1100L3.8通过调控NR4A1参与多发性骨髓瘤发病。

目的:尽管大量研究表明多种长链非编码RNA (lncRNA)参与多发性骨髓瘤(MM)的调控，但MM lncRNA谱和MM中新型功能lncRNA仍有待阐明。方法:采用rna测序(RNA-sequencing, RNAseq)技术对MM中的lncRNAs和mrna(信使核糖核酸)模式进行分析。对差异表达基因进行了定义，并形成了基于验证和预测的复杂调控网络。结果:lncRNA -seq数据分析共鉴定出539个DE lncRNA，其中RP11-1100L3.8是已知上调最多的lncRNA。随后，在一个扩大的队列中验证了RP11-1100L3.8的上调和临床应用价值。根据Cis邻近靶点及共表达分析结果，定义1对相关对rp11 - 1100l3.8 -核受体亚家族4A组成员1 (NR4A1)。值得注意的是，NR4A1是MM患者中前5位显著上调的DE mrna之一。此外，研究发现NR4A1过表达与MM患者预后不良相关，适合作为生物标志物。此外，spearman相关分析显示MM患者的RP11-1100L3.8与NR4A1呈正相关。此外，我们预测了NR4A1的显性相互作用基因，发现含有NR4A1的基因在磷脂酰肌醇3-激酶(PI3K)-AKT(蛋白激酶B)信号通路中显著富集。此外，体外实验表明，下调RP11-1100L3.8可降低U266和RPMI 8226 MM细胞中NR4A1的表达。RP11-1100L3.8的抑制作用降低了MM细胞的增殖，促进了细胞凋亡，并通过NR4A1过表达挽救了MM细胞。此外，我们发现RP11-1100L3.8的抑制抑制了MM细胞中PI3K和AKT的磷酸化和雷帕霉素的哺乳动物靶点，通过NR4A1过表达来拯救。结论:本研究确定RP11-1100L3.8为潜在的MM生物标志物，可能通过调控nr4a1介导的PI3K-AKT信号通路参与MM病理生理。这项研究为MM治疗提供了一种新的生物标志物候选物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Discovery medicine MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

5.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Discovery Medicine publishes novel, provocative ideas and research findings that challenge conventional notions about disease mechanisms, diagnosis, treatment, or any of the life sciences subjects. It publishes cutting-edge, reliable, and authoritative information in all branches of life sciences but primarily in the following areas: Novel therapies and diagnostics (approved or experimental); innovative ideas, research technologies, and translational research that will give rise to the next generation of new drugs and therapies; breakthrough understanding of mechanism of disease, biology, and physiology; and commercialization of biomedical discoveries pertaining to the development of new drugs, therapies, medical devices, and research technology.