LINC01082的m5C修饰通过调节miR-543-TNRC6A轴抑制骨肉瘤进展

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-08-15 DOI:10.1016/j.tranon.2025.102502

Yawei Hu , Jiawen Wu , Huaping Zeng , Jianhua Zhou , Ming Gong , Zengfeng Guo , Wang Zhang , Ningfeng Zhang , Hao Zhang

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引用次数: 0

摘要

骨肉瘤（OS）是一种主要影响儿童和青少年的高度恶性骨肿瘤，有相当一部分患者发生转移，预后较差。最近的研究发现，长链非编码rna （lncRNAs）在癌症进展中起着关键的调节作用。其中，LINC01082在多种癌症中显示出肿瘤抑制作用，但其在OS中的功能和调控机制尚不清楚。方法采用RT-qPCR、western blotting和细胞活力法研究LINC01082在OS组织和细胞系中的表达规律和生物学功能。通过MeRIP-qPCR、RNA免疫沉淀（RIP）和CRISPR/ dcas13b - nsun2介导的m5C靶向，评估5-甲基胞嘧啶（m5C） RNA修饰对LINC01082稳定性的调控影响。我们通过荧光素酶报告基因测定、RNA下拉和功能测定进一步探索了RNA诱导沉默复合物（RISCs）中LINC01082、miR-543和TNRC6A之间的相互作用。结果linc01082在OS组织和细胞系中显著下调，表达水平较低与患者生存期较差相关。NSUN2介导的M5C修饰通过与M5C读取器蛋白YBX1的相互作用稳定了LINC01082。CRISPR/ dcas13b - nsun2介导的m5C靶向增加LINC01082的表达，导致OS细胞增殖和迁移减少，凋亡增加。此外，研究发现LINC01082正向调节TNRC6A表达，miR-543调节risc内的这种相互作用。抑制TNRC6A逆转了LINC01082甲基化的肿瘤抑制作用，突出了LINC01082-TNRC6A轴在OS中的功能意义。我们的研究强调了LINC01082的一种新的m5C依赖调控机制，并证明了CRISPR/ dcas13b - nsun2介导的m5C编辑对这种lncRNA进行功能性调控并抑制骨肉瘤进展的潜力。

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m5C modification of LINC01082 inhibits osteosarcoma progression by modulating the miR-543-TNRC6A axis

Background

Osteosarcoma (OS) is a highly malignant bone tumor primarily affecting children and adolescents, with a significant portion of patients developing metastasis, leading to poor prognosis. Recent studies have identified long noncoding RNAs (lncRNAs) as critical regulators in cancer progression. Among these, LINC01082 has shown tumor-suppressive roles in various cancers, but its function and regulatory mechanisms in OS remain unclear.

Methods

We investigated the expression patterns and biological functions of LINC01082 in OS tissues and cell lines using RT-qPCR, western blotting, and cell viability assays. The regulatory impact of 5-methylcytosine (m5C) RNA modification on LINC01082 stability was assessed through MeRIP-qPCR, RNA immunoprecipitation (RIP), and CRISPR/dCas13b-NSUN2-mediated m5C targeting. We further explored the interaction between LINC01082, miR-543, and TNRC6A within RNA-induced silencing complexes (RISCs) using luciferase reporter assays, RNA pull-down, and functional assays.

Results

LINC01082 was significantly downregulated in OS tissues and cell lines, with lower expression levels correlating with poorer patient survival. M5C modification, mediated by NSUN2, stabilized LINC01082 through its interaction with the m5C reader protein YBX1. CRISPR/dCas13b-NSUN2-mediated m5C targeting increased LINC01082 expression, resulting in reduced OS cell proliferation and migration, and increased apoptosis. Further, LINC01082 was found to positively regulate TNRC6A expression, with miR-543 modulating this interaction within RISCs. Inhibition of TNRC6A reversed the tumor-suppressive effects of LINC01082 methylation, highlighting the functional significance of the LINC01082-TNRC6A axis in OS.

Conclusion

Our study highlights a novel m5C-dependent regulatory mechanism of LINC01082, and demonstrates the potential of CRISPR/dCas13b-NSUN2–mediated m5C editing to functionally modulate this lncRNA and suppress osteosarcoma progression.

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.