FTO-YTHDF2轴通过m6a依赖性FLAD1调控驱动肝细胞癌的免疫逃避和肿瘤进展

IF 2.2 4区 生物学 Q3 CELL BIOLOGY
Chen Xu, Liangjun Jiang, Xianzhou Lu, Wei Li
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引用次数: 0

摘要

本研究探讨FTO-YTHDF2轴通过m6A修饰调控FLAD1表达驱动肝细胞癌(HCC)免疫逃避和肿瘤进展的分子机制。通过TCGA-HCC数据的生物信息学分析,FLAD1被确定为一个关键的致癌驱动因子,在HCC组织和细胞中表达升高。功能实验显示,FLAD1敲低可抑制HCC的增殖、迁移、侵袭和PD-L1表达,同时增强CD8 + T细胞的细胞毒性(IFN-γ、TNF-α和LDH释放增加)。从机制上说,FTO是一种m6A去甲基化酶,通过去除m6A标记来抑制ythdf2介导的mRNA降解,从而上调FLAD1。在体内,FTO沉默降低了肿瘤生长和PD-L1水平,同时提高了促炎细胞因子,而这种作用被YTHDF2敲低所否定。这些发现表明FTO-YTHDF2轴通过m6a依赖性FLAD1的稳定促进HCC免疫逃避和肿瘤进展,突出了FTO-YTHDF2轴作为破坏肿瘤发生和恢复抗肿瘤免疫的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The FTO-YTHDF2 axis drives immune evasion and tumor progression in hepatocellular carcinoma via m6A-dependent FLAD1 regulation

This study investigates the molecular mechanism by which the FTO-YTHDF2 axis regulates FLAD1 expression through m6A modification to drive immune evasion and tumor progression in hepatocellular carcinoma (HCC). By bioinformatics analysis of TCGA-HCC data, FLAD1 was identified as a key oncogenic driver, with elevated expression in HCC tissues and cells. Functional experiments revealed that FLAD1 knockdown suppressed HCC proliferation, migration, invasion, and PD-L1 expression while enhancing CD8 + T cell cytotoxicity (evidenced by increased IFN-γ, TNF-α, and LDH release). Mechanistically, FTO, an m6A demethylase, upregulated FLAD1 by removing m6A marks to counteract YTHDF2-mediated mRNA degradation. In vivo, FTO silencing reduced tumor growth and PD-L1 levels while elevating pro-inflammatory cytokines, and the effects negated by YTHDF2 knockdown. These findings establish that the FTO-YTHDF2 axis promotes HCC immune evasion and tumor progression via m6A-dependent FLAD1 stabilization, highlighting the axis as a therapeutic target to disrupt tumorigenesis and restore anti-tumor immunity.

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来源期刊
Journal of Molecular Histology
Journal of Molecular Histology 生物-细胞生物学
CiteScore
5.90
自引率
0.00%
发文量
68
审稿时长
1 months
期刊介绍: The Journal of Molecular Histology publishes results of original research on the localization and expression of molecules in animal cells, tissues and organs. Coverage includes studies describing novel cellular or ultrastructural distributions of molecules which provide insight into biochemical or physiological function, development, histologic structure and disease processes. Major research themes of particular interest include: - Cell-Cell and Cell-Matrix Interactions; - Connective Tissues; - Development and Disease; - Neuroscience. Please note that the Journal of Molecular Histology does not consider manuscripts dealing with the application of immunological or other probes on non-standard laboratory animal models unless the results are clearly of significant and general biological importance. The Journal of Molecular Histology publishes full-length original research papers, review articles, short communications and letters to the editors. All manuscripts are typically reviewed by two independent referees. The Journal of Molecular Histology is a continuation of The Histochemical Journal.
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