METTL14/IGF2BP2-mediated m6A modification of PD-L1 promotes proliferation, metastasis, and immune escape in high-grade gliomas.

IF 3 3区医学 Q2 CLINICAL NEUROLOGY

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-11 DOI:10.1093/jnen/nlaf090

Zexiang Zhang, Xiaoyu Guo, Tengfei Qi, Chongcheng Wang, Xiaodong Zhai, Min Wang

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Abstract

N6-methyladenosine (m6A) RNA modification is involved in regulating the malignant progression and immune escape of glioblastoma multiforme (GBM). This study investigated the role of methyltransferase-like protein 14 (METTL14), the central component of the m6A methylated transferase complex, in GBM progression and immune escape. METTL14 and programmed death ligand 1 (PD-L1) levels were analyzed by qRT-PCR and Western blot in human GBM samples. Effects of METTL14 knockdown on GBM tumorigenesis were investigated in mouse tumor xenografts. GBM cell proliferation and metastasis were examined by colony formation assay and transwell assay; immune escape was assessed by detecting cytotoxicity, immune-related markers, and exhaustion markers. The interaction between PD-L1 and METTL14 or the m6A reader IGF2BP2 was confirmed by MeRIP assay and RIP assay. METTL14 was upregulated in GBM tissues and cells and its knockdown reduced GBM tumor growth in the xenografts. Downregulation of METTL14 could suppress GBM cell proliferation, metastasis, and immune escape. METTL14 stabilized PD-L1 mRNA; this modification could be recognized by IGF2BP2. Moreover, PD-L1 overexpression eliminated the inhibitory effect of METTL14 knockdown on GBM cell proliferation, metastasis, and immune escape. In conclusion, METTL14-mediated m6A modification of PD-L1 contributed to GBM cell proliferation, metastasis, and immune escape in an IGF2BP2-dependent manner.

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METTL14/ igf2bp2介导的m6A修饰PD-L1促进高级别胶质瘤的增殖、转移和免疫逃逸。

n6 -甲基腺苷（m6A） RNA修饰参与调节多形性胶质母细胞瘤（GBM）的恶性进展和免疫逃逸。本研究探讨了甲基转移酶样蛋白14 （METTL14）在GBM进展和免疫逃逸中的作用，METTL14是m6A甲基化转移酶复合物的核心成分。采用qRT-PCR和Western blot分析人GBM样品中METTL14和程序性死亡配体1 （PD-L1）的水平。研究了METTL14基因敲低对小鼠肿瘤异种移植物GBM发生的影响。用菌落形成法和transwell法观察GBM细胞的增殖和转移；通过检测细胞毒性、免疫相关标志物和衰竭标志物来评估免疫逃逸。通过MeRIP和RIP实验证实了PD-L1与METTL14或m6A读取器IGF2BP2之间的相互作用。METTL14在GBM组织和细胞中表达上调，其下调可减少异种移植物GBM肿瘤的生长。下调METTL14可抑制GBM细胞增殖、转移和免疫逃逸。METTL14稳定PD-L1 mRNA；这种修饰可以被IGF2BP2识别。此外，PD-L1过表达消除了METTL14敲低对GBM细胞增殖、转移和免疫逃逸的抑制作用。综上所述，mettl14介导的m6A修饰PD-L1以igf2bp2依赖的方式促进GBM细胞增殖、转移和免疫逃逸。

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

Journal of Neuropathology and Experimental Neurology 医学-病理学

CiteScore

5.40

自引率

6.20%

发文量

118

审稿时长

6-12 weeks

期刊介绍： Journal of Neuropathology & Experimental Neurology is the official journal of the American Association of Neuropathologists, Inc. (AANP). The journal publishes peer-reviewed studies on neuropathology and experimental neuroscience, book reviews, letters, and Association news, covering a broad spectrum of fields in basic neuroscience with an emphasis on human neurological diseases. It is written by and for neuropathologists, neurologists, neurosurgeons, pathologists, psychiatrists, and basic neuroscientists from around the world. Publication has been continuous since 1942.