N⁶-Methyladenosine (m⁶A) Reader IGF2BP1 Accelerates Gastric Cancer Development and Immune Escape by Targeting PD-L1.

IF 2.4 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Biotechnology Pub Date : 2024-10-01 Epub Date: 2023-10-10 DOI:10.1007/s12033-023-00896-8

Bingxi Tang, Lei Bi, Yanbin Xu, Lili Cao, Xinli Li

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Abstract

N⁶-methyladenosine (m⁶A) functions as an important regulator in various human cancers, including gastric cancer. The immunotherapy targeting PD-1/PD-L1 has brought hope for advanced gastric cancer therapeutic. Here, present research aims to investigate the roles of m⁶A reader IGF2BP1 on gastric cancer tumor development and immune escape. Results indicated that IGF2BP1 up-regulated in the gastric cancer tissue and correlated with poor prognosis of gastric cancer patients. IGF2BP1 overexpression augmented the proliferation of co-cultured gastric cancer cells, and mitigated the CD8+ T cells mediated anti-tumor response, including IFN-γ secretion, surface PD-L1 level, and cytotoxicity of CD8+ T cells. Meanwhile, IGF2BP1 silencing exerted the opposite effects. In silico analysis revealed that there was a remarkable m⁶A modified site on PD-L1 mRNA. Moreover, the IGF2BP1 overexpression enhanced the stability of PD-L1 mRNA, thereby deteriorating the immune escape of gastric cancer cells. Collectively, these results describe a novel regulatory mechanism of IGF2BP1 by regulating PD-L1 through m⁶A epigenetic modification, which might provide insights for gastric cancer immunotherapies.

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N6-甲基腺苷（m6A）阅读器IGF2BP1通过靶向PD-L1加速癌症的发展和免疫逃逸。

N6-甲基腺苷（m6A）在包括癌症在内的多种人类癌症中起着重要的调节作用。针对PD-1/PD-L1的免疫疗法为晚期癌症的治疗带来了希望。本研究旨在探讨m6A阅读器IGF2BP1在癌症肿瘤发生和免疫逃逸中的作用。结果表明IGF2BP1在癌症组织中表达上调，与癌症患者预后不良相关。IGF2BP1过表达增强了共培养的癌症细胞的增殖，并减轻了CD8+T细胞介导的抗肿瘤反应，包括IFN-γ分泌、表面PD-L1水平和CD8+T的细胞毒性。而IGF2BP1的沉默则产生相反的作用。计算机分析显示，PD-L1 mRNA上有一个显著的m6A修饰位点。此外，IGF2BP1过表达增强了PD-L1 mRNA的稳定性，从而恶化了癌症细胞的免疫逃逸。总之，这些结果描述了IGF2BP1通过m6A表观遗传学修饰调节PD-L1的新调节机制，这可能为癌症免疫治疗提供了见解。

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

Molecular Biotechnology 医学-生化与分子生物学

CiteScore

4.10

自引率

3.80%

发文量

165

审稿时长

6 months

期刊介绍： Molecular Biotechnology publishes original research papers on the application of molecular biology to both basic and applied research in the field of biotechnology. Particular areas of interest include the following: stability and expression of cloned gene products, cell transformation, gene cloning systems and the production of recombinant proteins, protein purification and analysis, transgenic species, developmental biology, mutation analysis, the applications of DNA fingerprinting, RNA interference, and PCR technology, microarray technology, proteomics, mass spectrometry, bioinformatics, plant molecular biology, microbial genetics, gene probes and the diagnosis of disease, pharmaceutical and health care products, therapeutic agents, vaccines, gene targeting, gene therapy, stem cell technology and tissue engineering, antisense technology, protein engineering and enzyme technology, monoclonal antibodies, glycobiology and glycomics, and agricultural biotechnology.