Department of Gastroenterology, Zibo Central Hospital, Zibo, 255036, China.
Department of Clinical Laboratory, Zibo Central Hospital, Zibo, 255036, China.
Mol Biotechnol. 2024 Oct;66(10):2850-2859. doi: 10.1007/s12033-023-00896-8. Epub 2023 Oct 10.
N-methyladenosine (mA) 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 mA 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 mA 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 mA epigenetic modification, which might provide insights for gastric cancer immunotherapies.
N6-甲基腺苷（m6A）作为一种重要的调节因子，在多种人类癌症中发挥作用，包括胃癌。针对 PD-1/PD-L1 的免疫疗法为晚期胃癌的治疗带来了希望。本研究旨在探讨 m6A 阅读器 IGF2BP1 在胃癌肿瘤发生和免疫逃逸中的作用。结果表明，IGF2BP1 在胃癌组织中上调，并与胃癌患者的不良预后相关。IGF2BP1 过表达增强了共培养的胃癌细胞的增殖，并减轻了 CD8+T 细胞介导的抗肿瘤反应，包括 IFN-γ 的分泌、表面 PD-L1 水平和 CD8+T 细胞的细胞毒性。同时，IGF2BP1 沉默则产生相反的效果。计算机分析显示 PD-L1 mRNA 上有一个明显的 m6A 修饰位点。此外，IGF2BP1 过表达增强了 PD-L1 mRNA 的稳定性，从而恶化了胃癌细胞的免疫逃逸。综上所述，这些结果描述了 IGF2BP1 通过 m6A 表观遗传修饰调节 PD-L1 的新调控机制，这可能为胃癌的免疫治疗提供新的思路。
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