Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China.
TCM Department, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.
J Cell Mol Med. 2024 Sep;28(17):e70060. doi: 10.1111/jcmm.70060.
Whether N6-Methyladenosine (m6A)- and ferroptosis-related genes act on immune responses to regulate glioma progression remains unanswered. Data of glioma and corresponding normal brain tissues were fetched from the TCGA database and GTEx. Differentially expressed genes (DEGs) were identified for GO and KEGG enrichment analyses. The FerrDb database was based to yield ferroptosis-related DEGs. Hub genes were then screened out using the cytoHubba database and validated in clinical samples. Immune cells infiltrating into the glioma tissues were analysed using the CIBERSORT R script. The association of gene signature underlying the m6A-related ferroptosis with tumour-infiltrating immune cells and immune checkpoints in low-grade gliomas was analysed. Of 6298 DEGs enriched in mRNA modifications, 144 were ferroptosis-related; NFE2L2 and METTL16 showed the strongest positive correlation. METTL16 knockdown inhibited the migrative and invasive abilities of glioma cells and induced ferroptosis in vitro. NFE2L2 was enriched in the anti-m6A antibody. Moreover, METTL16 knockdown reduced the mRNA stability and level of NFE2L2 (both p < 0.05). Proportions of CD8+ T lymphocytes, activated mast cells and M2 macrophages differed between low-grade gliomas and normal tissues. METTL16 expression was negatively correlated with CD8+ T lymphocytes, while that of NFE2L2 was positively correlated with M2 macrophages and immune checkpoints in low-grade gliomas. Gene signatures involved in the m6A-related ferroptosis in gliomas were identified via bioinformatic analyses. NFE2L2 interacted with METTL16 to regulate the immune response in low-grade gliomas, and both molecules may be novel therapeutic targets for gliomas.
N6-甲基腺苷（m6A）和铁死亡相关基因是否通过影响免疫反应来调节胶质瘤的进展尚不清楚。从 TCGA 数据库和 GTEx 中获取了胶质瘤和相应的正常脑组织数据。进行了 GO 和 KEGG 富集分析以识别差异表达基因（DEGs）。然后基于 FerrDb 数据库得出铁死亡相关 DEGs。使用 cytoHubba 数据库筛选出枢纽基因，并在临床样本中进行验证。使用 CIBERSORT R 脚本分析了浸润到胶质瘤组织中的免疫细胞。分析了与 m6A 相关铁死亡相关基因特征与低级别胶质瘤中肿瘤浸润免疫细胞和免疫检查点的关联。在 mRNA 修饰中富集的 6298 个 DEGs 中，有 144 个与铁死亡相关；NFE2L2 和 METTL16 显示出最强的正相关。METTL16 敲低抑制了胶质瘤细胞的迁移和侵袭能力，并在体外诱导铁死亡。NFE2L2 富集在抗 m6A 抗体中。此外，METTL16 敲低降低了 NFE2L2 的 mRNA 稳定性和水平（均 p<0.05）。低级别胶质瘤和正常组织之间 CD8+T 淋巴细胞、活化肥大细胞和 M2 巨噬细胞的比例不同。METTL16 表达与 CD8+T 淋巴细胞呈负相关，而 NFE2L2 表达与 M2 巨噬细胞和低级别胶质瘤中的免疫检查点呈正相关。通过生物信息学分析鉴定了胶质瘤中与 m6A 相关铁死亡相关的基因特征。NFE2L2 与 METTL16 相互作用调节低级别胶质瘤中的免疫反应，这两个分子可能是胶质瘤的新治疗靶点。
