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Abstract：
Mitochondrial RNA modification (MRM) plays a crucial role in regulating the expression of key mitochondrial genes and promoting tumor metastasis. Despite its significance, comprehensive studies on MRM in lower grade gliomas (LGGs) remain unknown. Single-cell RNA-seq data (GSE89567) was used to evaluate the distribution functional status, and correlation of MRM-related genes in different cell types of LGG microenvironment. We developed an MRM scoring system by selecting potential MRM-related genes using LASSO regression analysis and the Random Survival Forest algorithm, based on multiple bulk RNA-seq datasets from TCGA, CGGA, GSE16011, and E-MTAB-3892. Analysis was performed on prognostic and immunological features, signaling pathways, metabolism, somatic mutations and copy number variations (CNVs), treatment responses, and forecasting of potential small-molecule agents. A total of 35 MRM-related genes were selected from the literature. Differential expression analysis of 1120 normal brain tissues and 529 LGGs revealed that 22 and 10 genes were upregulated and downregulated, respectively. Most genes were associated with prognosis of LGG. METLL8, METLL2A, TRMT112, and METTL2B were extensively expressed in all cell types and different cell cycle of each cell type. Almost all cell types had clusters related to mitochondrial RNA processing, ribosome biogenesis, or oxidative phosphorylation. Cell-cell communication and Pearson correlation analyses indicated that MRM may promoting the development of microenvironment beneficial to malignant progression via modulating NCMA signaling pathway and ICP expression. A total of 11 and 9 MRM-related genes were observed by LASSO and the RSF algorithm, respectively, and finally 6 MRM-related genes were used to establish MRM scoring system (TRMT2B, TRMT11, METTL6, METTL8, TRMT6, and TRUB2). The six MRM-related genes were then validated by qPCR in glioma and normal tissues. MRM score can predict the malignant clinical characteristics, abundance of immune infiltration, gene variation, clinical outcome, the enrichment of signaling pathways and metabolism. In vitro experiments demonstrated that silencing METTL8 significantly curbs glioma cell proliferation and enhances apoptosis. Patients with a high MRM score showed a better response to immunotherapies and small-molecule agents such as arachidonyl trifluoromethyl ketone, MS.275, AH.6809, tacrolimus, and TTNPB. These novel insights into the biological impacts of MRM within the glioma microenvironment underscore its potential as a target for developing precise therapies, including immunotherapeutic approaches.
摘要：
线粒体RNA修饰(MRM)在调控线粒体关键基因的表达和促进肿瘤转移中起着至关重要的作用。尽管意义重大,关于低级别胶质瘤（LGGs）中MRM的综合研究仍然未知。单细胞RNA-seq数据（GSE89567）用于评估分布功能状态，以及不同细胞类型LGG微环境中MRM相关基因的相关性。我们通过使用LASSO回归分析和随机生存森林算法选择潜在的MRM相关基因，开发了MRM评分系统，基于来自TCGA的多个批量RNA-seq数据集，CGGA,GSE16011和E-MTAB-3892。对预后和免疫学特征进行分析，信号通路，新陈代谢，体细胞突变和拷贝数变异（CNVs），治疗反应，并预测潜在的小分子药物。从文献中总共选择了35个MRM相关基因。1120个正常脑组织和529个LGGs的差异表达分析显示，有22个和10个基因上调和下调，分别。大多数基因与LGG的预后相关。METLL8,METLL2A,TRMT112和METTL2B在所有细胞类型和每种细胞类型的不同细胞周期中广泛表达。几乎所有细胞类型都有与线粒体RNA加工相关的簇，核糖体生物发生，或氧化磷酸化。细胞间通讯和Pearson相关分析显示MRM可能通过调节NCMA信号通路和ICP表达促进微环境的发展，从而促进恶性进展。通过LASSO和RSF算法共观察到11个和9个MRM相关基因,分别,最后用6个MRM相关基因建立MRM评分系统(TRMT2B,TRMT11、METTL6、METTL8、TRMT6和TRUB2)。然后通过qPCR在神经胶质瘤和正常组织中验证了六个MRM相关基因。MRM评分可以预测恶性肿瘤的临床特征,丰富的免疫浸润，基因变异，临床结果，信号通路和代谢的富集。体外实验表明，沉默METTL8可显着抑制神经胶质瘤细胞的增殖并增强细胞凋亡。MRM评分高的患者对免疫疗法和小分子药物如花生四烷基三氟甲基酮有更好的反应，MS.275,AH.6809,他克莫司,和TTNPB。这些对神经胶质瘤微环境中MRM的生物学影响的新见解强调了其作为开发精确疗法的目标的潜力。包括免疫治疗方法。
