Su Xiaoyan, Liu Junzhe, Tu Zewei, Ji Qiankun, Li Jingying, Liu Fanrong
Department of Pathology, the 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Department of Neurosurgery, the 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Transl Cancer Res. 2024 Apr 30;13(4):1786-1806. doi: 10.21037/tcr-23-1943. Epub 2024 Apr 22.
DNMT3A is the main molecule responsible for DNA methylation in cells. DNMT3A affects the progression of inflammation, degenerative diseases, and malignant tumors, and exhibits significant aberrantly expression in tumor tissues.
Transcriptome data and relevant clinical information were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) datasets. Differential expression analysis and prognostic analysis were conducted based on above statistics. We constructed a clinical prognostic model and identified as an independent prognostic factor to accurately predict patient prognosis. Differential gene enrichment analysis revealed that DNMT3A affects the progression of glioma through multiple pathways, among which the tumor necrosis factor-α (TNF-α)/nuclear factor-kappa B (NF-κB) pathway shows a strong correlation. Immunological analysis also revealed a certain correlation between DNMT3A and tumor immunity. We demonstrated through gene editing that DNMT3A can affect the release of TNF-α in cells, thereby affecting the progression of glioma. Functional experiments have also demonstrated that DNMT3A plays a crucial role in tumors.
RNA-sequencing and survival analyses of lower-grade glioma (LGG) patients in TCGA, CGGA, and GEO cohorts showed that high expression correlated with poor prognosis of LGG patients. Univariate and multivariate Cox regression analyses showed that expression was an independent prognostic indicator in LGG. The prognosis prediction nomogram with age, World Health Organization (WHO) grading, and expression showed reliable performance in predicting the 1-, 3-, and 5-year overall survival (OS) of LGG patients. Functional enrichment analysis, gene set enrichment analysis (GSEA), and ESTIMATE algorithm analyses showed that DNMT3A expression was associated with the tumor infiltration of immune cells and predicted response to immunotherapy in two immunotherapy cohorts of pan-cancer patients. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of DNMT3A in the LGG cell lines suppressed proliferation, migration, and invasion of LGG cells by downregulating the TNF-α/NF-κB signaling pathway.
Our data showed that DNMT3A was a potential prognostic biomarker in glioma. DNMT3A promoted proliferation and malignancy of LGG cells through the TNF-α/NF-κB signaling pathway. DNMT3A is a promising therapeutic target for treating patients with LGG.
DNMT3A是细胞中负责DNA甲基化的主要分子。DNMT3A影响炎症、退行性疾病和恶性肿瘤的进展，并且在肿瘤组织中表现出显著的异常表达。
从癌症基因组图谱（TCGA）、中国胶质瘤基因组图谱（CGGA）和基因表达综合数据库（GEO）数据集中下载转录组数据和相关临床信息。基于上述统计数据进行差异表达分析和预后分析。我们构建了一个临床预后模型，并将其确定为一个独立的预后因素，以准确预测患者的预后。差异基因富集分析表明，DNMT3A通过多种途径影响胶质瘤的进展，其中肿瘤坏死因子-α（TNF-α）/核因子-κB（NF-κB）途径显示出很强的相关性。免疫分析还揭示了DNMT3A与肿瘤免疫之间存在一定的相关性。我们通过基因编辑证明，DNMT3A可以影响细胞中TNF-α的释放，从而影响胶质瘤的进展。功能实验也证明了DNMT3A在肿瘤中起着至关重要的作用。
对TCGA、CGGA和GEO队列中的低级别胶质瘤（LGG）患者进行RNA测序和生存分析表明，高表达与LGG患者的不良预后相关。单因素和多因素Cox回归分析表明，表达是LGG中的一个独立预后指标。结合年龄、世界卫生组织（WHO）分级和表达的预后预测列线图在预测LGG患者1年、3年和5年总生存期（OS）方面表现出可靠的性能。功能富集分析、基因集富集分析（GSEA）和ESTIMATE算法分析表明，DNMT3A表达与免疫细胞的肿瘤浸润相关，并在泛癌患者的两个免疫治疗队列中预测对免疫治疗的反应。此外，在LGG细胞系中，短发夹RNA（shRNA）介导的DNMT3A敲低通过下调TNF-α/NF-κB信号通路抑制了LGG细胞的增殖、迁移和侵袭。
我们的数据表明，DNMT3A是胶质瘤中一个潜在的预后生物标志物。DNMT3A通过TNF-α/NF-κB信号通路促进LGG细胞的增殖和恶性化。DNMT3A是治疗LGG患者的一个有前景的治疗靶点。
