Shen Shen, Yan Jingya, Zhang Yize, Dong Zihui, Xing Jiyuan, He Yuting
Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Ann Transl Med. 2021 Jan;9(1):59. doi: 10.21037/atm-20-7396.
N6-methyladenosine (m6A)-mediated ribonucleic acid (RNA) methylation is considered to be the most significant and abundant epigenetic modification in eukaryotic cells, and plays an essential role in the carcinogenesis and molecular pathogenesis of hepatocellular carcinoma (HCC). However, the relationship between m6A regulation and immune cell infiltration of the tumor immune microenvironment (TIME) has not yet been clarified. We aimed to investigate the roles of m6A RNA gene regulators in HCC immune regulation and prognosis.
The Cancer Genome Atlas (TCGA) database was used, and unsupervised clustering of 21 m6A regulators was performed based on differential gene expression. Gene Set Variation Analysis (GSVA), single-sample Gene Set Enrichment Analysis (ssGSEA), the empirical Bayes method, and m6A scores were used in our analyses.
Of 433 samples, 101 (23.22%) had m6A regulatory factor mutations. From these, we identified three m6A subtypes, which correlated with different TIME phenotypes: immune rejection, immune infiltration, and immune deficiency. Tumors with low methyltransferase-like 3 () expression had increased infiltration of dendritic cells (DCs) in the TIME. Reduced expression also led to an overall increase in expression of major histocompatibility complex (MHC) molecules, costimulatory molecules, and adhesion molecules. The m6A subtypes were scored and analyzed for correlations. Patients with epithelial-mesenchymal transition (EMT) subtypes had lower m6A scores than the other three molecular subtypes. Survival analysis found that patients with low m6A scores had better overall survival [hazard ratio (HR) 1.6 (1.1-2.3)] and a 1.16 times better 5-year survival rate than patients with high m6A scores (56% 48%).
Our results demonstrated that three different m6A modification subtypes contribute to immune regulation in HCC and have potential as novel prognostic indicators and immune therapeutic targets.
N6-甲基腺苷（m6A）介导的核糖核酸（RNA）甲基化被认为是真核细胞中最重要且最丰富的表观遗传修饰，在肝细胞癌（HCC）的致癌作用和分子发病机制中起着至关重要的作用。然而，m6A调控与肿瘤免疫微环境（TIME）中免疫细胞浸润之间的关系尚未阐明。我们旨在研究m6A RNA基因调节因子在HCC免疫调节和预后中的作用。
使用癌症基因组图谱（TCGA）数据库，并基于差异基因表达对21种m6A调节因子进行无监督聚类。我们的分析中使用了基因集变异分析（GSVA）、单样本基因集富集分析（ssGSEA）、经验贝叶斯方法和m6A评分。
在433个样本中，101个（23.22%）存在m6A调节因子突变。从中，我们鉴定出三种m6A亚型，它们与不同的TIME表型相关：免疫排斥、免疫浸润和免疫缺陷。甲基转移酶样3（）表达低的肿瘤在TIME中树突状细胞（DC）浸润增加。表达降低还导致主要组织相容性复合体（MHC）分子、共刺激分子和粘附分子的表达总体增加。对m6A亚型进行评分并分析相关性。上皮-间质转化（EMT）亚型的患者m6A评分低于其他三种分子亚型。生存分析发现，m6A评分低的患者总生存期更好[风险比（HR）1.6（1.1 - 2.3）]，5年生存率比m6A评分高的患者高1.16倍（56%对vs 48%）。
我们的结果表明，三种不同的m6A修饰亚型有助于HCC的免疫调节，具有作为新型预后指标和免疫治疗靶点的潜力。
