The methylation at position N6 of adenine is called N6-methyladenosine (m6A). This transcriptional RNA modification exerts a very active and important role in RNA metabolism and in other biological processes. However, the activities of m6A associated with malignant liver hepatocellular carcinoma (LIHC) are unknown and are worthy of study.

Using the data of University of California, Santa Cruz (UCSC), the expression of M6A methylation regulators in pan-cancer was evaluated as a screening approach to identify the association of M6A gene expression and 18 cancer types, with a specific focus on LIHC. LIHC datasets of The Cancer Genome Atlas (TCGA) were used to explore the expression of M6A methylation regulators and their clinical significance. Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were used to explore the underlying mechanism based on the evaluation of aberrant expression of m6A methylation regulators.

The expression alterations of m6A-related genes varied across cancer types. In LIHC, we found that in univariate Cox regression analysis, up-regulated m6A modification regulators were associated with worse prognosis, except for ZC3H13. Kaplan–Meier survival curve analysis indicated that higher expression of methyltransferase-like protein 3 (METTL3) and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) genes related to the worse survival rate defined by disease-related survival (DSS), overall survival (OS), progression-free interval (PFI), and disease-free interval (DFI). Up-regulated m6A methylation regulator group (cluster2) obtained by consensus clustering was associated with poor prognosis. A six-gene prognostic signature established using the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm performed better in the early (I + II; T1 + T2) stages than in the late (III + IV; T3 + T4) stages of LIHC. Using the gene signature, we constructed a risk score and found that it was an independent predictive factor for prognosis. Using GSEA, we identified processes involved in DNA damage repair and several biological processes associated with malignant tumors that were closely related to the high-risk group.

In summary, our study identified several genes associated with m6A in LIHC, especially METTL3 and YTHDF1, and confirmed that a risk signature comprised of m6A-related genes was able to forecast prognosis.

腺嘌呤 N6 位的甲基化称为 N6-甲基腺苷 (m6A)。这种转录 RNA 修饰在 RNA 代谢和其他生物过程中发挥着非常活跃和重要的作用。然而，与恶性肝细胞癌（LIHC）相关的m6A的活性尚不清楚，值得研究。

使用加州大学圣克鲁斯分校 (UCSC) 的数据，评估泛癌中 M6A 甲基化调节因子的表达作为一种筛选方法，以确定 M6A 基因表达与 18 种癌症类型的关联，特别关注 LIHC。癌症基因组图谱 (TCGA) 的 LIHC 数据集用于探索 M6A 甲基化调节因子的表达及其临床意义。基于对 m6A 甲基化调节因子异常表达的评估，使用基因本体 (GO) 分析和基因集富集分析 (GSEA) 来探索潜在机制。

m6A 相关基因的表达改变因癌症类型而异。在 LIHC 中，我们发现在单变量 Cox 回归分析中，除 ZC3H13 外，上调的 m6A 修饰调节因子与较差的预后相关。Kaplan-Meier 生存曲线分析表明，甲基转移酶样蛋白 3 (METTL3) 和 YTH N6-甲基腺苷 RNA 结合蛋白 1 (YTHDF1) 基因的高表达与疾病相关生存 (DSS) 定义的较差生存率、总生存率有关(OS)、无进展间期 (PFI) 和无病间期 (DFI)。通过共识聚类获得的上调 m6A 甲基化调节组 (cluster2) 与预后不良有关。使用最小绝对收缩和选择算子 (LASSO) Cox 回归算法建立的六基因预后特征在早期 (I + II; T1 + T2) 阶段比在晚期 (III + IV; T3 + T4) 阶段表现更好LIHC 的。使用基因特征，我们构建了风险评分，发现它是预后的独立预测因素。使用 GSEA，我们确定了涉及 DNA 损伤修复的过程以及与高危人群密切相关的恶性肿瘤相关的几个生物学过程。

总之，我们的研究确定了 LIHC 中与 m6A 相关的几个基因，尤其是 METTL3 和 YTHDF1，并证实了由 m6A 相关基因组成的风险特征能够预测预后。