N6-methyladenosine (m6A)-mediated messenger RNA signatures and the tumor immune microenvironment can predict the prognosis of hepatocellular carcinoma

Background: 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. Methods: 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. Results: 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 (METTL3) expression had increased infiltration of dendritic cells (DCs) in the TIME. Reduced METTL3 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% vs. 48%). Conclusions: 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.

Automated summary

This study identified three different m6A modification subtypes in hepatocellular carcinoma (HCC) patients, which were associated with different immune cell infiltration phenotypes in the tumor immune microenvironment (TIME). Low expression of METTL3 was correlated with increased infiltration of dendritic cells (DCs) in the TIME, and patients with low m6A scores had better overall survival and 5-year survival rates.