The Effect of m6A Methylation Regulatory Factors on the Malignant Progression and Clinical Prognosis of Hepatocellular Carcinoma

The modification level of the transcript N(6)-methyladenosine (m6A), dynamically regulated by methyltransferases, binding proteins and demethylases, is closely related to the occurrence, and progression of tumors. Here, 13 differentially expressed m6A methylation regulators were confirmed in 374 hepatocellular carcinoma (HCC) patients, among which RBM15, YTHDC1, YTHDF1, and YTHDF2 were significantly variant in different stages and grades. Further consensus clustering analysis identified two HCC subtypes (cluster1/2) in this cohort, finding an active role of the m6A methylation regulators in the malignant progression of HCC. Furthermore, GESA enrichment analysis showed that PPAR signaling pathway, and the pathways involved in retinol metabolism and peroxisome were related to tumor progression. Additionally, a 4-gene risk model (ROC = 0.729) that can be used as a prognostic marker and a predictor for clinicopathological characteristics of HCC was constructed via univariate and multivariate Cox regression analyses. Analysis on overall survival and disease-free survival demonstrated that METTL3 and YTHDF1 out of the four genes in the model could serve as independent prognostic factors for HCC. Overall, this study systematically investigated the effect of m6A methylation regulators on the malignant progression of HCC and proposed a 4-gene risk prediction model, laying a theoretical foundation for the further research on HCC prognosis.