The comprehensive expression and functional analysis of m6A modification “readers” in hepatocellular carcinoma

Abstract

N6-methyladenosine (m6A) modification regulators are essential for the diagnosis and treatment of various cancers. However, the comprehensive analysis about roles of m6A “readers” in hepatocellular carcinoma (HCC) remains unclear. UALCAN, GEPIA2, HPA, Kaplan Meier plotter, cBioPortal, STRING WebGestalt, Metascape and TIMER 2.0 database and Cytoscape software were used to comprehensively analyze the bioinformatic data. We found that m6A “readers” were upregulated at the mRNA level and protein level in HCC patients. Highly expressed YTHDF1, IGF2BP3 and NKAP were positively correlated with advanced HCC stage and had a poor prognosis in OS and PFS. The gene alterations of m6A “readers” happened frequently, and YTHDF3 had the highest mutation rate. The function of m6A “readers” on HCC may be closely correlated with splicing related proteins (including HNRNP family, SNRP family, and SR family), metabolic process, protein binding and RNA splicing related signaling pathways. Moreover, although the correlation of YTHDF3 and CD8+ T cell infiltration, and the correlation of IGF2BP3 and infiltration of mast cells and CAF are negative, most m6A “readers” had a positive correlation with immune cells (including CD8+ T cell, CD4+ T cell, Tregs, B cell, neutrophil, monocyte, macrophage, myeloid dendritic cell, nature killer cell, mast cell, and CAF). Macrophages, CD4+ T cell, Treg, B cell, monocyte, and myeloid dendritic cell had a positively strong correlation (Rho>0.4) with most m6A “readers” (such as YTHDC1, YTHDC2, YTHDF1, IGF2BP3, HNRNPA2B1 and HNRNPC). In conclusion, by comprehensive analysis of m6A “readers”, we found that they were involved in the prognosis of HCC, and m6A “readers” might regulate the development and progression of HCC by participating in some metabolism-related and RNA splicing-related signaling pathways as well as immune cell infiltration.