Identification of Key N7-Methylguanosine-Associated Factors in NASH-Related HCC

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been the common causes of hepatocellular carcinoma (HCC). Methyltransferase-like 1 (METTL1) is a key factor regulating N⁷-methylguanosine (m7G) methylation. This study aimed to determine the specific roles of METTL1 and m7G in NASH-related HCC, and identify potential miRNA/mRNA axis regulated by METTL1 and m7G.

Methods: The expression of METTL1 was determined in microarray GSE83596, the Cancer Genome Atlas (TCGA) database, and Human Protein Atlas (HPA) database. Microarray GSE52821 was downloaded for identifying key m7G-regulated miRNAs. TargetScan was introduced to predict target genes of miR-760. The database for annotation, visualization, and integrated discovery database (DAVID) was used for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. Protein-protein interaction (PPI) analysis was used to found hub genes. Using R, we conducted a prognosis model for HCC. Drug Pair Seeker (DPS) was employed to identify potential drug combinations against NASH-related HCC.

Results: METTL1 was upregulated in NASH-related HCC, it was also related with stemness. miR-760 was identified as the key downstream miRNA of METTL1, it may be regulated by m7G methylation. 52 downregulated genes were predicted as potential target genes of METTL1/miR-760 axis. GO and KEGG analysis showed that these genes were enriched in multiple key pathways such as mitogen-activated protein kinase (MAPK) pathway and linked to the development of HCC. A prognostic signature was conducted based on METTL1 and FGF1. Finally, drug combinations were predicted, a histone deacetylase (HDAC) inhibitor, trichostatin is a potential therapeutic strategy against NASH-related HCC.

Conclusions: In the study, METTL1/miR-760 was identified as a key m7G-related axis in NASH-related HCC, targeting this axis may be a novel strategy against NASH-related HCC.