Combined screening analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma

Jisen Cao; Ruiqiang Zhang; Ye Zhang; Yijun Wang

doi:10.21037/jgo-21-866

Combined screening analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma

J Gastrointest Oncol. 2022 Feb;13(1):311-325. doi: 10.21037/jgo-21-866.

Authors

Jisen Cao^#¹, Ruiqiang Zhang^#², Ye Zhang¹, Yijun Wang¹

Affiliations

¹ Department of Hepatobiliary Surgery, The Third Central Hospital of Tianjin, Tianjin, China.
² Department of Orthopedics, General Hospital of Tianjin Medical University, Tianjin, China.

^# Contributed equally.

Abstract

Background: Methylation plays an important role in hepatocellular carcinoma (HCC) by altering the expression of key genes. The aim of this study was to screen the aberrantly methylated-differentially expressed genes (DEGs) in HCC and elucidate their underlying molecular mechanism.

Methods: Gene expression microarrays (GSE101685) and gene methylation microarrays (GSE44909) were selected. DEGs and differentially methylated genes (DMGs) were screened. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the Database for Annotation, Visualization, and Integrated discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to analyze the functional protein-protein interaction (PPI) network. Molecular Complex Detection (MCODE) analysis was performed using the Cytoscape software. Hub genes were verified in The Cancer Genome Atlas (TCGA) database.

Results: A total of 80 hypomethylation-high expression genes (Hypo-HGs) were identified. Pathway enrichment analysis showed DNA replication, cell cycle, viral carcinogenesis, and the spliceosome. The top 5 hub genes were minichromosome maintenance complex component 3 (MCM3), checkpoint kinase 1 (CHEK1), kinesin family member 11 (KIF11), PDZ binding kinase (PBK), and Rac GTPase activating protein 1 (RACGAP1). In addition, 189 hypermethylation-low expression genes (Hyper-LGs) were identified. Pathway enrichment analysis indicated enrichment in metabolic pathways, drug metabolism-other enzymes, and chemical carcinogenesis. The top 5 hub genes were leukocyte immunoglobulin like receptor B2 (LILRB2), formyl peptide receptor 1 (FPR1), S100 calcium binding protein A9 (S100A9), S100 calcium binding protein A8 (S100A8), and myeloid cell nuclear differentiation antigen (MNDA). The methylation status and mRNA expression of MCM3, CHEK1, KIF11, PBK, and S100A9 were consistent in the TCGA database and significantly correlated with the prognosis of patients.

Conclusions: Combined screening of aberrantly methylated-DEGs based on bioinformatic analysis may provide new clues for elucidating the epigenetic mechanism in HCC. Hub genes, including MCM3, CHEK1, KIF11, PBK, and S100A9, may serve as biomarkers for the precise diagnosis of HCC.

Keywords: Methylation; bioinformatics; gene expression; hepatocellular carcinoma (HCC).