Bioinformatics Analysis based on Multiple Databases Identifies Hub Genes Associated with Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is the most common liver cancer and the mechanisms of hepatocarcinogenesis remain elusive.

Objective: This study aims to mine hub genes associated with HCC using multiple databases.

Methods: Data sets GSE45267, GSE60502, GSE74656 were downloaded from GEO database. Differentially expressed genes (DEGs) between HCC and control in each set were identified by limma software. The GO term and KEGG pathway enrichment of the DEGs aggregated in the datasets (aggregated DEGs) were analyzed using DAVID and KOBAS 3.0 databases. Protein-protein interaction (PPI) network of the aggregated DEGs was constructed using STRING database. GSEA software was used to verify the biological process. Association between hub genes and HCC prognosis was analyzed using patients' information from TCGA database by survminer R package.

Results: From GSE45267, GSE60502 and GSE74656, 7583, 2349, and 553 DEGs were identified respectively. A total of 221 aggregated DEGs, which were mainly enriched in 109 GO terms and 29 KEGG pathways, were identified. Cell cycle phase, mitotic cell cycle, cell division, nuclear division and mitosis were the most significant GO terms. Metabolic pathways, cell cycle, chemical carcinogenesis, retinol metabolism and fatty acid degradation were the main KEGG pathways. Nine hub genes (TOP2A, NDC80, CDK1, CCNB1, KIF11, BUB1, CCNB2, CCNA2 and TTK) were selected by PPI network and all of them were associated with prognosis of HCC patients.

Conclusion: TOP2A, NDC80, CDK1, CCNB1, KIF11, BUB1, CCNB2, CCNA2 and TTK were hub genes in HCC, which may be potential biomarkers of HCC and targets of HCC therapy.

Keywords: Hepatocellular carcinoma; bioinformatics; database; differentially expressed gene; hub gene; mRNA.

Fig. (1)

The volcano of GSE45267 DEGs (A), GSE60502 DEGs (B) and GSE74656 DEGs (C).

Fig. (2)

The heatmap of the top 20 up-regulated and down-regulated DEGs aggregated in GSE45267, GSE60502 and GSE74656. The values in each box represents logFC values, logFC > 0 were up-regulated genes, and logFC < 0 were down-regulated genes.

Fig. (3)

The number of genes enriched in the top five biological process (BP), molecular function (MF) and cellular component (CC) terms (A) and the circle diagram of the top five GO enriched biological process (BP), molecular function (MF) and cellular component (CC) terms (B).

Fig. (4)

The relationship between the enriched KEGG pathways and the DEGs aggregated in GSE45267, GSE60502 and GSE74656 (A) and the protein-protein interaction (PPI) network of the these DEGs (B). Yellow (gray) represents KEGG pathways ID; Red (deep color) nodes indicate up-regulated DEGs; Green (light dark) nodes represent down-regulated DEGs; The lines between nodes represent the interactions between proteins.

Fig. (5)

HCC enrichment gene sets by GSEA database. (A) Mitotic spindle; (B) G2M checkpoint; (C) E2F targets; (D) Spermatogenesis; (E) DNA repair.

Fig. (6)

Associations of the mRNA expression levels of hub genes with the overall survival of HCC patients. (A) TOP2A; (B) NDC80; (C) CDK1; (D) CCNB1; (E) KIF11; (F) BUB1; (G) CCNB2; (H) CCNA2; (I) TTK. The area around each survival curve represents the confidence interval of the survival curve.