Ann Hepatobiliary Pancreat Surg.  2022 Feb;26(1):58-68. 10.14701/ahbps.21-108.

Identification of key genes and carcinogenic pathways in hepatitis B virus-associated hepatocellular carcinoma through bioinformatics analysis

Affiliations
  • 1Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 2Department of Surgery, Jeonbuk National University Hospital, Jeonju, Korea

Abstract

Backgrounds/Aims
Mechanisms for the development of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected patients remain unclear. The aim of the present study was to identify genes and pathways involved in the development of HBV-associated HCC.
Methods
The GSE121248 gene dataset, which included 70 HCCs and 37 adjacent liver tissues, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in HCCs and adjacent liver tissues were identified. Gene ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analyses were then performed.
Results
Of 134 DEGs identified, 34 were up-regulated and 100 were down-regulated in HCCs. The 34 up-regulated DEGs were mainly involved in nuclear division, organelle fission, spindle and midbody formation, histone kinase activity, and p53 signaling pathway, whereas the 100 down-regulated DEGs were involved in steroid and hormone metabolism, collagen-coated extracellular matrix, oxidoreductase activity, and activity on paired donors, including incorporation or reduction of molecular oxygen, monooxygenase activity, and retinol metabolism. Analyses of protein-protein interaction networks with a high degree of connectivity identified significant modules containing 14 hub genes, including ANLN , ASPM , BUB1B , CCNB1, CDK1, CDKN3, ECT2 , HMMR , NEK2 , PBK , PRC1, RACGAP1, RRM2 , and TOP2A , which were mainly associated with nuclear division, organelle fission, spindle formation, protein serine/threonine kinase activity, p53 signaling pathway, and cell cycle.
Conclusions
This study identified key genes and carcinogenic pathways that play essential roles in the development of HBV-associated HCC. This may provide important information for the development of diagnostic and therapeutic targets for HCC.

Keyword

Carcinogenesis; Genes; Hepatitis B virus; Bioinformatics; Oncogenesis

Figure

  • Fig. 1 Volcano plot of differentially expressed genes identified in hepatocellular carcinoma (HCC) vs. adjacent normal liver tissues obtained from patients with hepatitis B virus-associated HCC. FDR, false discovery rate; FC, fold change.

  • Fig. 2 Heatmap of the top 100 differentially expressed genes (DEGs) with log2 FC > 2. Blue, down-regulated DEGs; red, up-regulated DEGs. FC, fold change.

  • Fig. 3 Gene ontology enrichment analysis of the 34 up-regulated differentially expressed genes with log2 FC > 2. FC, fold change; BP, biological process; CC, cellular component; MF, molecular function.

  • Fig. 4 Gene ontology enrichment analysis of the 100 down-regulated differentially expressed genes with log2 FC < -2. FC, fold change; BP, biological process; CC, cellular component; MF, molecular function.

  • Fig. 5 Enriched Kyoto Encyclopedia of Genes and Genome pathway analysis of the 134 differentially expressed genes.

  • Fig. 6 Overall protein-protein interaction network.

  • Fig. 7 Protein-protein interaction network of the top 14 hub genes with a high degree of connectivity.

  • Fig. 8 Enrichment analyses of the 14 hub genes in the most significantly enriched module. Results of gene ontology (A) and Kyoto Encyclopedia of Genes and Genome (B) enrichment analyses are shown.

  • Fig. 9 Statistical analysis of expression of the 14 hub genes in GSE121248. HCC, hepatocellular carcinoma.

  • Fig. 10 Expression levels of mRNAs encoded by the 14 hub genes based on TCGA database. (A–N) ANLN, ASPM, BUB1B, CCNB1, CDK1, CDKN3, ECT2, HMMR, NEK2, PBK, PRC1, RACGAP1, RRM2, and TOP2A, respectively. LIHC, liver hepatocellular carcinoma; T, tumor; N, normal. *p-value < 0.05 versus normal.

  • Fig. 11 Kaplan-Meier analysis of overall patient survival relative to the expression of the 14 hub genes based on the TCGA database. (A–N) ANLN, ASPM, BUB1B, CCNB1, CDK1, CDKN3, ECT2, HMMR, NEK2, PBK, PRC1, RACGAP1, RRM2, and TOP2A, respectively. T, tumor; N, normal. *p-value < 0.05 versus normal.


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