Integrated Bioinformatics Analysis Reveals Key Candidate Genes and Pathways Associated With Clinical Outcome in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) accounts for approximately 85–90% of all liver cancer cases and has poor relapse-free survival. There are many gene expression studies that have been performed to elucidate the genetic landscape and driver pathways leading to HCC. However, existing studies have been limited by the sample size and thus the pathogenesis of HCC is still unclear. In this study, we performed an integrated characterization using four independent datasets including 320 HCC samples and 270 normal liver tissues to identify the candidate genes and pathways in the progression of HCC. A total of 89 consistent differentially expression genes (DEGs) were identified. Gene-set enrichment analysis revealed that these genes were significantly enriched for cellular response to zinc ion in biological process group, collagen trimer in the cellular component group, extracellular matrix (ECM) structural constituent conferring tensile strength in the molecular function group, protein digestion and absorption, mineral absorption and ECM-receptor interaction. Network system biology based on the protein–protein interaction (PPI) network was also performed to identify the most connected and important genes based on our DEGs. The top five hub genes including osteopontin ( SPP1 ), Collagen alpha-2(I) chain ( COL1A2 ), Insulin-like growth factor I ( IGF1 ), lipoprotein A ( LPA ), and Galectin-3 ( LGALS3 ) were identified. Western blot and immunohistochemistry analysis were employed to verify the differential protein expression of hub genes in HCC patients. More importantly, we identified that these five hub genes were significantly associated with poor disease-free survival and overall survival. In summary, we have identified a potential clinical significance of these genes as prognostic biomarkers for HCC patients who would benefit from experimental approaches to obtain optimal outcome.

Key Members of the CmPn as Biomarkers Distinguish Histological and Immune Subtypes of Hepatic Cancers

“…Our results illustrated that up-regulated DEGs in HCC primary tumors significantly affected cell cycle regulation, protein binding, ATP-dependent activity, histone phosphorylation and cancer signaling pathways including DNA replication, spliceosomes/lysosomes, pancreatic cancer, and hormone signaling pathways including oocyte meiosis and progesterone-mediated oocyte maturation ( Figure 2 (C-2), left panels and Supplementary Table S2A ). Down-regulated DEGs significantly affected actin filament-based processes, protein digestion and absorption (also seen in a recent analysis of HCC tumors using four separate independent databases) [ 44 ], and pancreatic secretion ( Figure 2 (C-2), right panels and Supplementary Table S2A ). Interestingly, dysfunction of pancreatic secretion has been reported as a metabolic change resulting from liver cancer [ 45 , 46 ].…”

Network Pharmacology Integrated with Transcriptomics Deciphered the Potential Mechanism of Codonopsis pilosula against Hepatocellular Carcinoma

“…HMOX1 was significantly enriched in the mineral absorption pathway, and the biological processes of its enrichment are primarily related to the metabolism of metal ions (Figures 2(a) and 2(b) ). A study reported that there is a remarkable correlation between mineral absorption pathways and HCC development [ 35 ]. Furthermore, metal ion metabolism plays an essential role in the progression and treatment of HCC [ 36 , 37 ].…”

Revealing the potential mechanism of Astragalus membranaceus improving prognosis of hepatocellular carcinoma by combining transcriptomics and network pharmacology

“…2 A, B). A study revealed that Mineral absorption is significantly associated with the occurrence and development of HCC [ 29 ]. In addition, the metabolism of metal ions plays important roles in HCC progression and therapy [ 30 , 31 ].…”