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Identification of Biomarkers Related to Immune Cell Infiltration in Hepatocellular Carcinoma Using Gene Co-Expression Network.

ABSTRACT: Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. Due to the lack of effective biomarkers and its complex immune microenvironment, the effects of current HCC therapies are not ideal. In this study, we used the GSE57957 microarray data from Gene Expression Omnibus database to construct a co-expression network. The weighted gene co-expression network analysis and CIBERSORT algorithm, which quantifies cellular composition of immune cells, were used to identify modules related to immune cells. Four hub genes (EFTUD2, GAPDH, NOP56, PA2G4) were identified by co-expression network and protein-protein interactions network analysis. We examined these genes in TCGA database, and found that the four hub genes were highly expressed in tumor tissues in multiple HCC groups, and the expression levels were significantly correlated with patient survival time, pathological stage and tumor progression. On the other hand, methylation analysis showed that the up-regulation of EFTUD2, GAPDH, NOP56 might be due to the hypomethylation status of their promoters. Next, we investigated the correlations between the expression levels of four hub genes and tumor immune infiltration using Tumor Immune Estimation Resource (TIMER). Gene set variation analysis suggested that the four hub genes were associated with numerous pathways that affect tumor progression or immune microenvironment. Overall, our results showed that the four hub genes were closely related to tumor prognosis, and may serve as targets for treatment and diagnosis of HCC. In addition, the associations between these genes and immune infiltration enhanced our understanding of tumor immune environment and provided new directions for the development of drugs and the monitoring of tumor immune status.

SUBMITTER: Zhou W

PROVIDER: S-EPMC8262220 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The dreadful prognosis of hepatocellular carcinoma (HCC) is primarily due to the low early diagnosis rate, rapid progression, and high recurrence rate. Valuable prognostic biomarkers are urgently needed for HCC. In this study, microarray data were downloaded from GSE14520, GSE22058, International Cancer Genome Consortium (ICGC), and The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were identified among GSE14520, GSE22058, and ICGC databases. Weighted gene co-expression network analysis (WGCNA) was used to establish gene co-expression modules of DEGs, and genes of key modules were examined to identify hub genes using univariate Cox regression in the ICGC cohort. Expression levels and time-dependent receiver operating characteristic (ROC) and area under the curve (AUC) were determined to estimate the prognostic competence of the hub genes. These hub genes were also validated in the Gene Expression Profiling Interactive Analysis (GEPIA) and TCGA databases. TIMER algorithm and GSCALite database were applied to analyze the association of the hub genes with immunocytotic infiltration and their pathway enrichment. Altogether, 276 DEGs were identified and WGCNA described a unique and significantly DEGs-associated co-expression module containing 148 genes, with 10 hub genes selected by univariate Cox regression in the ICGC cohort (BIRC5, FOXM1, CENPA, KIF4A, DTYMK, PRC1, IGF2BP3, KIF2C, TRIP13, and TPX2). Most of the genes were validated in the GEPIA databases, except IGF2BP3. The results of multivariate Cox regression analysis indicated that the abovementioned hub genes are all independent predictors of HCC. The 10 genes were also confirmed to be associated with immune cell infiltration using the TIMER algorithm. Moreover, four-gene signature was developed, including BIRC5, CENPA, FOXM1, DTYMK. These hub genes and the model demonstrated a strong prognostic capability and are likely to be a therapeutic target for HCC. Moreover, the association of these genes with immune cell infiltration improves our understanding of the occurrence and development of HCC.

Project description:Hepatocellular carcinoma (HCC) has a high degree of malignancy and a poor prognosis. Immune infiltration-related genes have shown good predictive value in the prognosis of many solid tumours. In this study, we established and verified prognostic biomarkers consisting of immune infiltration-related genes in HCC. Gene expression data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Differential gene expression analysis, univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression algorithm were used to screen prognostic immune infiltration-related genes and to construct a risk scoring model. Kaplan-Meier (KM) survival plots and receiver operating characteristic (ROC) curve analysis were used to evaluate the prognostic performance of the risk scoring model in the TCGA-HCC cohort. In addition, a nomogram model with a risk score was established, and its predictive performance was verified by ROC analysis and calibration plot analysis in the TCGA-HCC cohort. Gene set enrichment analysis (GSEA) identified pathways and biological processes that may be enriched in the high-risk group. Finally, immune infiltration analysis was used to explore the characteristics of the tumour microenvironment related to the risk score. We identified 17 immune infiltration-related genes with prognostic value and constructed a risk scoring model. ROC analysis showed that the risk scoring model can accurately predict the 1-year, 3-year, and 5-year overall survival (OS) of HCC patients in the TCGA-HCC cohort. KM analysis showed that the OS of the high-risk group was significantly lower than that of the low-risk group (P < 0.001). The nomogram model effectively predicted the OS of HCC patients in the TCGA-HCC cohort. GSEA indicated that the immune infiltration-related genes may be involved in biological processes such as amino acid and lipid metabolism, matrisome and small molecule transportation, immune system regulation, and hepatitis virus infection. Immune infiltration analysis showed that the level of immune cell infiltration in the high-risk group was low, and the risk score was negatively correlated with infiltrating immune cells. Our prognostic model based on immune infiltration-related genes in HCC could help the prognostic assessment of HCC patients and provide potential targets for HCC inhibition.

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Identification of Biomarkers Related to Immune Cell Infiltration in Hepatocellular Carcinoma Using Gene Co-Expression Network.

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