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.

Bioinformatics Analysis Using ATAC-seq and RNA-seq for the Identification of 15 Gene Signatures Associated With the Prediction of Prognosis in Hepatocellular Carcinoma

“…Another study reported that interventional treatment of primary liver cancer can reduce serum HTATIP2/TIP30 and B7-H4 levels, improve liver function and quality of life and prolong the survival times of patients (20). A number of studies reported that SEMA3F, UCK2, NOL10, RAP2A, ZIC2 and SAC3D1 are associated with prognosis and tumour immune infiltration in hepatocellular carcinomas (21)(22)(23)(24)(25). In addition, KIF18A was reported to be associated with tumour immune cell infiltration in adrenocortical carcinomas (26).…”

The roles of NOP56 in cancer and SCA36

“…Moreover, NOP56 is significantly correlated with the survival prognosis, pathological stage, immune infiltration, and tumor progression of patients with hepatocellular carcinoma, and may be used as a target for the diagnosis and treatment of hepatocellular carcinoma in the future. The methylation analysis indicated that the hypomethylation of the NOP56 promoter may lead to the overexpression of NOP56, which proved that expression of NOP56 may be a potential biomarker of hepatocellular carcinoma (66,67). In hepatocellular carcinoma, NOP56 is considered as a potential immune marker associated with HBV virus, which can be processed and presented by antigenpresenting cells (APCs) to induce immune responses.…”