Abstract
IntroductionHepatocellular carcinoma (HCC) is the most common primary liver cancer with a low 5-year survival rate. The heterogeneity of HCC makes monotherapy unlikely. The development of diagnostic programs and new treatments targeting common genetic events in the carcinogenic process are providing further insights into the management of HCC. The aim of this study was firstly to validate key genes that are involved in promoting HCC development and as biomarkers for early diagnosis and, secondly, to define their links with antitumor immunity including inhibitory checkpoints.MethodsMultiple databases including Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan–Meier Plotter, UALCAN, and Oncomine were used for target gene screening and establishment of a co-expression network. Clinical data and RNAseq of 367 HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. The diagnostic and prognostic value of screened genes were tested by receiver operating characteristic (ROC) curve and correlation analysis. The links with the key genes in HCC and antitumor immunity were defined using both blood and liver tissue collected prospectively from HCC patients in our center.ResultsUpregulation of CCNB1, CDC20, and CENPF was commonly observed in HCC and are involved in the p53 signal pathway. The hepatic mRNA expression levels of these three genes were strongly associated with patients’ prognosis and expressed high value of area under the ROC curve (AUC). Further analysis revealed that these three genes were positively correlated with the gene expression levels of IFN-γ, TNF-α, and IL-17 in peripheral blood. In addition, the expression of CENPF showed positive correlation with the percentage of CD8pos T cells and negative correlation with the percentage of CD4pos T cells in the peripheral blood. In the HCC microenvironment, the transcript levels of these three genes and inhibitory checkpoint molecules including PD-1, CTLA-4, and TIM-3 were positively correlated.ConclusionThe upregulation of CCNB1, CDC20, and CENPF genes was a common event in hepatocarcinogenesis. Expression levels of CCNB1, CDC20, and CENPF showed potential for early diagnosis and prediction of prognosis in HCC patients. There is a close association between three genes and Th1/Th17 cytokines as well as the count of CD4pos and CD8pos T cells. The positive correlation between the three genes and inhibitory checkpoint genes, PD-1, CTLA-4, and TIM-3, indicates that these genes are linked with weakened antitumor immunity in HCC. Our findings may provide further insights into developing novel therapies for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a low 5-year survival rate
We aim to identify the key genes in the HCC environment, which are associated with the antitumor immunity including adaptive immunity, such as Th1/Th17, and immunoregulation with inhibitory checkpoints
A group of 12 genes were identified to be associated with poor prognosis and were significantly upregulated in HCC cancer tissue (Figure 1D)
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a low 5-year survival rate. The development of diagnostic programs and new treatments targeting common genetic events in the carcinogenic process are providing further insights into the management of HCC. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers and is a global health problem [1]. It is ranked as the fourth leading cause of cancer-related death in the world with a growing incidence [2]. With the advent of deep sequencing technology, increasing information regarding genetic mutations in HCC has identified several important pathways related to cancer formation [4,5,6,7]. Research on p53 gene mutations has provided models for developing clinical treatments for HCC
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