Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis. Some E3 ubiquitin-protein ligases play essential roles in HCC development. We aimed to explore a hub E3 ubiquitin-protein ligase gene and verify its association with prognosis and immune cell infiltration in HCC. We identified cell division cycle 20 (CDC20) as a hub E3 ubiquitin-protein ligase in HCC by determining the intersecting genes in a protein-protein interaction (PPI) network of differentially expressed genes (DEGs) in HCC data from the International Cancer Genome Consortium (ICGC) and 919 E3 ubiquitin-protein ligase genes from the Integrated annotations for Ubiquitin and Ubiquitin-like Conjugation Database (IUUCD). DEGs and their correlations with clinicopathological features were explored in The Cancer Genome Atlas (TCGA), ICGC, and Gene Expression Omnibus (GEO) databases via the Wilcoxon signed-rank test. The prognostic value of CDC20 was illustrated by Kaplan-Meier (K-M) curves and Cox regression analyses. Subsequently, the correlation between CDC20 and immune infiltration was demonstrated via the Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). CDC20 expression was significantly higher in HCC than in normal tissues (all P < 0.05). K-M curves and Cox regression analyses showed that high CDC20 expression predicted a poor prognosis and might be an independent risk factor for HCC prognosis (P < 0.05). Additionally, the TIMER and GEPIA results indicated that CDC20 is correlated with the immune infiltration of CD8 + T cells, T cells (general), monocytes, and exhausted T cells. This research revealed the potential prognostic value of CDC20 in HCC and demonstrated that CDC20 might be an immune-associated therapeutic target in HCC because of its correlation with immune infiltration.
Background: Hepatocellular carcinoma (HCC) has become the third leading cause of death from cancer worldwide, and PI3K/AKT signaling pathway acts as the most common carcinogenic pathway in HCC. But few studies have reported the prognostic value of PI3K/AKT associated genes (PAGs) and their association with immune infiltration in HCC.Methods: The mRNA sequencing data and clinical information were gained from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) database. The 105 PAGs gene sets were from the Gene set enrichment analysis (GSEA) website. The biological processes of differently expressed PAGs were explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A four-gene prognostic signature (SFN, PRKAA2, PITX2 and CDK1) was built based on the multivariate analyses results. Its prognostic value was trained in TCGA database and tested in GEO database and ICGC database. The association between risk score and immune infiltration were explored by CIBERSORT method.Results: a total of nine differently expressed PAGs were identified. GO and KEGG revealed these genes were correlated with different carcinogenic pathways. The patients were divided into high-risk group and low-risk group according to the median risk score. The high-risk group had shorter survival time compared with the low-risk group in Kaplan-Meier (KM) curves. Receiver operating characteristic (ROC) curves showed the better prognostic value of risk score (ROC=0.736) compared with other clinicopathological characteristics (AUC ≤ 0.511). The consistent results were obtained in the GEO database and ICGC database. The nomogram predicted the 1-year, 3-year, and 5-year overall survival rates in HCC. The risk score was correlated with immune infiltration of monocytes and M0 macrophages, and the expression of immune checkpoints (PDCD1, CTLA4, TIM3 and TIGIT) were related to risk score. Conclusion: Our study established a novel four-gene prognostic signature by integrated bioinformatic analysis. It provided new insight into the immunotherapy targets and may direct the individualized treatment in HCC.
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