Abstract
Objectives: To identify the prognostic value of aberrantly methylated differentially expressed genes (DEGs) in hepatocellular carcinoma (HCC) and to explore the underlying mechanisms of tumorigenesis.Methods: Gene expression profiles (GSE65372 and GSE37988) were analyzed using GEO2R to obtain aberrantly methylated DEGs. Functional enrichment analysis of screened genes was performed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Cytoscape software was used to analyze the PPI network and to select hub genes. Transcriptional and proteinic expression data of hub genes were obtained through UALCAN and the Human Protein Reference Database. Finally, we analyzed the prognostic value of hub genes with the Kaplan–Meier Plotter and MethSurv database.Results: In total, 24 up-hypomethylated oncogenes and 37 down-hypermethylated tumor suppressor genes (TSGs) were identified, and 8 hub genes, including 4 up-hypomethylated oncogenes (CDC5L, MERTK, RHOA and YBX1) and 4 down-hypermethylated TSGs (BCR, DFFA, SCUBE2 and TP63), were selected by PPI. Higher expression of methylated CDC5L-cg05671347, MERTK-cg08279316, RHOA-cg05657651 and YBX1-cg16306148, and lower expression of methylated BCR-cg25410636, DFFA-cg20696875, SCUBE2-cg19000089 and TP63-cg06520450, were associated with better overall survival (OS) in HCC patients. Multivariate analysis also showed they were independent prognostic factors for OS of HCC patients.Conclusions: In summary, different expression of methylated genes above mentioned were associated with better prognosis in HCC patients. Altering the methylation status of these genes may be a therapeutic target for HCC, but it should be further evaluated in clinical studies.
Highlights
Hepatocellular carcinoma (HCC) is a global malignant disease, ranking third in cancer-related mortality and causing more than 600,000 deaths each year [1,2]
We found that mRNA expression levels of all the hypermethylated down-regulated tumor suppressor genes (TSGs) (BCR, DFFA, SCUBE2, TP63) were not associated with overall survival (OS) (BCR, HR = 0.81, 95% CI: 0.57–1.16, P=0.25; DFFA, HR = 1.29, 95% CI: 0.91–1.83, P=0.15; SCUBE2, HR = 0.74, 95% CI: 0.52–1.04, P=0.084; TP63, HR = 0.75, 95% CI: 0.52–1.09, P=0.13) (Figure 6A1,B1,C1,D1)
Our results revealed that HCC patients with hypermethylation of these four genes had better OS (BCR-cg25410636, HR = 2.309, 95% CI: 1.51–3.529, P=3.2E-05; DFFA-cg20696875, HR = 2.102, 95% CI: 1.315–3.357, P=0.00078; SCUBE2-cg19000089, HR = 1.495, 95% CI: 1.048–2.134, P=0.025; TP63-cg06520450, HR = 2.00, 95% CI: 1.415–2.826, P=0.00013) (Figure 6A2,B2,C2,D2)
Summary
Hepatocellular carcinoma (HCC) is a global malignant disease, ranking third in cancer-related mortality and causing more than 600,000 deaths each year [1,2]. The mortality caused by HCC has increased significantly in the past 20 years, and the deaths in the Asia-Pacific region account for the vast majority in the world [3]. A number of factors can cause HCC, such as chronic viral infections (hepatitis B virus and hepatitis C virus), the deposition of iron and copper, fat accumulation, and so on [5]. It has been found that the occurrence and development of HCC is a multistage process that is caused by the inactivation of tumor suppressor genes (TSGs) or the activation of proto-oncogenes by genetic alterations and epigenetic abnormalities. As an important part of epigenetic regulation, DNA methylation has been found to play a pivotal role in tumorigenesis [6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
