Aberrant DNA methylation leads to altered gene expression, resulting in cancerous features. Numerous tumor suppressor genes are silenced by DNA methylation during hepatocarcinogenesis. Promoter CpG island hypermethylation is an important mechanism for inactivating tumor suppressor genes in hepatocellular carcinoma (HCC). Hypermethylation of CpG islands in the p16 (INK4a) and p15 (INK4b) promoters may increase the risk of developing HCC, particularly hepatitis B virus-related HCC. Environmental factors can lead to geographic variations in the methylation status of CpG islands. Aberrant DNA methylation of CpG islands is catalyzed by DNA methyltransferases (DNMTs). Thus, abnormal variations of DNMTs can contribute to hepatocarcinogenesis. In hepatitis-related HCC, microRNAs participate in hepatocarcinogenesis by directly targeting DNMTs, during which hepatitis B virus X acts as a regulator. DNA methylation may also contribute to HCC tumorigenesis by regulating the cell cycle. Based on the importance of DNA methylation in tumor suppression of HCC, certain DNA methylations may predict the risk of tumor development, tumor staging, patient survival and HCC recurrence.

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Aberrant DNA methylation in hepatocellular carcinoma tumor suppression (Review)

Objective: To quantitatively investigate the effect of GSTP1 hypermethylation on hepatocellular carcinoma (HCC) using a meta-analysis of available case–control studies. Materials and Methods: Previous studies have primarily evaluated the incidence of GSTP1 hypermethylation in HCC and corresponding control groups, and compared the incidence of GSTP1 hypermethylation in tumor tissues, pericancer liver tissues, normal liver issues, and nontumor liver tissues with that in other diseases. Data regarding publication information, study characteristics, and incidence of GSTP1 hypermethylation in both groups were collected from these studies and summarized. Eleven studies, including 546 cases of HCC and 575 nontumor cases, were identified for meta-analysis. Results: Statistically significant odds ratios (ORs) of GSTP1 hypermethylation were obtained from tumor tissues and nontumorous liver tissues of HCC patients (OR 2.63, 95% confidence interval [CI]: 1.77–3.89%, P Conclusions: The results of this meta-analysis suggest that GSTP1 hypermethylation induces the inactivation of GSTP1 gene, plays an important role in hepatocarcinogenesis, and is associated with an increased risk of HCC.

Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: A meta-analysis.

Methylation and liver cancer

Background: Aberrant methylation and histone deacetylation of tumor suppressor genes (TSGs) are the most epigenetic alterations involving in tumorigenesis. Overexpression of DNA methyltransferases (DNMTs) and histone deacetylase 1 (HDAC1) have been reported in several cancers. The reversion of hypermethylation and deacetylation by epi-drugs such as 5-aza-2'-deoxycytidine (5-AZA-CdR) and vorinostat (SAHA) can restore normal expression of TSGs. Previously, we reported that 5-AZA-CdR and valproic acid (VPA) can inhibit DNMT1 in hepatocellular carcinoma (HCC). The aim of this study was to investigate the effect of 5-AZA-CdR in combination to and in comparison with SAHA on DNMT1, DNMT3a, DNMT3b, histone deacetylase 1 (HDAC1), glutathione S-transferase 1 (GSTP1) and suppressor of cytokine signaling 1 (SOCS1) genes expression, cell growth inhibition and apoptotic induction in hepatocellular LCL-PI 11 cell line. Materials and Methods: The cells were treated with 5-AZA-CdR and SAHA and then MTT assay, cell apoptosis assay and Real-time quantitative RT-PCR (qRT-PCR) were done. Results: Both agents indicated significant inhibitory and apoptotic effect (P< 0.001). The apoptotic effect of SAHA was more than that of 5-Aza-CdR. The result of qRT-PCR indicated that 5-Aza-CdR decreased DNMT1, DNMT3a, DNMT3b and increased GSTP1and SOCS1 genes expression and SAHA decreased HDAC1 and increased GSTP1 and SOCS1 genes expression significantly. Maximal apoptosis and genes expression were seen with combined treatment. Conclusion: 5-AZA-CdR and SAHA down-regulated DNMT1, DNMT3a, DNMT3b, and HDAC1 and up-regulated GSTP1 and SOCS1 gene expression by which inhibited cell viability and induced apoptosis, suggesting that they could be used in the treatment of HCC.

The Effect of 5-Aza-2'-Deoxycytidine in Combination to and in Comparison with Vorinostat on DNA Methyltransferases, Histone Deacetylase 1, Glutathione S-Transferase 1 and Suppressor of Cytokine Signaling 1 Genes Expression, Cell Growth Inhibition and Apoptotic Induction in Hepatocellular LCL-PI 11 Cell Line.

Purpose We conducted this meta-analysis of published case-control studies aiming to evaluate the relationship between abnormal suppression of cytokine signaling-1 (SOCS-1) promoter methylation and the risk of hepatocellular carcinoma (HCC). Methods Relevant studies were retrieved from PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and China Biological Medicine (CBM) databases without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. We calculated odds ratio (OR) and its 95 % confidence interval (95% CI) to estimate the correlations. Results Sixteen case-control studies with a total of 941 HCC patients and 114 individuals with benign liver diseases met our inclusion criteria. Our results demonstrated that the frequency of SOCS-1 promoter methylation in cancer tissues was significantly higher than in adjacent non-tumorous tissues and benign tissues (cancer tissue vs adjacent tissue: OR=3.05, 95%CI 1.62-5.77, p=0.001; cancer tissue vs benign tissue: OR=11.55, 95%CI 5.93-22.49, p=0.000). Subgroup analyses by ethnicity, detecting method and sample size also suggested that abnormal SOCS-1 promoter methylation was correlated to the risk of HCC in the majority of these subgroups. Conclusion Our findings provide empirical evidence that abnormal SOCS-1 promoter methylation may contribute to the pathogenesis of HCC. Thus, detection of SOCS-1 promoter methylation may be a valuable diagnostic biomarker for HCC.

Aberrant promoter methylation of SOCS-1 gene may contribute to the pathogenesis of hepatocellular carcinoma: a meta-analysis.

Objective To investigate the methylation frequencies of multiple tumor suppressor genes （TSGs） in hepatoeellular carcinoma （HCC） and the clinical implication of aberrant DNA methylation in molecular carcinogenesis of HCC. Methods Sixty samples of HCC and the paired adjacent liver tissue, 16 samples from post-hepatitis cirrhotic livers, 5 from livers with chronic hepatitis and 5 from normal livers were collected. Eight TSGs frequently silenced by hypermethylation of their promoters in various types of digestive tumors were selected, including APC, RASSF1A, pl6, GSTP1, MGMT, DAPK, SOCS-1 and RIZ1. The status of promoter methylation in these 8 genes was investigated using methylation-specific polymerase chain reaction. The clinicopathological data of HCC were also analyzed in order to evaluate the clinical implication of aberrant methylation in HCC. Results Methylation of the 8 TSGs was quite frequent in HCC, with a methylation rate of 95.0% in RASSF1A, 90.0% in APC, 73.3% in GSTP1, 65.0% in p16, 61.6% in RIZ1 and 60.0% in MGMT. Methylation of the 6 genes was more frequent in HCC than that in adjacent tissues （P 〈0.05）. The methylation rate of MGMT, GSTP1 and RIZ1 in the adjacent tissues was 41.6% , 40.0% and 25.0%, respectively, significantly higher than that in cirrhotic liver （ P 〈 0. 05 ）. p16 methylation was more frequently observed in HCC in elderly patients. The frequency of MGMT methylaiton was tended to be higher in giant HCC than that in the other types of HCC. Patients with MGMT methylation in the tumor were found to have a shorter disease free survival. Conclusion Different frequency of methylation in hepatocellular carcinomas, adjacent liver tissues and cirrhotic livers implies that epigenetic alteration in the hepatocellular carcinogenesis may be a gradually progressive process. Methylation status of MGMT, GSTP1 and RIZ1 may be promising in risk assessment of hepatocellular carcinoma and in early diagnosis. Furthermore, MGMT methylation might be also used as a potential prognostic biomarker for hepatocellular carcinoma patients.

Key words: 
Methylation ;  Hepatocellular carcinoma

Aberrant methylation of multiple genes and its clinical implication in hepatocellular carcinoma

Objective To screen and determine the regions of copy number variation （CNV） associated with hepatocellular carcinoma （HCC） using SNP array and fluorescence quantitative PCR. Methods The CNV from HCC cell fine TJ3ZX-O1 was analyzed using GeneChip Human Mapping 500K SNP array. According to the data obtained by SNP array analysis, four candidate amplification regions were verified in 41 primary HCC samples by fluorescence quantitative PCR. Results Four regions of copy number amplification at 1q21.2, 1q22 -23.1, 7p22.1 and 22q13.1 were detected by SNP array analysis. The four candidate amplicons occurred in 56.1% （23/41） of HCC samples at 1q21.2; 80.5% （33/41） at 1q22 - 23.1 ; 75.6% （31/41） at 7p22.1 and 31.7% （13/41） at 22q13.1 analyzed with sequence tagged site （STS） markers by quantitative PCR. Conclusion In four candidate amplification regions selected by SNP array analysis and detected by fluorescence quantitative PCR, three amplification regions show increased copy number in more than 50.0% HCC tissues. This result indicates that these amplification regions are associated with pathogenesis of hepatocellular carcinoma.

Key words: 
Liver neoplasms ;  Gene amplification ;  Polymorphism, single nucleotide ;  Fluorescence quantitative PCR

Identification of the regions of copy number amplification associated with hepatocellular carcinoma

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Aberrant methylation of multiple genes and its clinical implication in hepatocellular carcinoma

Identification of the regions of copy number amplification associated with hepatocellular carcinoma