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DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma.

ABSTRACT: Alcohol is a well-known risk factor for hepatocellular carcinoma (HCC), but the mechanisms underlying the alcohol-related hepatocarcinogenesis are still poorly understood. Alcohol alters the provision of methyl groups within the hepatic one-carbon metabolism, possibly inducing aberrant DNA methylation. Whether specific pathways are epigenetically regulated in alcohol-associated HCC is, however, unknown. The aim of the present study was to investigate the genome-wide promoter DNA methylation and gene expression profiles in non-viral, alcohol-associated HCC. From eight HCC patients undergoing curative surgery, array-based DNA methylation and gene expression data of all annotated genes were analyzed by comparing HCC tissue and homologous cancer-free liver tissue.After merging the DNA methylation with gene expression data, we identified 159 hypermethylated-repressed, 30 hypomethylated-induced, 49 hypermethylated-induced, and 56 hypomethylated-repressed genes. Notably, promoter DNA methylation emerged as a novel regulatory mechanism for the transcriptional repression of genes controlling the retinol metabolism (ADH1A, ADH1B, ADH6, CYP3A43, CYP4A22, RDH16), iron homeostasis (HAMP), one-carbon metabolism (SHMT1), and genes with a putative, newly identified function as tumor suppressors (FAM107A, IGFALS, MT1G, MT1H, RNF180).A genome-wide DNA methylation approach merged with array-based gene expression profiles allowed identifying a number of novel, epigenetically regulated candidate tumor-suppressor genes in alcohol-associated hepatocarcinogenesis. Retinol metabolism genes and SHMT1 are also epigenetically regulated through promoter DNA methylation in alcohol-associated HCC. Due to the reversibility of epigenetic mechanisms by environmental/nutritional factors, these findings may open up to novel interventional strategies for hepatocarcinogenesis prevention in HCC related to alcohol, a modifiable dietary component.

SUBMITTER: Udali S

PROVIDER: S-EPMC4419480 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma.

Udali Silvia S Guarini Patrizia P Ruzzenente Andrea A Ferrarini Alberto A Guglielmi Alfredo A Lotto Valentina V Tononi Paola P Pattini Patrizia P Moruzzi Sara S Campagnaro Tommaso T Conci Simone S Olivieri Oliviero O Corrocher Roberto R Delledonne Massimo M Choi Sang-Woon SW Friso Simonetta S

Clinical epigenetics 20150414

<h4>Background</h4>Alcohol is a well-known risk factor for hepatocellular carcinoma (HCC), but the mechanisms underlying the alcohol-related hepatocarcinogenesis are still poorly understood. Alcohol alters the provision of methyl groups within the hepatic one-carbon metabolism, possibly inducing aberrant DNA methylation. Whether specific pathways are epigenetically regulated in alcohol-associated HCC is, however, unknown. The aim of the present study was to investigate the genome-wide promoter D ...[more]

PMID: 25945129

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Project description:Background:Hepatocellular carcinoma (HCC) includes cryptogenic hepatocellular carcinomas (CR-HCC) that lack a defined cause. Specific DNA methylation patterns and comparisons of the aberrant alterations in DNA methylation between CR-HCC and adjacent peritumor tissues (APTs) have not yet been reported. Methods:The SureSelectXT Methyl-Seq Target Enrichment System was used to sequence targeted DNA methylation in three paired CR-HCC tissues and APTs. Gene Ontology (GO) enrichment and KEGG pathway analysis were performed to investigate the DNA methylation mechanism of CR-HCC. The mRNA expression levels of HOXB-AS3, HOXB6, HOXB3, USP18, MAP3K6, TIRAP, TNNI2, SHC3, CTTN, and TFAP2A, selected from the identified signaling pathways, were evaluated by quantitative real-time PCR (qPCR). Results:A total of 1728 differentially methylated regions (DMRs) were identified in tumor tissues compared with non-tumor tissues, of which 868 DMRs were hypermethylated and 860 were hypomethylated. The DMRs were mapped within 2091 DMR-associated genes (DMGs). The mRNA expression of HOXB-AS3, HOXB3, and MAP3K6 was downregulated in CR-HCC tissues compared to the APTs. However, the mRNA expression of TIRAP, SHC3, and CTTN was upregulated in the CR-HCC tissues. Differences between the mRNA expression of HOXB6, USP18, TNNI2, and TFAP2A in the CR-HCC and APTS tissues were not statistically significant. GO analysis showed that the molecular functions of "binding", "protein binding", and "cytoskeletal protein binding" were the main categories for the hypermethylated DMGs. The hypomethylated DMGs were mostly enriched in the molecular functions "binding", "protein binding", "calcium ion binding", among others. KEGG pathway analysis showed that the hypermethylated DMGs were enriched in several pathways such as "estrogen signaling pathway", while hypomethylated DMGs were enriched in several pathways such as "proteoglycans in cancer", suggesting that epigenetic modifications play important roles in the cryptogenic hepatocarcinogenesis. Conclusion:These results provide useful information for future work to characterize the functions of epigenetic mechanisms on CR-HCC.

Project description:BackgroundImmediate early response 3 (IER3) is correlated to the prognosis of several cancers, but the precise mechanisms underlying the regulation by IER3 of the occurrence and development of hepatocellular carcinoma (HCC) remain unknown.MethodsThe expression level of IER3 was examined by using in-house immunohistochemistry (IHC), public gene chip, and public RNA-sequencing (RNA-seq). The standardized mean difference (SMD) was calculated to compare the expression levels of IER3 between HCC patients and controls. The summary receiver operating characteristics (sROC) was plotted to comprehensively understand the discriminatory capability of IER3 between HCC and non-HCC group. The Kaplan-Meier curves and the combined hazard ratios (HRs) were used to determine the prognostic value of IER3 in HCC. Moreover, differentially expressed genes (DEGs) and co-expression genes (CEGs) were used to explored the molecular mechanisms of IER3 underlying HCC. hTFtarget was used to predict the transcription factors (TFs) of IER3. The binding site of TFs and the IER3 promoter region was forecasted using the JASPAR website. The relevant ChIP-seq data were used to determine whether TF peaks were present in the IER3 transcription initiation.ResultsA significantly increased expression of IER3 protein was found in HCC tissue relative to non-HCC tissue as detected by IHC (p < 0.001). Compared to 1,263 cases of non-HCC tissues, IER3 in 1483 cases of HCC tissues was upregulated (SMD = 0.42, 95% confidence interval [CI] [0.09-0.76]). The sROC showed that IER3 had a certain ability at differentiating HCC tissues (area under the curve (AUC) = 0.65, 95% CI [0.61-0.69]). Comprehensive analysis of the effect of IER3 on the prognosis of patients with HCC demonstrated that higher IER3 expression was associated with poor prognosis in HCC (HRs = 1.30, 95% CI [1.03-1.64]). Pathway enrichment analysis revealed that IER3-related genes were mostly enriched in the PI3K-Akt signaling pathway, cancer-related signaling pathways, the p53 signaling pathway, and other signaling pathways. Regulatory factor X5 (RFX5) was identified as a possible regulator of IER3-related TF.ConclusionIER3 may be a potential prognostic marker for HCC. The molecular mechanisms of IER3 in HCC warrant further study.

Project description:Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ? 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ? 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.

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DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma.

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DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma.

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