DNA methylation in hepatocellular carcinoma

Tischoff, Iris; Tannapfel, Andrea

doi:10.3748/wjg.14.1741

Cited by 165 publications

(152 citation statements)

References 88 publications

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“…21 In general, cancer cells have global hypomethylation, but they have hypermethylation in some specific genes. DNA hypermethylation in promoter regions is associated with silencing of tumor suppressor genes because of direct or indirect prevention to accessing transcription factors in the promoter region.…”

Section: Discussionmentioning

confidence: 99%

“…DNA hypermethylation in promoter regions is associated with silencing of tumor suppressor genes because of direct or indirect prevention to accessing transcription factors in the promoter region. 22 Recent studies 21,23,24 have demonstrated that CpG island hypermethylation, via silencing of key cancer-related genes, plays a major causal role in cancer, including HCC.…”

Section: Discussionmentioning

confidence: 99%

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DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

Liu

Dong

Robertson

et al. 2011

The American Journal of Pathology

104

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Carbamoyl phosphate synthetase 1 (CPS1) is a liverspecific, intramitochondrial, rate-limiting enzyme in the urea cycle. A previous study showed that CPS1 is the antigen for hepatocyte paraffin 1 antibody, a commonly used antibody in surgical pathology practice; and CPS1 expression appears to be down-regulated in liver cancer tissue and cell lines. The aim of this study is to understand how the CPS1 gene is regulated in liver carcinogenesis. In this report, we show that human hepatocellular carcinoma (HCC) cells do not express CPS1, whereas cultured human primary hepatocytes express abundant levels. In addition, CPS1 was silenced or down-regulated in liver tumor tissues compared with the matched noncancerous tissues. The expression of CPS1 in HCC cells was restored with a demethylation agent, 5-azacytidine. We show that two CpG dinucleotides, located near the transcription start site, and a CpG-rich region in the first intron were hypermethylated in HCC cells. The hypermethylation of the two CpG dinucleotides was also detected in HCC tumor tissues compared with noncancerous tissues. Further molecular analysis with mutagenesis indicated that the two CpG dinucleotides play a role in promoter activity of the CPS1 gene. In conclusion, our study demonstrates that DNA methylation is a key mechanism of silencing CPS1 expression in human HCC cells, and CPS1 gene hypermethylation of the two CpG dinucleotides is a potential biomarker for HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

Liu

Dong

Robertson

et al. 2011

The American Journal of Pathology

104

View full text Add to dashboard Cite

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“…In this regard, the HCV genome is not controlled by epigenetic factors such as DNA methylation or histone modifications. Nonetheless, this virus has been found to be associated with aberrant host gene promoter methylation in HCC (Tischoff and Tannapfe, 2008).…”

Section: Hepatitis B Virusmentioning

confidence: 99%

“…In the case of HBV, chronic inflammation and accumulation of genetic alterations in infected hepatocytes induced by the host (Cougot et al, 2005;Gurtsevitch, 2008) and epigenetic alterations produced by viral proteins (Tischoff and Tannapfe, 2008;Herceg and Paliwal, 2009;Shon et al, 2009;Zheng et al, 2009) are mainly responsible for the carcinogenesis induced by HBV.…”

Section: Hepatitis B Virusmentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.

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“…28,31 have been reported and recently reviewed. 32,33 In a study using 15 hepatoma cell lines after treatment with decitabine, epigenetic silencing through hypermethylation of scavenger receptor class A, member 5 (SCARA5) was observed and confirmed in a panel of human HCC samples. 34 Here, we have performed an array-based methylation analysis on 27,578 methylation sites in 13 primary HCC samples in comparison to nontumorous cirrhotic tissue (n ¼ 17) and normal liver (n ¼ 12).…”

mentioning

confidence: 98%

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma

Ammerpohl

Pratschke

Schafmayer

et al. 2011

Intl Journal of Cancer

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Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a ''cirrhotic'' methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands.Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and globally the third most common cause of cancer mortality. 1,2 Approximately one million new cases are diagnosed globally each year. The highest incidences are observed in sub-Saharan Africa and Eastern Asia, where hepatitis B virus and hepatitis C virus infections are endemic. HCC incidence is rising also due to an increase in incidence of alcoholic cirrhosis and nonalcoholic steatohepatitis. 3,4 As for many other tumors, the development of HCC is a multistep process characterized by the accumulation of genetic and epigenetic alterations leading to the activation of oncogenes and inactivation or loss of tumor suppressor genes. Genomic alterations as part of the somatic evolution of the cancer genome are common in human cancer in general and also in

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DNA methylation in hepatocellular carcinoma

Cited by 165 publications

References 88 publications

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

Viral epigenomes in human tumorigenesis

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma

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