Alteration of Epigenetic Profile in Human Hepatocellular Carcinoma and Its Clinical Implications

Abstract

Hepatocellular carcinoma (HCC) is a common cancer worldwide and develops against a background of chronic liver damage. A variety of HCC-related genes are known to be altered by genetic and epigenetic mechanisms. Therefore, information regarding alteration of the genetic and epigenetic profiles in HCC is essential for understanding the biology of this type of tumor. Methylation at CpG sites in gene promoters is known to affect the transcription of the corresponding genes. Abnormal regional hypermethylation is observed in the 5′ region of several tumor suppressor genes (TSGs) in HCC, and this hypermethylation may promote carcinogenesis through the transcriptional inactivation of downstream TSGs. The DNA damage induced by oxidation is a trigger of abnormal DNA methylation and inactivation of TSGs through recruitment of the polycomb repressive complex to the promoter sequence. Thus, oxidative stress may be responsible for the emergence of HCC from chronic hepatitis and liver cirrhosis through the epigenetic alteration of TSGs. There have been several attempts to apply epigenetic information to the diagnosis and treatment of HCC. The predictive value of selected methylation events on survival in HCC patients has been reported, and the methylation profile of background liver could be associated with recurrence-free survival of HCC patients who have undergone hepatectomy. Another study detected methylated DNA from HCC cells in serum, and the circulating tumor DNA was regarded as a potential tumor marker. In addition, several trials of HCC therapy have targeted the epigenetic machinery and were based upon comprehensive analyses of DNA methylation of this type of tumor. Here, we present an overview of research regarding DNA methylation status in human HCC and describe the clinical application of epigenetic information to HCC.

Genome-Wide Profiling of DNA Methylation and Tumor Progression in Human Hepatocellular Carcinoma

“…It is well known that carcinogenesis is a multistep process involving mutation and subsequent clonal expansion of the mutated cells, and the accumulation of genetic and epigenetic alterations are hallmarks of the cancer genome, including HCC [3,6]. In this study, we tried to clarify alterations in DNA methylation in HCC, one of the characteristics of epigenetic alterations, using the HumanMethylation450 BeadChip array.…”

“…Several reports have suggested that hepatocarcinogenesis involves multiple molecular pathways with the accumulation of genetic and epigenetic alterations, including point mutations and abnormal DNA methylation [3,4,5,6]. …”

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice

“…In the liver, the hypermethylation of CpG-10.11 (14,15), CpG-21 and the hypomethylation of CpG-12 in Msh2, which were all uniquely detected in non-tumor groups, may be associated with tumor-free status following MNU induction. Similarly, in the kidney, the hypermethylation of CpG-5, CpG-20 may be associated with tumor-free status following MNU induction.…”

“…DNA methylation is the best-known epigenetic modification, and aberrant methylation in the promoter region 5'-C-phosphate-G-3' (CpG) islands is associated with gene silencing, as this downregulates transcription (12,13). In human types of cancer, altered methylation patterns epigenetically repress tumor suppressor genes, providing a direct link between epigenetic regulation and cancer (14).…”

Identification of Epigenetically Inactivated Genes in Human Hepatocellular Carcinoma by Integrative Analyses of Methylation Profiling and Pharmacological Unmasking

“…Recent technical advancement in genomic sequencing and comprehensive methylation analyses give us a profound insight into the molecular events that drive carcinogenesis, including HCC [3,4,5,6,7,8]. Several studies have noted abnormal DNA methylation in HCC; DNA methylation of specific sequences on the promoters of tumor suppressor genes (TSGs) is a key epigenetic alteration that marks HCC pathogenesis [2,9].…”