Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. It shows a wide geographical variation with low incidence areas in North America and Europe and high incidence areas in Africa and Asia. 70%-80% of hepatocellular carcinoma occurs in cirrhotic liver. In high incidence areas, such as Asia and Africa, HCC is strongly associated with chronic viral hepatitis B and C and liver cirrhosis. Nutritional factors, toxins and metabolic diseases contribute also to hepatocarcinogenesis[1,2
As for many other tumors, development of HCC is due to a multistep process with accumulation of genetic and epigenetic alterations in regulatory genes, leading to activation of oncogenes and inactivation or loss of tumor suppressor genes (TSG).
In the last three decades, cancer has been understood as a summary of altered genetic and epigenetic events. The epigenetic pathway is, in contrast to genetic events, a reversible alteration and characterized by three main mechanisms: (1) DNA hypermethylation leading to inactivation, (2) DNA hypomethylation causing genomic instability, (3) histone modifications affecting chromatin conformation.
These processes, especially aberrant DNA methylation and histone modifications, are closely linked with each other by a protein complex of transcript activators and repressors and alter mRNA transcript expression of affected genes[3
Characteristically, DNA methylation does not change the genetic information. It just alters the readability of the DNA and results in inactivation of genes by subsequent mRNA transcript repression.
In humans and other mammals, CpG island methylation is an important physiological mechanism. The inactivated X-chromosome of females, silenced alleles of imprinted genes or inserted viral genes and repeat elements are inactivated through promoter methylation[4,5