In hepatocellular carcinoma (HCC), heterogeneity is a well known biological feature reflecting the diverse etiological factors and the different geographical sites of development of the disease [1]. Identification of the tumor's molecular singularities is an important issue to improve the efficacy of molecular therapies in HCC. As in other types of solid tumors, numerous genetic, and epige-netic alterations accumulate during hepatocarcinogenesis that lead to misregulation of mRNA and miRNA profiles. While several laboratories have concentrated their research on the comprehensive characterization of structural DNA damage (such as point mutations and chromosomal rearrangements) in HCC in relation to clinical parameters, the study of the role of epigenetic events in HCC needs to be further explored as they are key drivers of specific tumoral processes. Epigenetic alterations are defined as heritable changes in gene expression that are not due to any alteration in the DNA sequence. They consist of modification of DNA methylation and of post-translational modifications of his-tones that change the chromatin structure and promoter activity (Fig. 1). Currently, in cancer, the best studied epigenetic marker is DNA methylation. Two main modifications have been described in tumors, a genome wide DNA hypomethylation that might contribute to the generation of chromosomal instability, the reactivation of transposable elements or the loss of imprinting, and the hypermethylation of the CpG islands in the promoter regions of tumor suppressor genes that leads to their inactivation [2]. All these epigenetic events lead to either activation of oncogenes or to the loss of function of tumor suppressor genes [3]. Furthermore, epigenetic abnormalities are potentially reversible in contrast to gene mutations, and different compounds that act as either deme-thylating agents or histone deacetylase inhibitors are available for the design of an epigenetic therapy of cancer.
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