Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers. HCC is characterized by an acquisition of multiple abnormal phenotypes driven by genetic and epigenetic alterations, especially abnormal DNA methylation. Most of the existing clinical and experimental reports provide only a snapshot of abnormal DNA methylation patterns in HCC rather than their dynamic changes. This makes it difficult to elucidate the significance of these changes in the development of HCC. In the present study, we investigated hepatic gene expression and gene-specific DNA methylation alterations in mice using the Stelic Animal Model (STAM) of non-alcoholic steatohepatitis (NASH)-derived liver carcinogenesis. Analysis of the DNA methylation status in aberrantly expressed epigenetically regulated genes showed the accumulation of DNA methylation abnormalities during the development of HCC, with the greatest number of aberrantly methylated genes being found in full-fledged HCC. Among these genes, only one gene, tubulin, beta 2B class IIB (Tubb2b), was increasingly hypomethylated and over-expressed during the progression of the carcinogenic process. Furthermore, the TUBB2B gene was also over-expressed and hypomethylated in poorly differentiated human HepG2 cells as compared to well-differentiated HepaRG cells. The results of this study indicate that unique gene-expression alterations mediated by aberrant DNA methylation of selective genes may contribute to the development of HCC and may have diagnostic value as the disease-specific indicator.
Highlights
Hepatocellular carcinoma (HCC), which accounts for almost 90% of all primary liver malignancies, is one of the most aggressive and enigmatic human cancers with steadily increasing incidence in the United States and worldwide (Llovet et al, 2016; Bertuccio et al, 2017)
We demonstrated that the development of NASHderived HCC in male Stelic Animal Model (STAM) mice was characterized by substantial stage-dependent alterations in gene expression as compared to the age-matched control mice
In this study, using the STAM mouse model of non-alcoholic steatohepatitis (NASH)-derived liver carcinogenesis that depicts the sequential development of clinical and pathomorphological characteristics of NASH in diabetic patients, we demonstrated that NASH-related liver carcinogenesis is characterized by progressive accumulation of gene expression and gene-specific DNA methylation changes, with the greatest magnitude being found in full-fledged HCC; it is highly unlikely that all transcriptomic and DNA methylation aberrations found in full-fledged HCC may have significance in the development of HCC and its progression
Summary
Hepatocellular carcinoma (HCC), which accounts for almost 90% of all primary liver malignancies, is one of the most aggressive and enigmatic human cancers with steadily increasing incidence in the United States and worldwide (Llovet et al, 2016; Bertuccio et al, 2017). The development of HCC is associated with wellidentified etiological risk factors, including chronic hepatitis B (HBV) and C (HCV) viral infections, chemical exposure, and excessive alcohol consumption (Llovet et al, 2016); the contribution of specific risk factors to HCC development varies greatly by geographic location. The contribution of specific etiological factors to the development of HCC is dynamic and expected to change due to recent progress in the primary prevention of HCC induced by HBV and HCV infection, the arrival of a new generation of direct HCV antiviral drugs, and the fast-rising incidence of NAFLD. While the role of genetic abnormalities and sequential progression of pathomorphological lesions in liver carcinogenesis are wellcharacterized, the underlying epigenetic mechanisms, in general, and cancer-related cytosine DNA methylation aberrations, in particular, in the development of HCC are still poorly understood and require special attention. Cytosine DNA methylation, mainly but not exclusively, functions as a transcriptional “ON-OFF” switch at regulatory regions: the occurrence of DNA methylation at unmethylated CpG sites inhibits transcription, whereas demethylation of methylated CpG sequences activates transcription (Bestor et al, 2015)
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