The Expression of DNA Methyltransferase DNMT3a in Classical and Fibrolamellar Hepatocellular Carcinoma

Abstract

The epigenetic regulation of DNA-templated processes has been studied extensively during the last 15 years. As was revealed, DNA modification such as methylation possess great impact on cell fate and can result in abnormal protein expression patterns what can lead to the induction of carcinogenesis. DNA (cytosine-5)-methyltransferases are enzymes that catalyses the transfer of methyl groups to specific CpG structures in DNA. The methylation of these sequences can lead to inappropriate gene expression such as the silencing of tumor suppressor genes in cancer cells. DNA (cytosine-5)-methyltransferase 3A (DNMT3a) gene encodes a DNA methyltransferase that is thought to function mainly in de novo methylation. In the normal liver DNMT3a is usually expressed on the medium level, as was described in literature. Hepatocellular carcinoma (HCC) still remains one of the most common cause of death among patients with cancer. Fibrolamellar hepatocellular carcinoma (FL) represents rare subtype, which affects usually young people (an onset between 20-30 years) and its etiology is poorly understood. In our study we compared the presence of DNMT3a protein between two different types of HCC-common type and fibrolamellar one. We performed immunohistochemical staining of formalin fixed paraffin embedded tissue sections obtained from 30 patients (22 HCC and 8 FL). We found that DNMT3a immunoreactivity is significantly more pronounced in the non-fibrolamellar variant of HCC than in the fibrolamellar one. The DNMT3a immunoreactivity was predominantly localized in cancer cell nuclei in a form of separate large granules spotted in proximity to heterochromatin region. The reduced presence of DNMT3a in the fibrolamellar variant of HCC may suggest that different epigenetic mechanisms are involved in development of this particular type of liver cancer. Improving our understanding of the roles of DNMT proteins in hepatocarcinogenesis can benefit in the development of epigenetic -based therapy designed for specific HCC subtype.