9 Interestingly, protumorigenic effects of MAT1A inhibition are reversed by blocking of DNA methyltransferases with 5–azacytidine, indicating that DNA methylation is a key mechanism of hepatocarcinogenesis induced by SAMe deficiency.10, 11 Overall, these observations suggest that MAT1A
and MAT2A are important epigenetic regulators whose expression is context–specific and is dependent on the stage of differentiation in the corresponding liver cells. Deregulation of MAT signaling is frequently observed during chronic liver disease progression and malignant transformation, but the mechanisms behind this tightly controlled regulation are largely unknown.5 Thus, a more detailed understanding of the MAT/SAMe metabolism and consecutive deregulation of DNA methylation selleckchem ultimately leading to carcinogenesis such SCH772984 mouse as that provided by Yang and colleagues12 contributes significantly to our understanding of liver cancer and helps to identify new diagnostic, prognostic, and therapeutic targets. MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate gene expression as a part of the RNA interference machinery. miRNAs were first discovered in 1993 in Caenorhabditis
elegans. Since then, miRNA expression has been linked to virtually all known cellular processes, including proliferation, differentiation, and apoptosis.13 More recent studies have demonstrated PFKL that miRNAs can act as disease modifiers and that aberrant regulation of several miRNAs contributes considerably to cancer initiation, propagation, and progression. Almost every type of human cancer has been associated with a specific pattern of deregulated miRNA activity, thereby promoting these molecules to attractive
targets for diagnostic and therapeutic interventions. miRNAs have also been associated with HCC development and progression by targeting a large number of critical oncogenic features (e.g., differentiation and metastasis) as well as key molecules involved in hepatocarcinogenesis.14 In liver cancer development, as well as that of other cancers, two functional subclasses of miRNAs have been discovered with either tumor–suppressive or oncogenic activity.15 With the advent of high–throughput technologies, current miRNA profiles are able to precisely dissect etiological subclasses and histological or clinical phenotypes in liver cancer.16 Additionally, a diagnostic and/or prognostic relevance could be attributed to several miRNAs. Although genomic analyses indicate that almost half of the known miRNAs are located on cancer–associated regions, the exact regulation of miRNAs during carcinogenesis still remains elusive.15 However, it seems abundantly clear that miRNAs not only contribute to epigenetic regulation during tumor development, but are also tightly regulated by epigenetic alterations such as DNA methylation.