DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma

Abstract

Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC.

Upregulated expression of miR-106a by DNA hypomethylation plays an oncogenic role in hepatocellular carcinoma

“…Their aberrant expression is associated with various malignant tumors including HCC [32]. So far, downregulation of miR-let-7g, -22, -26, -29, -99a, -122, -124, -139, -145, -199b, and -185 acting as tumor suppressor genes and upregulation of miR-10b, -17-5p, -21, -135a, -155, -182, -221, and -222 acting as candidate oncogenes have already been observed in HCC [13].…”

Betaine chemistry, roles, and potential use in liver disease

“…For example, one-carbon metabolism in the nucleus plays a critical role in DNA replication and repair and in DNA methylation, a regulatory epigenetic process [19]. A simple abnormality in the methylation pathway, compounded with further assaults from environmental and infectious agents can lead to a wide range of conditions including, for example, cardiovascular disease, neurotransmitter imbalances, cancer, diabetes, abnormal immune function, and chronic inflammation.…”

Analysis of DNA Methylation in Plasma for Monitoring Hepatocarcinogenesis

“…Despite the unclear molecular pathogenesis of HCC, it has been confirmed that epigenetic aberrance, especially DNA methylation, plays an important role in the progression of carcinoma (Chen et al, 2013;Anwar and Lehmann, 2014;Dong and Wang, 2014). The silence of many tumor suppressor genes (TSGs), caused by the aberrant CpG island methylation of gene promoter, is considered as an early event for HCC pathogenesis (Chang et al, 2008;Nishida et al, 2008;Moribe et al, 2009).…”