Epigenetic Deregulation of MicroRNAs: New Opportunities to Target Oncogenic Signaling Pathways in Hepatocellular Carcinoma

Zhuo      Yu; Alfred      Sze-Lok Cheng

Abstract

Hepatocellular carcinoma (HCC) is one of the few cancers with a worldwide increasing trend of incidence, representing the third largest cause of cancer-related death. The initiation and progression of HCC depend on progressive accumulation of genetic and epigenetic defects that alter an array of signaling cascades via deregulation of signal activators and inhibitors. MicroRNAs (miRNAs) are small RNA molecules that post-transcriptionally repress gene expression including those signal molecules and thus are critical for many cellular pathways. However, the balance of this fine-tuning function is broken by the abnormal expression of miRNAs in various cancers through genomic alterations or epigenetic mechanisms. This review summarizes the current knowledge of the role of epigenetic aberrations, including histone methylation and deacetylation as well as DNA hypermethylation and hypomethylation in the aberrant regulation of miRNAs leading to activation of signaling pathways such as Ras, STAT3 and AKT/mTOR in HCC. Conceivably, the therapeutic efficacy of current chromatin-modifying drugs might be related to their capacity to reactivate previously silenced tumor-suppressive miRNAs and cause down-regulation of target oncogenes. Better understanding of the epigenetics-miRNA regulatory cascades in the control of the functionally significant pathways will provide new opportunities for the development of more effective therapeutic modality for HCC.

Keywords: Histone modifications, DNA hypermethylation and hypomethylation, hepatocellular carcinoma, signal transduction pathways, epigenetic defects, signal activators, MicroRNAs (miRNAs), gene expression, STAT3, AKT/mTOR