Review
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World J Gastroenterol. Jun 28, 2014; 20(24): 7894-7913
Published online Jun 28, 2014. doi: 10.3748/wjg.v20.i24.7894
DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma
Sumadi Lukman Anwar, Ulrich Lehmann
Sumadi Lukman Anwar, Department of Surgery, Faculty of Medicine Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
Sumadi Lukman Anwar, Ulrich Lehmann, Institute of Pathology, Medizinische Hochschule Hannover, D30625 Hannover, Germany
Author contributions: Anwar SL and Lehmann U contributed to this manuscript.
Supported by Grant from the German Research Council (DFG), SFB-TRR77 “Liver cancer” (Project B1)
Correspondence to: Sumadi Lukman Anwar, MD, PhD, Department of Surgery, Faculty of Medicine Universitas Gadjah Mada, Jl. Kesehatan 1, Yogyakarta 55281, Indonesia. sl.anwar@ugm.ac.id
Telephone: +62-274-581333 Fax: +62-274-581333
Received: December 24, 2013
Revised: January 24, 2014
Accepted: March 6, 2014
Published online: June 28, 2014
Processing time: 184 Days and 18.7 Hours
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.

Keywords: DNA methylation; MicroRNA; Epigenetics; Hepatocellular carcinoma; Biomarker

Core tip: A comprehensive review of the literature revealed that epigenetic inactivation of microRNA genes is a frequent event in hepatocellular carcinoma (HCC). Hypermethylation of microRNA genes can discriminate HCC from benign liver tumors and correlates with poor prognosis, representing a promising new diagnostic and prognostic marker in HCC. Aberrant DNA methylation of microRNA genes affects several key signaling pathways important in hepatocarcinogenesis and for maintenance of cancer stem cell phenotype.