RETRACTED: Methylation Mediated Silencing of MicroRNA-1 Gene and Its Role in Hepatocellular Carcinogenesis

Abstract

MicroRNAs (miR) are a class of small (f21 nucleotide) noncoding RNAs that, in general, negatively regulate gene expression. Some miRs harboring CGIs undergo methylationmediated silencing, a characteristic of many tumor suppressor genes. To identify such miRs in liver cancer, the miRNA expression profile was analyzed in hepatocellular carcinoma (HCC) cell lines treated with 5-azacytidine (DNA hypomethylating agent) and/or trichostatin A (histone deacetylase inhibitor). The results showed that these epigenetic drugs differentially regulate expression of a few miRs, particularly miR-1-1, in HCC cells. The CGI spanning exon 1 and intron 1 of miR-1-1 was methylated in HCC cell lines and in primary human HCCs but not in matching liver tissues. The miR-1-1 gene was hypomethylated and activated in DNMT1À/À HCT 116 cells but not in DNMT3B null cells, indicating a key role for DNMT1 in its methylation. miR-1 expression was also markedly reduced in primary human hepatocellular carcinomas compared with matching normal liver tissues. Ectopic expression of miR-1 in HCC cells inhibited cell growth and reduced replication potential and clonogenic survival. The expression of FoxP1 and MET harboring three and two miR-1 cognate sites, respectively, in their respective 3 ¶-untranslated regions, was markedly reduced by ectopic miR-1. Up-regulation of several miR-1 targets including FoxP1, MET, and HDAC4 in primary human HCCs and down-regulation of their expression in 5-AzaC-treated HCC cells suggest their role in hepatocarcinogenesis. The inhibition of cell cycle progression and induction of apoptosis after re-expression of miR-1 are some of the mechanisms by which DNA hypomethylating agents suppress hepatocarcinoma cell growth. [Cancer Res 2008;68(13):5049-58]

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

“…A recent analysis of the methylation signature in PCa cell lines demonstrated that indeed histone methylation leads to the silencing of the entire mir-22l/222 cluster (Ke et al, 2009). Deregulation of several of the downregulated miRNAs identified in our prognostic profile has been demonstrated also in other human malignancies or diseases such as breast ) and colorectal cancer (Michael et al, 2003) for the mir-143/145 cluster; breast cancer (Zhao et al, 2008) and glioblastoma (Gillies and Lorimer, 2007) for the mir-221/222 cluster; and liver cancer (Datta et al, 2008) or cardiac hypertrophy (Care et al, 2007) for the mir-1/ 133 cluster.…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…Among the various mechanisms of carcinogenesis the hypermethylation of related genes results in a reduction of the miR-1 levels. It results in the overexpression of certain oncogenes, FoxP1 and MET, as potential targets, thus promoting cell proliferation (Datta et al, 2008). Two other mechanisms of miR-1 action are given by (Wei et al, 2012;Li et al, 2012a).…”

The role and clinical implications of microRNAs in hepatocellular carcinoma

“…Aberrant patterns of epigenetic modifications, such as DNA methylation or histone acetylation, are important molecular mechanisms underpinning development of cancer, including HCC [72][73][74][75]. Recent evidence has suggested links between miRNAs and epigenetic pathways in hepatocarcinogenesis.…”