Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis.

Abstract

MicroRNAs (miR) are a class of small ( approximately 21 nucleotide) noncoding RNAs that, in general, negatively regulate gene expression. Some miRs harboring CGIs undergo methylation-mediated 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 DNMT1-/- 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.

• Authors: Jharna Datta, Huban Kutay, Mohd W Nasser, Gerard J Nuovo, Bo Wang, Sarmila Majumder, Chang-Gong Liu, Stefano Volinia, Carlo M Croce, Thomas D Schmittgen, Kalpana Ghoshal, Samson T Jacob
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 13 Pg. 5049-58 (Jul 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18593903 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Retracted Publication)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• MicroRNAs
• DNA (Cytosine-5-)-Methyltransferases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (genetics)
• Carcinoma, Hepatocellular (genetics)
• Cell Cycle (genetics)
• Cell Proliferation
• Cluster Analysis
• CpG Islands (drug effects, genetics)
• DNA (Cytosine-5-)-Methyltransferases (antagonists & inhibitors)
• DNA Methylation
• Disease Progression
• Enzyme Inhibitors (pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Silencing (drug effects, physiology)
• HCT116 Cells
• Histone Deacetylase Inhibitors
• Humans
• Liver Neoplasms (genetics)
• MicroRNAs (genetics, physiology)
• Oligonucleotide Array Sequence Analysis
• Phenotype
• Transfection
• Tumor Cells, Cultured