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

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

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Abstract

MicroRNAs (miR) are a class of small (∼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.

Original languageEnglish (US)
Pages (from-to)5049-5058
Number of pages10
JournalCancer Research
Volume68
Issue number13
DOIs
StatePublished - Jul 1 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Datta, J., Kutay, H., Nasser, M. W., Nuovo, G. J., Wang, B., Majumder, S., Liu, C. G., Volinia, S., Croce, C. M., Schmittgen, T. D., Ghoshal, K., & Jacob, S. T. (2008). Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Research, 68(13), 5049-5058. https://doi.org/10.1158/0008-5472.CAN-07-6655