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MicroRNA‐140 acts as a liver tumor suppressor by controlling NF‐κB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression
Author(s) -
Takata Akemi,
Otsuka Motoyuki,
Yoshikawa Takeshi,
Kishikawa Takahiro,
Hikiba Yohko,
Obi Shuntaro,
Goto Tadashi,
Kang Young Jun,
Maeda Shin,
Yoshida Haruhiko,
Omata Masao,
Asahara Hiroshi,
Koike Kazuhiko
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26011
Subject(s) - microrna , dnmt1 , biology , carcinogenesis , epigenetics , gene silencing , dna methyltransferase , cancer research , dna methylation , regulation of gene expression , methyltransferase , gene expression , microbiology and biotechnology , gene , genetics , methylation
MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA‐containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced nuclear factor‐κB (NF‐κB) activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF‐κB activity by preferentially regulating the function of the NF‐κB‐suppressing miRNA‐140, we hypothesized that impairment of miRNA‐140 function may be involved in hepatocarcinogenesis. DNA methyltransferase 1 (Dnmt1) was identified as a direct target of miRNA‐140, and increased Dnmt1 expression in DDX20‐deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF‐κB activity. MiRNA‐140‐knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA‐140 plays a central role in DDX20 deficiency‐related pathogenesis. Conclusion : These results indicate that miRNA‐140 acts as a liver tumor suppressor, and that impairment of miRNA‐140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis. (H EPATOLOGY 2013)