MicroRNA-22 and microRNA-140 suppress NF-κB activity by regulating the expression of NF-κB coactivators
ABSTRACT Nuclear factor κB (NF-κB) is a transcription factor that regulates a set of genes that are critical to many biological phenomena, including liver tumorigenesis. To identify microRNAs (miRNAs) that regulate NF-κB activity in the liver, we screened 60 miRNAs expressed in hepatocytes for their ability to modulate NF-κB activity. We found that miRNA-22 and miRNA-140-3p significantly suppressed NF-κB activity by regulating the expression of nuclear receptor coactivator 1 (NCOA1) and nuclear receptor-interacting protein 1 (NRIP1), both of which are NF-κB coactivators. Our results provide new information about the roles of miRNAs in the regulation of NF-κB activity.
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ABSTRACT: The different frequency of hepatocellular carcinoma (HCC) in humans at risk suggests a polygenic predisposition. However, detection of genetic variants is difficult in genetically heterogeneous human population. Studies on mouse and rat models identified 7 hepatocarcinogenesis susceptibility (Hcs) and 2 resistance (Hcr) loci in mice, and 7 Hcs and 9 Hcr loci in rats, controlling multiplicity and size of neoplastic liver lesions. Six liver neoplastic nodule remodeling (Lnnr) loci control number and volume of re-differentiating lesions in rat. A Hcs locus, with high phenotypic effects, and various epistatic gene-gene interactions were identified in rats, suggesting a genetic model of predisposition to hepatocarcinogenesis with different subset of low-penetrance genes, at play in different subsets of population, and a major locus. This model is in keeping with human HCC epidemiology. Several putative modifier genes in rodents, deregulated in HCC, are located in chromosomal segments syntenic to sites of chromosomal aberrations in humans, suggesting possible location of predisposing loci. Resistance to HCC is associated with lower genomic instability and downregulation of cell cycle key genes in preneoplastic and neoplastic lesions. p16(INK4A) upregulation occurs in susceptible and resistant rat lesions. p16(INK4A)-induced growth restraint was circumvented by Hsp90/Cdc37 chaperons and E2f4 nuclear export by Crm1 in susceptible, but not in resistant rats and human HCCs with better prognosis. Thus, protective mechanisms seem to be modulated by HCC modifiers, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.Biochimica et Biophysica Acta 05/2006; 1765(2):126-47. DOI:10.1016/j.bbcan.2005.08.007 · 4.66 Impact Factor
- Cellular & molecular immunology 03/2012; 9(2):103-4. DOI:10.1038/cmi.2011.43 · 4.19 Impact Factor
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ABSTRACT: Vitamin D deficiency is associated with the high risk of colon cancer and a variety of other diseases. The active vitamin D metabolite 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) regulates gene transcription via its nuclear receptor (VDR), and posttranscriptional regulatory mechanisms of gene expression have also been proposed. We have identified microRNA-22 (miR-22) and several other miRNA species as 1,25(OH)(2)D(3) targets in human colon cancer cells. Remarkably, miR-22 is induced by 1,25(OH)(2)D(3) in a time-, dose- and VDR-dependent manner. In SW480-ADH and HCT116 cells, miR-22 loss-of-function by transfection of a miR-22 inhibitor suppresses the antiproliferative effect of 1,25(OH)(2)D(3). Additionally, miR-22 inhibition increases cell migration per se and decreases the antimigratory effect of 1,25(OH)(2)D(3) in both cell types. In silico analysis shows a significant overlap between genes suppressed by 1,25(OH)(2)D(3) and miR-22 putative target genes. Consistently, miR-22 inhibition abrogates the 1,25(OH)(2)D(3)-mediated suppression of NELL2, OGN, HNRPH1, RERE and NFAT5 genes. In 39 out of 50 (78%) human colon cancer patients, miR-22 expression was found lower in the tumour than in the matched normal tissue and correlated directly with that of VDR. Our results indicate that miR-22 is induced by 1,25(OH)(2)D(3) in human colon cancer cells and it may contribute to its antitumour action against this neoplasia.Human Molecular Genetics 03/2012; 21(10):2157-65. DOI:10.1093/hmg/dds031 · 6.68 Impact Factor