UNLABELLED: miR-122 is a highly abundant, hepatocyte-specific microRNA. The biomedical significance and regulatory mechanisms of miR-122 remain obscure. We explored the role of miR-122 in tumorigenesis in the context of gene regulatory network. The miR-122 promoter and its transactivator were identified by way of luciferase reporter system, electrophoretic mobility shift, and chromatin immunoprecipitation assays. The miR-122 regulatory circuitry and its implication in hepatocarcinogenesis were identified using livers of different development stages, human hepatocellular carcinoma (HCC) tissues and cell lines, and aflatoxin B₁ (AFB₁)-transformed cells. We characterized the -5.3 to -4.8 kb region upstream of miR-122 precursor as miR-122 promoter. Further investigation revealed that deletion of predicted CCAAT/enhancer-binding protein alpha (C/EBPα) binding sites C/EBPα knockdown significantly reduced miR-122 promoter activity and endogenous miR-122 expression; and C/EBPα directly interacted with the miR-122 promoter in vitro and in vivo. These data suggest that C/EBPα is a transactivator for miR-122 transcription. We further demonstrated that miR-122 suppressed insulin-like growth factor 1 receptor (IGF-1R) translation and sustained glycogen synthase kinase-3 beta (GSK-3β) activity. The activated GSK-3β not only repressed cell proliferation, but also activated C/EBPα, which maintained miR-122 levels and thereby enforced IGF-1R suppression. Interestingly, down-regulation of miR-122 and C/EBPα, and up-regulation of IGF-1R were frequently observed in HCC tissues, and decreased miR-122 levels were associated with worse survival of HCC patients. Moreover, AFB₁ exposure resulted in decreased activity in GSK-3β, C/EBPα, and miR-122 and increased levels of IGF-1R, whereas restoration of miR-122 suppressed the tumorigenicity of HCC and AFB₁-transformed cells.
CONCLUSION: We have identified a novel GSK-3β-C/EBPα-miR-122-IGF-1R regulatory circuitry whose dysfunction may contribute to the development of HCC. Our findings provide new insight into miR-122's function and the mechanisms of hepatocarcinogenesis.

[Untagged]
━ Inclusion
━ ━ 1,3-butadiene
━ ━ ━ Mouse
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ 4-Aminobiphenyl
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ Histone modification
━ ━ Aflatoxins
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ Rat
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ Other
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ Benzene
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ Rat
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Benzidine
━ ━ ━ Mouse
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Benzo[a]pyrene
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ Rat
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ Other
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Coke production
━ ━ ━ Human
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ DNA methylation
━ ━ Formaldehyde
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ Rat
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ Other
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ Histone modification
━ ━ MOCA
━ ━ ━ Rat
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ Histone modification
━ ━ Occupational exposure as a painter
━ ━ ━ Human
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Sulfur Mustard
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ microRNA
━ ━ Vinyl chloride
━ ━ ━ Human
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ Exclusion
━ ━ no epigenetics
━ ━ ━ y-H2AX
━ ━ ━ histone-carcinogen binding
━ ━ not chemical of interest
━ ━ cannot access full text
━ ━ review or comment
━ ━ other
━ ━ ━ carcinogen binding to (existant) methylated cytosines
━ ━ ━ caricinogen binding and (existant) chromatin structure

References (1685 found)

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