A novel GSK-3 beta–C/EBP alpha–miR-122–insulin-like growth factor 1 receptor regulatory circuitry in human hepatocellular carcinoma
✍ Scribed by Chunxian Zeng; Ruizhi Wang; Daochuan Li; Xue-Jia Lin; Qing-Kun Wei; Yunfei Yuan; Qing Wang; Wen Chen; Shi-Mei Zhuang
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 550 KB
- Volume
- 52
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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.