NF-κB signaling relieves negative regulation by miR-194 in hepatocellular carcinoma by suppressing the transcription factor HNF-1α.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Association for the Advancement of Science
    • Subject Terms:
      Signal Transduction*; Carcinoma, Hepatocellular/*metabolism ; Hepatocyte Nuclear Factor 1-alpha/*metabolism ; Liver Neoplasms/*metabolism ; MicroRNAs/*metabolism ; NF-kappa B/*metabolism ; Neoplasm Proteins/*metabolism ; RNA, Neoplasm/*metabolism; Animals ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; HEK293 Cells ; Hep G2 Cells ; Hepatocyte Nuclear Factor 1-alpha/genetics ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Mice ; Mice, Nude ; MicroRNAs/genetics ; NF-kappa B/genetics ; Neoplasm Proteins/genetics ; RNA, Neoplasm/genetics
    • Abstract:
      Constitutive activation of the proinflammatory transcription factor nuclear factor κB (NF-κB) plays an important role in progression of hepatocellular carcinoma (HCC). Emerging modulators of NF-κB signaling are noncoding RNAs, especially microRNAs (miRNAs). We previously identified miRNAs that reduced the induction of NF-κB activity upon addition of tumor necrosis factor-α (TNFα) to HCC cells. We found that among these miRNAs, the abundance of liver-enriched miR-194 was decreased in HCC tissue and that low abundance of miR-194 correlated with a high occurrence of vascular invasion. Overexpressing miR-194 suppressed HCC cell migration and invasiveness in culture and metastatic seeding in mice. Transcripts encoding tripartite motif containing 23 (TRIM23), a ubiquitin ligase involved in NF-κB activation, and chromosome 21 open reading frame 91 (C21ORF91), a protein of unknown function, were identified as direct targets of miR-194 in HCC cells; knocking down either protein decreased the activity of a luciferase NF-κB reporter. Furthermore, the NF-κB pathway activator TNFα, an inflammatory cytokine, inhibited the transcription of miR-194 by decreasing the abundance of hepatocyte nuclear factor-1α (HNF-1α). The abundance of miR-194 positively correlated with that of HNF-1α and inversely correlated with that of TNFα in human HCC tissue. Thus, we identified a pathway in which TNFα-NF-κB signaling switches off negative regulation by suppressing HNF-1α-mediated expression of miR-194, revealing insight into the mechanisms linking inflammatory pathways, miRNA, and HCC metastasis.
      (Copyright © 2015, American Association for the Advancement of Science.)
    • Accession Number:
      0 (HNF1A protein, human)
      0 (Hepatocyte Nuclear Factor 1-alpha)
      0 (MIRN194 microRNA, human)
      0 (MicroRNAs)
      0 (NF-kappa B)
      0 (Neoplasm Proteins)
      0 (RNA, Neoplasm)
    • Publication Date:
      Date Created: 20150730 Date Completed: 20160427 Latest Revision: 20160513
    • Publication Date:
      20231215
    • Accession Number:
      10.1126/scisignal.aaa8441
    • Accession Number:
      26221053