Hepatitis B virus X protein upregulates mTOR signaling through IKKβ to increase cell proliferation and VEGF production in hepatocellular carcinoma.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Signal Transduction*; Carcinoma, Hepatocellular/*pathology ; I-kappa B Kinase/*metabolism ; Liver Neoplasms/*pathology ; TOR Serine-Threonine Kinases/*metabolism ; Trans-Activators/*metabolism ; Vascular Endothelial Growth Factor A/*biosynthesis; Adult ; Aged ; Animals ; Carcinoma, Hepatocellular/blood supply ; Carcinoma, Hepatocellular/diagnosis ; Carcinoma, Hepatocellular/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Liver Neoplasms/blood supply ; Liver Neoplasms/diagnosis ; Liver Neoplasms/metabolism ; Male ; Mice ; Middle Aged ; Neovascularization, Pathologic ; Phosphorylation ; Prognosis ; Tuberous Sclerosis Complex 1 Protein ; Tumor Suppressor Proteins/metabolism ; Up-Regulation ; Viral Regulatory and Accessory Proteins
    • Abstract:
      Hepatocellular carcinoma (HCC), a major cause of cancer-related death in Southeast Asia, is frequently associated with hepatitis B virus (HBV) infection. HBV X protein (HBx), encoded by a viral non-structural gene, is a multifunctional regulator in HBV-associated tumor development. We investigated novel signaling pathways underlying HBx-induced liver tumorigenesis and found that the signaling pathway involving IκB kinase β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1), was upregulated when HBx was overexpressed in hepatoma cells. HBx-induced S6K1 activation was reversed by IKKβ inhibitor Bay 11-7082 or silencing IKKβ expression using siRNA. HBx upregulated cell proliferation and vascular endothelial growth factor (VEGF) production, and these HBx-upregulated phenotypes were abolished by treatment with IKKβ inhibitor Bay 11-7082 or mTOR inhibitor rapamycin. The association of HBx-modulated IKKβ/mTOR/S6K1 signaling with liver tumorigenesis was verified in a HBx transgenic mouse model in which pIKKβ, pS6K1, and VEGF expression was found to be higher in cancerous than non-cancerous liver tissues. Furthermore, we also found that pIKKβ levels were strongly correlated with pTSC1 and pS6K1 levels in HBV-associated hepatoma tissue specimens taken from 95 patients, and that higher pIKKβ, pTSC1, and pS6K1 levels were correlated with a poor prognosis in these patients. Taken together, our findings demonstrate that HBx deregulates TSC1/mTOR signaling through IKKβ, which is crucially linked to HBV-associated HCC development.
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    • Accession Number:
      0 (TSC1 protein, human)
      0 (Trans-Activators)
      0 (Tsc1 protein, mouse)
      0 (Tuberous Sclerosis Complex 1 Protein)
      0 (Tumor Suppressor Proteins)
      0 (Vascular Endothelial Growth Factor A)
      0 (Viral Regulatory and Accessory Proteins)
      0 (hepatitis B virus X protein)
      EC 2.7.11.1 (TOR Serine-Threonine Kinases)
      EC 2.7.11.10 (I-kappa B Kinase)
    • Publication Date:
      Date Created: 20120801 Date Completed: 20130110 Latest Revision: 20211203
    • Publication Date:
      20221213
    • Accession Number:
      PMC3407061
    • Accession Number:
      10.1371/journal.pone.0041931
    • Accession Number:
      22848663