ArticlePloS one2012
Hepatitis B virus X protein upregulates mTOR signaling through IKKβ to increase cell proliferation and VEGF production in hepatocellular carcinoma.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- Interplay between Cellular Autophagy and Hepatitis B Virus Replication: A Systematic Review.Cells · 2020Pooled it
- The role and significance of the PI3K/Akt-mTOR signaling pathway in infectious diseases.Frontiers in cellular and infection microbiology · 2026Review
- Biomedical informatics analysis has revealed a novel hub gene of the HBx in the pathogenesis and progression of DLBCL.iScience · 2025Article
- Review
- Cooperation Between Aflatoxin-Induced p53 Aberrations and Hepatitis B Virus in Hepatocellular Carcinoma.Journal of xenobiotics · 2025Review
- Review
- mTOR Signaling: Roles in Hepatitis B Virus Infection and Hepatocellular Carcinoma.International journal of biological sciences · 2024Review
- EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis.Cancer cell international · 2023Article
- Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy.Biomedicines · 2023Review
- Hepatitis B virus X protein promotes MAN1B1 expression by enhancing stability of GRP78 via TRIM25 to facilitate hepatocarcinogenesis.British journal of cancer · 2023Article
- Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Inhibits FIH-1 Expression to Promote Tumor Angiogenesis in HBV-Related Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2023Article
- Review
- CaMicroorganisms · 2022Article
- Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection.Frontiers in immunology · 2022Review
- mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication.Virologica Sinica · 2021Review
- Role of TSC1 in physiology and diseases.Molecular and cellular biochemistry · 2021Review
- Short chain fatty acids delay the development of hepatocellular carcinoma in HBx transgenic mice.Neoplasia (New York, N.Y.) · 2021Article
- Mechanisms by Which Probiotic Bacteria Attenuate the Risk of Hepatocellular Carcinoma.International journal of molecular sciences · 2021Review
- Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma.Frontiers in cell and developmental biology · 2020Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
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