Hepatitis B Virus X Protein Upregulates MTOR Signaling Through IKKβ to Increase Cell Proliferation and VEGF Production in Hepatocellular Carcinoma
Overview
Authors
Affiliations
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.
VEGF-Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications.
Sanchez-Martinez C, Grueso E, Calvo-Lopez T, Martinez-Ortega J, Ruiz A, Almendral J Cells. 2024; 13(21.
PMID: 39513922 PMC: 11545703. DOI: 10.3390/cells13211815.
mTOR Signaling: Roles in Hepatitis B Virus Infection and Hepatocellular Carcinoma.
Mei L, Sun H, Yan Y, Ji H, Su Q, Chang L Int J Biol Sci. 2024; 20(11):4178-4189.
PMID: 39247820 PMC: 11379076. DOI: 10.7150/ijbs.95894.
Chen H, Cao D, Han N, Zhang M, Jiang W, Wang X J Hepatocell Carcinoma. 2024; 10:2337-2353.
PMID: 38163053 PMC: 10757782. DOI: 10.2147/JHC.S436926.
Wu C, Chien Y, Yen C, Wu J, Bai L, Yu Y Cancer Cell Int. 2023; 23(1):199.
PMID: 37689710 PMC: 10493019. DOI: 10.1186/s12935-023-03002-9.
Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy.
Kouroumalis E, Tsomidis I, Voumvouraki A Biomedicines. 2023; 11(4).
PMID: 37189787 PMC: 10135776. DOI: 10.3390/biomedicines11041166.