title: Hepatitis B virus X protein upregulates mTOR signaling through IKKβ to increase cell proliferation and VEGF production in hepatocellular carcinoma.
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.
authors: Institute of Clinical Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan.
authors: Chia-Jui
authors: CJ
authors: Yen
authors: Yih-Jyh
authors: YJ
authors: Lin
authors: Chia-Sheng
authors: CS
authors: Yen
authors: Hung-Wen
authors: HW
authors: Tsai
authors: Ting-Fen
authors: TF
authors: Tsai
authors: Kwang-Yu
authors: KY
authors: Chang
authors: Wei-Chien
authors: WC
authors: Huang
authors: Pin-Wen
authors: PW
authors: Lin
authors: Chi-Wu
authors: CW
authors: Chiang
authors: Ting-Tsung
authors: TT
authors: Chang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008113:Liver Neoplasms / Q000098:blood supply / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C000624650:TSC1 protein, human; D015534:Trans-Activators; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase