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.
Highlights
Hepatocellular carcinoma (HCC), which occurs frequently in Southeast Asia, is one of the most important causes of cancerrelated death in the world [1,2,3]
We further used an HBV X protein (HBx) transgenic mouse model to verify whether HBx upregulates inhibitor of nuclear factor kB (IkB) kinase b (IKKb)/tuberous sclerosis 1 (TSC1)/mammalian target of rapamycin (mTOR) signaling in vivo, and to examine the association of upregulated IKKb/TSC1/mTOR signaling with increased vascular endothelial growth factor (VEGF) expression and angiogenesis in liver tumorigenesis
While there were no significant differences in total protein levels of IKKb, TSC1, S6 kinase 1 (S6K1) in cells with or without overexpression of HBx (Fig. 1C), we found overexpression HBx enhanced levels of pIKKb, pTSC1, and pS6K1
Summary
Hepatocellular carcinoma (HCC), which occurs frequently in Southeast Asia, is one of the most important causes of cancerrelated death in the world [1,2,3]. TNF-a is considered one of the most important factors involved in inflammation-mediated tumorigenesis [24,25,26], and the transcription factor NF-kB, a downstream signaling transducer of TNF-a, has been implicated in oncogenesis by promoting expression of genes related to cell proliferation and survival [27]. It was recently reported that IKKb increased tumor development and tumor angiogenesis by activating the mTOR signaling pathway through inhibiting tuberous sclerosis 1 (TSC1) [36,37,38]. Aberrant activation of the mTOR/ribosomal protein S6 kinase 1 (S6K1) signaling pathway increased cell proliferation and angiogenesis in a rat HCC model [39,40]. We found that HBx modulated IKKb/TSC1/mTOR signaling and upregulated cell proliferation and VEGF production in both unstimulated and TNF-a-stmulated hepatoma cells. We conclude that IKKb activates mTOR signaling through TSC1 suppression to contribute to one crucial mechanism underlying HBx-dependent pathogenesis of HCC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
