PMID- 22848663
OWN - NLM
STAT- MEDLINE
DCOM- 20130110
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 7
DP  - 2012
TI  - Hepatitis B virus X protein upregulates mTOR signaling through IKKbeta to increase 
      cell proliferation and VEGF production in hepatocellular carcinoma.
PG  - e41931
LID - 10.1371/journal.pone.0041931 [doi]
LID - e41931
AB  - 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 IkappaB kinase beta (IKKbeta), 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 IKKbeta inhibitor Bay 11-7082 or silencing IKKbeta 
      expression using siRNA. HBx upregulated cell proliferation and vascular 
      endothelial growth factor (VEGF) production, and these HBx-upregulated phenotypes 
      were abolished by treatment with IKKbeta inhibitor Bay 11-7082 or mTOR inhibitor 
      rapamycin. The association of HBx-modulated IKKbeta/mTOR/S6K1 signaling with liver 
      tumorigenesis was verified in a HBx transgenic mouse model in which pIKKbeta, pS6K1, 
      and VEGF expression was found to be higher in cancerous than non-cancerous liver 
      tissues. Furthermore, we also found that pIKKbeta levels were strongly correlated 
      with pTSC1 and pS6K1 levels in HBV-associated hepatoma tissue specimens taken 
      from 95 patients, and that higher pIKKbeta, 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 IKKbeta, which is crucially linked 
      to HBV-associated HCC development.
FAU - Yen, Chia-Jui
AU  - Yen CJ
AD  - Institute of Clinical Medicine, National Cheng Kung University College of 
      Medicine and Hospital, Tainan, Taiwan.
FAU - Lin, Yih-Jyh
AU  - Lin YJ
FAU - Yen, Chia-Sheng
AU  - Yen CS
FAU - Tsai, Hung-Wen
AU  - Tsai HW
FAU - Tsai, Ting-Fen
AU  - Tsai TF
FAU - Chang, Kwang-Yu
AU  - Chang KY
FAU - Huang, Wei-Chien
AU  - Huang WC
FAU - Lin, Pin-Wen
AU  - Lin PW
FAU - Chiang, Chi-Wu
AU  - Chiang CW
FAU - Chang, Ting-Tsung
AU  - Chang TT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120727
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (TSC1 protein, human)
RN  - 0 (Trans-Activators)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Viral Regulatory and Accessory Proteins)
RN  - 0 (hepatitis B virus X protein)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Carcinoma, Hepatocellular/blood supply/diagnosis/metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - I-kappa B Kinase/*metabolism
MH  - Liver Neoplasms/blood supply/diagnosis/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Neovascularization, Pathologic
MH  - Phosphorylation
MH  - Prognosis
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Trans-Activators/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/metabolism
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/*biosynthesis
MH  - Viral Regulatory and Accessory Proteins
PMC - PMC3407061
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/08/01 06:00
MHDA- 2013/01/11 06:00
PMCR- 2012/07/27
CRDT- 2012/08/01 06:00
PHST- 2012/02/18 00:00 [received]
PHST- 2012/06/27 00:00 [accepted]
PHST- 2012/08/01 06:00 [entrez]
PHST- 2012/08/01 06:00 [pubmed]
PHST- 2013/01/11 06:00 [medline]
PHST- 2012/07/27 00:00 [pmc-release]
AID - PONE-D-11-08927 [pii]
AID - 10.1371/journal.pone.0041931 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(7):e41931. doi: 10.1371/journal.pone.0041931. Epub 2012 Jul 27.