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  • 1 School of Chemical and Biomedical Engineering, College of Engineering, Nanyang Technological University, Singapore, Singapore
  • | 2 School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyag Drive, Singapore, 637459, Singapore
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Abstract

Chronic hepatitis B virus (HBV) carriers may develop hepatocellular carcinoma (HCC) by a wide range of mechanisms including angiogenesis. We show that HBV replication induces the expression of angiogenic proteins interleukin 6 (IL6) and cyclooxygenase-2 (Cox2). Interestingly, ibuprofen (a Cox2 inhibitor) is found to attenuate the levels of IL6 and Cox 2 which are induced by HBV replication.

The mechanism of attenuation of angiogenic proteins by ibuprofen was further investigated. Our results show that HBx is involved in the increase of the expression of Cox2 through the NFκB pathway. However, the expression of Cox2 is decreased when the HBx-expressing cells are incubated with ibuprofen. The contrasting effect of HBx on Cox2 is found to be determined by differential dimer formation among the members of the NFκB family of proteins, including NFκB, RelA, and C-rel. Specifically, HBx alone results in dimer formation between NFκB and RelA, while the combined presence of HBx and ibuprofen leads to the formation of NFκB and C-rel. Additional information on the interaction network involving HBx, ibuprofen, and NFκB pathways is revealed by two-dimensional liquid chromatography-tandem mass spectrometry proteomics analysis. Taken together, our findings provide new insights on the angiogenesis induced by HBV replication.

  • 1. M.A. Avila K.P. Lu 2007 Hepatitis B virus X protein and pin1 in liver cancer: “les liaisons dangereuses” Gastroenterology 132 1180 1183.

    • Search Google Scholar
    • Export Citation
  • 2. M.A. Feitelson J. Lee 2007 Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis Cancer Lett 252 157 170.

  • 3. S.W. Lee Y.M. Lee S.K. Bae S. Murakami Y. Yun K.W. Kim 2000 Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis Biochem Biophys Res Commun 268 456 461.

    • Search Google Scholar
    • Export Citation
  • 4. S.S. Brigitte Vollmar M. D. Menger 1998 An intravital fluorescence microscopic study of hepatic microvascular and cellular derangements in developing cirrhosis in rats Hepatology 27 1544 1553.

    • Search Google Scholar
    • Export Citation
  • 5. K. Sugimachi S. Tanaka T. Terashi K. Taguchi T. Rikimaru 2002 The mechanisms of angiogenesis in hepatocellular carcinoma: angiogenic switch during tumor progression Surgery 131 S135 S141.

    • Search Google Scholar
    • Export Citation
  • 6. Y.G. Yoo S.H. Oh E.S. Park H. Cho N. Lee H. Park D.K. Kim D.Y. Yu J.K. Seong M.O. Lee 2003 Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1alpha through activation of mitogen-activated protein kinase pathway J Biol Chem 278 39076 39084.

    • Search Google Scholar
    • Export Citation
  • 7. E.J. Moon C.H. Jeong J.W. Jeong K.R. Kim D.Y. Yu S. Murakami C.W. Kim K.W. Kim 2004 Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1alpha Faseb J 18 382 384.

    • Search Google Scholar
    • Export Citation
  • 8. D. Kremsdorf P. Soussan P. Paterlini-Brechot C. Brechot 2006 Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis Oncogene 25 3823 3833.

    • Search Google Scholar
    • Export Citation
  • 9. P. Sanz-Cameno S. Martin-Vilchez E. Lara-Pezzi M.J. Borque J. Salmeron P. Munoz de Rueda J.A. Solis M. Lopez-Cabrera R. Moreno-Otero 2006 Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV×protein Am J Pathol 169 1215 1222.

    • Search Google Scholar
    • Export Citation
  • 10. S. Tanaka J.R. Wands S. Arii 2006 Induction of angiopoietin-2 gene expression by COX-2: a novel role for COX-2 inhibitors during hepatocarcinogenesis J Hepatol 44 233 235.

    • Search Google Scholar
    • Export Citation
  • 11. S.S. Adams P. Bresloff C.G. Mason 1976 Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the (−)-isomer J Pharm Pharmacol 28 256 257.

    • Search Google Scholar
    • Export Citation
  • 12. M.F. Landoni A. Soraci 2001 Pharmacology of chiral compounds: 2-arylpropionic acid derivatives Curr Drug Metab 2 37 51.

  • 13. A. Marzo E. Heftmann 2002 Enantioselective analytical methods in pharmacokinetics with specific reference to genetic polymorphic metabolism J Biochem Biophys Methods 54 57 70.

    • Search Google Scholar
    • Export Citation
  • 14. O. Dormond A. Foletti C. Paroz C. Ruegg 2001 NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis Nat Med 7 1041 1047.

    • Search Google Scholar
    • Export Citation
  • 15. P.M. Rothwell M. Wilson C.E. Elwin B. Norrving A. Algra C.P. Warlow T.W. Meade 2010 Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials Lancet 376 1741 1750.

    • Search Google Scholar
    • Export Citation
  • 16. M. Yao W. Zhou S. Sangha A. Albert A.J. Chang T.C. Liu M.M. Wolfe 2005 Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer Clin Cancer Res 11 1618 1628.

    • Search Google Scholar
    • Export Citation
  • 17. R. Aebersold M. Mann 2003 Mass spectrometry-based proteomics Nature 422 198 207.

  • 18. N. Takahashi H. Kaji M. Yanagida T. Hayano T. Isobe 2003 Proteomics: advanced technology for the analysis of cellular function J Nutr 133 2090S 2096S.

    • Search Google Scholar
    • Export Citation
  • 19. J.B. Whitlam K.F. Brown M.J. Crooks G.F. Room 1981 Transsynovial distribution of ibuprofen in arthritic patients Clin Pharmacol Ther 29 487 492.

    • Search Google Scholar
    • Export Citation
  • 20. J. Zhang D. Niu J. Sui C.B. Ching W.N. Chen 2009 Protein profile in hepatitis B virus replicating rat primary hepatocytes and HepG2 cells by iTRAQ-coupled 2-D LC-MS/MS analysis: Insights on liver angiogenesis Proteomics 9 2836 2845.

    • Search Google Scholar
    • Export Citation
  • 21. F. Fazal K.M. Bijli M. Minhajuddin T. Rein J.N. Finkelstein A. Rahman 2009 Essential role of cofilin-1 in regulating thrombin-induced RelA/p65 nuclear translocation and intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells J Biol Chem 284 21047 21056.

    • Search Google Scholar
    • Export Citation
  • 22. X. Jiang N. Takahashi K. Ando T. Otsuka T. Tetsuka T. Okamoto 2003 NF-kappa B p65 transactivation domain is involved in the NFkappa B-inducing kinase pathway Biochem Biophys Res Commun 301 583 590.

    • Search Google Scholar
    • Export Citation
  • 23. J.Y. Kim H. Kim K. Suk W.H. Lee 2010 Activation of CD147 with cyclophilin a induces the expression of IFITM1 through ERK and PI3K in THP-1 cells Mediators Inflamm 2010 821940.

    • Search Google Scholar
    • Export Citation
  • 24. S.K. Dhar B.C. Lynn C. Daosukho D.K. St Clair 2004 Identification of nucleophosmin as an NF-kappaB co-activator for the induction of the human SOD2 gene J Biol Chem 279 28209 28219.

    • Search Google Scholar
    • Export Citation
  • 25. A. Ryo F. Suizu Y. Yoshida K. Perrem Y.C. Liou G. Wulf R. Rottapel S. Yamaoka K.P. Lu 2003 Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA Mol Cell 12 1413 1426.

    • Search Google Scholar
    • Export Citation
  • 26. G.P. Atkinson S.E. Nozell D.K. Harrison M.S. Stonecypher D. Chen E.N. Benveniste 2009 The prolyl isomerase Pin1 regulates the NFkappaB signaling pathway and interleukin-8 expression in glioblastoma Oncogene 28 3735 3745.

    • Search Google Scholar
    • Export Citation
  • 27. M. Swiatkowska J. Szemraj C.S. Cierniewski 2005 Induction of PAI-1 expression by tumor necrosis factor alpha in endothelial cells is mediated by its responsive element located in the 4G/5G site FEBS J 272 5821 5831.

    • Search Google Scholar
    • Export Citation
  • 28. I.V. Guzhova Z.A. Darieva A.R. Melo B.A. Margulis 1997 Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells Cell Stress Chaperones 2 132 139.

    • Search Google Scholar
    • Export Citation
  • 29. K. Schulze-Osthoff H. Schenk W. Droge 1995 Effects of thioredoxin on activation of transcription factor NF-kappa B Methods Enzymol 252 253 264.

    • Search Google Scholar
    • Export Citation
  • 30. F. Su C.N. Theodosis R.J. Schneider 2001 Role of NF-kappaB and myc proteins in apoptosis induced by hepatitis B virus HBx protein J Virol 75 215 225.

    • Search Google Scholar
    • Export Citation
  • 31. S.Y. Foo G.P. Nolan 1999 NF-kappaB to the rescue: RELs, apoptosis and cellular transformation Trends Genet 15 229 235.

  • 32. R.M. Moonen I. Reyes G. Cavallaro G. Gonzalez-Luis J.A. Bakker E. Villamor 2010 The T1405N carbamoyl phosphate synthetase polymorphism does not affect plasma arginine concentrations in preterm infants PLoS One 5 e10792.

    • Search Google Scholar
    • Export Citation
  • 33. L.C. Schulz J.M. Bahr 2003 Glucose-6-phosphate isomerase is necessary for embryo implantation in the domestic ferret Proc Natl Acad Sci U S A 100 8561 8566.

    • Search Google Scholar
    • Export Citation
  • 34. B. Schepens S.A. Tinton Y. Bruynooghe R. Beyaert S. Cornelis 2005 The polypyrimidine tract-binding protein stimulates HIF-1alpha IRES-mediated translation during hypoxia Nucleic Acids Res 33 6884 6894.

    • Search Google Scholar
    • Export Citation
  • 35. K. Okamura Y. Sato T. Matsuda R. Hamanaka M. Ono K. Kohno M. Kuwano 1991 Endogenous basic fibroblast growth factor-dependent induction of collagenase and interleukin-6 in tumor necrosis factor-treated human microvascular endothelial cells J Biol Chem 266 19162 19165.

    • Search Google Scholar
    • Export Citation

2019  
Scimago
H-index
11
Scimago
Journal Rank
0,220
Scimago
Quartile Score
Medicine (miscellaneous) Q3
Scopus
Cite Score
155/133=1,2
Scopus
Cite Score Rank
General Medicine 199/529 (Q2)
Scopus
SNIP
0,343
Scopus
Cites
206
Scopus
Documents
23

 

Interventional Medicine and Applied Science
Language English
Size  
Year of
Foundation
2009
Publication
Programme
changed title
Volumes
per Year
 
Issues
per Year
 
Founder Akadémiai Kiadó
Founder's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2061-1617 (Print)
ISSN 2061-5094 (Online)

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