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PMID: 19190755 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition.

PloS one ·Vol. 4 ·No. 2 ·2009-00-00 ·Pages e4355

Battaglia S, Benzoubir N, Nobilet S, Charneau P, Samuel D, Zignego AL, Atfi A, Bréchot C, Bourgeade MF

Abstract

Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.

MeSH Terms
Animals Cell Death/drug effects Cell Line, Tumor Cell Proliferation/drug effects Epithelium/drug effects,pathology Hepatocytes/drug effects,metabolism,virology Humans Liver Neoplasms/pathology,virology Mesoderm/drug effects,pathology Mice Mutant Proteins/metabolism Smad3 Protein/metabolism Transforming Growth Factor beta/pharmacology Viral Core Proteins/metabolism
Chemicals
Mutant Proteins Smad3 Protein Transforming Growth Factor beta Viral Core Proteins nucleocapsid protein, Hepatitis C virus
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Battaglia Serena
Inserm, Unité 785, Villejuif, France.
Benzoubir Nassima
Nobilet Soizic
Charneau Pierre
Samuel Didier
Zignego Anna Linda
Atfi Azeddine
Bréchot Christian
Bourgeade Marie-Françoise
References (47)
47 references, click to expand
  1. The epithelial-mesenchymal transition generates cells with properties of stem cells.
    Cell. 2008 May 16;133(4):704-15 PMID: 18485877
  2. Jun N-terminal kinase 1 regulates epithelial-to-mesenchymal transition induced by TGF-beta1.
    J Cell Sci. 2008 Apr 1;121(Pt 7):1036-45 PMID: 18334556
  3. Viral hepatitis and liver cancer: the case of hepatitis C.
    Oncogene. 2006 Jun 26;25(27):3834-47 PMID: 16799625
  4. Changing the pathogenetic roadmap of liver fibrosis? Where did it start; where will it go?
    J Gastroenterol Hepatol. 2008 Jul;23(7 Pt 1):1024-35 PMID: 18505415
  5. Human hepatocyte culture.
    Methods Mol Biol. 2006;320:283-93 PMID: 16719400
  6. Hepatitis C virus core protein: possible roles in viral pathogenesis.
    Curr Top Microbiol Immunol. 2000;242:117-34 PMID: 10592658
  7. Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling.
    Mol Cell. 2006 Aug;23(4):547-59 PMID: 16916642
  8. Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-beta/Smad3-mediated transcriptional activation.
    Oncogene. 2004 Oct 14;23(47):7821-38 PMID: 15334054
  9. Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma.
    Cancer Res. 2007 Mar 1;67(5):1970-8 PMID: 17332324
  10. Smad-dependent and Smad-independent pathways in TGF-beta family signalling.
    Nature. 2003 Oct 9;425(6958):577-84 PMID: 14534577
  11. Immunohistochemical detection of hcv in cirrhosis, dysplastic nodules, and hepatocellular carcinomas with parallel-tissue quantitative RT-PCR.
    Mod Pathol. 2001 May;14(5):496-505 PMID: 11353061
  12. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway.
    Oncogene. 2005 Sep 8;24(40):6119-32 PMID: 16007207
  13. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.
    Nat Rev Mol Cell Biol. 2007 Dec;8(12):970-82 PMID: 18000526
  14. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer.
    Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):41-58 PMID: 16310402
  15. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression.
    Cancer Sci. 2007 Oct;98(10):1512-20 PMID: 17645776
  16. Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma.
    Gastroenterology. 2005 Nov;129(5):1375-83 PMID: 16285938
  17. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway.
    Cell. 2006 Jun 2;125(5):929-41 PMID: 16751102
  18. Complex networks orchestrate epithelial-mesenchymal transitions.
    Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42 PMID: 16493418
  19. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer.
    Biochim Biophys Acta. 2007 Jan;1775(1):21-62 PMID: 16904831
  20. Hepatitis C virus biology.
    Cell Death Differ. 2003 Jan;10 Suppl 1:S27-38 PMID: 12655344
  21. Non-Smad TGF-beta signals.
    J Cell Sci. 2005 Aug 15;118(Pt 16):3573-84 PMID: 16105881
  22. Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis.
    J Virol. 1998 May;72(5):3691-7 PMID: 9557650
  23. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition.
    J Biol Chem. 2007 Aug 10;282(32):23337-47 PMID: 17562716
  24. Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro.
    J Biol Chem. 2007 Jul 27;282(30):22089-101 PMID: 17513865
  25. Human papillomavirus type 5 E6 oncoprotein represses the transforming growth factor beta signaling pathway by binding to SMAD3.
    J Virol. 2006 Dec;80(24):12420-4 PMID: 17020941
  26. Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection.
    Hepatology. 2007 Dec;46(6):1704-12 PMID: 17935229
  27. Mouse models of transforming growth factor beta impact in breast development and cancer.
    Endocr Relat Cancer. 2005 Dec;12(4):749-60 PMID: 16322320
  28. Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis.
    Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):19-27 PMID: 16290023
  29. Smad transcriptional corepressors in TGF beta family signaling.
    Curr Top Microbiol Immunol. 2001;254:145-64 PMID: 11190572
  30. E1A inhibits transforming growth factor-beta signaling through binding to Smad proteins.
    J Biol Chem. 1999 Oct 1;274(40):28716-23 PMID: 10497242
  31. Activation of the interferon-inducible protein kinase PKR by hepatocellular carcinoma derived-hepatitis C virus core protein.
    Oncogene. 2001 Sep 13;20(41):5836-45 PMID: 11593389
  32. Hepatitis C virus genetic variability: pathogenic and clinical implications.
    Clin Liver Dis. 2003 Feb;7(1):45-66 PMID: 12691458
  33. p38-mediated regulation of an Fas-associated death domain protein-independent pathway leading to caspase-8 activation during TGFbeta-induced apoptosis in human Burkitt lymphoma B cells BL41.
    Mol Biol Cell. 2001 Oct;12(10):3139-51 PMID: 11598198
  34. A highly efficient, stable, and rapid approach for ex vivo human liver gene therapy via a FLAP lentiviral vector.
    Hepatology. 2003 Jul;38(1):114-22 PMID: 12829993
  35. The human papilloma virus E7 oncoprotein inhibits transforming growth factor-beta signaling by blocking binding of the Smad complex to its target sequence.
    J Biol Chem. 2002 Oct 11;277(41):38557-64 PMID: 12145312
  36. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium.
    Cancer Res. 1982 Sep;42(9):3858-63 PMID: 6286115
  37. Transitions between epithelial and mesenchymal states in development and disease.
    Semin Cell Dev Biol. 2008 Jun;19(3):294-308 PMID: 18343170
  38. Differential expression of the cyclin-dependent kinase inhibitor P27 in primary hepatocytes in early-mid G1 and G1/S transitions.
    Oncogene. 1999 Aug 12;18(32):4577-85 PMID: 10467402
  39. Properties of the hepatitis C virus core protein: a structural protein that modulates cellular processes.
    J Viral Hepat. 2000 Jan;7(1):2-14 PMID: 10718937
  40. The two faces of transforming growth factor beta in carcinogenesis.
    Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8621-3 PMID: 12861075
  41. Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis.
    J Gastroenterol Hepatol. 2008 Mar;23 Suppl 1:S122-7 PMID: 18336655
  42. Smads: transcriptional activators of TGF-beta responses.
    Cell. 1998 Dec 11;95(6):737-40 PMID: 9865691
  43. Hepatitis C virus core protein modulates TRAIL-mediated apoptosis by enhancing Bid cleavage and activation of mitochondria apoptosis signaling pathway.
    J Immunol. 2005 Feb 15;174(4):2160-6 PMID: 15699147
  44. Biology of transforming growth factor beta in hepatocarcinogenesis.
    Microsc Res Tech. 2001 Feb 15;52(4):430-6 PMID: 11170302
  45. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542.
    Mol Pharmacol. 2002 Jul;62(1):58-64 PMID: 12065755
  46. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses.
    EMBO J. 2002 Jul 15;21(14):3749-59 PMID: 12110587
  47. Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein.
    Oncogene. 2004 Apr 1;23(14):2472-83 PMID: 14968111
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0004355
Published
2009-00-00
Epub
2009-00-03
Pages
e4355
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2629560
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0004355 PMC Full Text View journal details
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