EBV EXPRESSION IN NASOPHARYNGEAL CARCINOMA

Summary

Principal Investigator: Nancy Raab-Traub
Affiliation: University of North Carolina
Country: USA
Abstract: The goal of this research is to determine the role of EBV in the etiology of nasopharyngeal carcinoma (NPC), an epithelial malignancy that develops with high incidence in Southern China, Northern Africa, and among Eskimos. The viral genes that are expressed in NPC include the latent membrane proteins, LMP1 and 2, and a new family of mRNAs, transcribed through the BamHI A fragment. Sequence analysis of the intricately spliced cDNAs representing the BamHI A transcripts has revealed four previously unidentified open reading frames. To determine how EBV affects epithelial cell growth, the viral proteins will be expressed in epithelial cell lines and in primary keratinocytes. Cell lines expressing LMP1 will be analyzed to test the hypothesis that LMP1 alters epithelial cell growth through the induction of expression of the epidermal growth factor receptor and by inhibiting p53-mediated apoptosis. The NFKB complexes induced by LMP1 and the mechanism of activation of NFKB will also be determined in epithelial cell lines. Cell lines expressing LMP2 will be analyzed to determine whether LMP2 blocks differentiation induced by extracellular Ca++ and to identify a possible interaction with a cellular tyrosine kinase. The ability of EBV to transform epithelial cells will be determined in primary epithelial cells or cell lines that are stably infected with EBV that has been genetically altered and contains a selectable marker. Genetically altered EBV lacking specific genes will be tested in this system. The BamHI A open reading frames that are formed by splicing will be translated in vivo to screen human sera for reactivity to the putative proteins. Glutathionein transferase fusion proteins will be synthesized to produce monospecific antisera to identify the proteins in transfected cell lines and in NPC tumor tissues. The proteins will be tested for interactions with cellular proteins and for transactivation of the LMP1 promoter. To investigate the high incidence in specific populations and to explore a possible genetic contribution to NPC, additional NPC samples will be obtained from Chinese, Caucasian, Black, and possibly Inuit Americans. When possible the samples will be obtained viably for transplantation into SCID mice. Additional NPC samples and any samples passaged in SCID mice will be used for identification of viral proteins and interactive cellular proteins and characterization of the EBV strain. To test the hypothesis that loss of heterozygosity on chromosomes 3 or 9 contributes to the development of NPC, tumor tissue and normal tissue from patients from Chinese, Mediterranean, and American populations will be analyzed for LOH in these regions.
Funding Period: 1983-06-01 - 2000-05-31
more information: NIH RePORT

Top Publications

  1. pmc Epstein-Barr Virus Latent Membrane Protein 2 Effects on Epithelial Acinus Development Reveal Distinct Requirements for the PY and YEEA motifs
    Julie A Fotheringham
    Lineberger Comprehensive Cancer Center
    J Virol 87:13803-15. 2013
  2. pmc Modulation of B-cell exosome proteins by gamma herpesvirus infection
    David G Meckes
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 110:E2925-33. 2013
  3. pmc Epstein-Barr virus LMP1 modulates lipid raft microdomains and the vimentin cytoskeleton for signal transduction and transformation
    David G Meckes
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 87:1301-11. 2013
  4. ncbi Novel mechanisms of EBV-induced oncogenesis
    Nancy Raab-Traub
    Sarah Graham Kenan Distinguished Professor, Department of Microbiology and Immunology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599 7295, USA
    Curr Opin Virol 2:453-8. 2012
  5. pmc Epstein-Barr virus latent membrane protein-2A induces ITAM/Syk- and Akt-dependent epithelial migration through αv-integrin membrane translocation
    Julie A Fotheringham
    Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 86:10308-20. 2012
  6. pmc The role of miRNAs and EBV BARTs in NPC
    Aron R Marquitz
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
    Semin Cancer Biol 22:166-72. 2012
  7. pmc Human tumor virus utilizes exosomes for intercellular communication
    David G Meckes
    The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 107:20370-5. 2010
  8. pmc Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta
    Che Pei Kung
    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Virol 85:4399-408. 2011
  9. pmc The Epstein-Barr Virus BART microRNAs target the pro-apoptotic protein Bim
    Aron R Marquitz
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Virology 412:392-400. 2011
  10. pmc Microvesicles and viral infection
    David G Meckes
    Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 85:12844-54. 2011

Scientific Experts

  • David N Everly
  • Aron R Marquitz
  • Nancy Raab-Traub
  • David G Meckes
  • Che Pei Kung
  • Kathy H Y Shair
  • Bernardo A Mainou
  • Julie A Fotheringham
  • Rachel H Edwards
  • Rachel Hood Edwards
  • J A Fotheringham
  • Caroline I Schnegg
  • Natalie J Thornburg
  • Rosemary J Tierney
  • Jennifer A Morrison
  • Jack D Griffith
  • Phillip R Heaton
  • Blossom Damania
  • Harsha P Gunawardena
  • Sezgin Ozgur
  • Nathan F Menaker
  • Robert M Dekroon
  • Judith N Nielsen
  • Nicole E Coalson
  • Dominic T Moore
  • Katharine M Bendt
  • S Mazzucca
  • N Raab-Traub
  • Alan B Rickinson
  • Deborah Croom-Carter
  • Diane Sitki-Green
  • Sushmita Roy
  • Qing yun Yao

Detail Information

Publications26

  1. pmc Epstein-Barr Virus Latent Membrane Protein 2 Effects on Epithelial Acinus Development Reveal Distinct Requirements for the PY and YEEA motifs
    Julie A Fotheringham
    Lineberger Comprehensive Cancer Center
    J Virol 87:13803-15. 2013
    ..These findings indicate that LMP2 has considerable transforming properties that are not evident in standard tissue culture and requires the ability of LMP2A to bind ubiquitin ligases and Src family kinases. ..
  2. pmc Modulation of B-cell exosome proteins by gamma herpesvirus infection
    David G Meckes
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 110:E2925-33. 2013
    ..The changes in exosome content identified in this study suggest ways that these oncogenic viruses modulate the tumor microenvironment and may provide diagnostic markers specific for EBV and KSHV associated malignancies. ..
  3. pmc Epstein-Barr virus LMP1 modulates lipid raft microdomains and the vimentin cytoskeleton for signal transduction and transformation
    David G Meckes
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 87:1301-11. 2013
    ..These findings indicate that LMP1 reorganizes membrane and cytoskeleton microdomains to modulate signal transduction...
  4. ncbi Novel mechanisms of EBV-induced oncogenesis
    Nancy Raab-Traub
    Sarah Graham Kenan Distinguished Professor, Department of Microbiology and Immunology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599 7295, USA
    Curr Opin Virol 2:453-8. 2012
    ....
  5. pmc Epstein-Barr virus latent membrane protein-2A induces ITAM/Syk- and Akt-dependent epithelial migration through αv-integrin membrane translocation
    Julie A Fotheringham
    Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 86:10308-20. 2012
    ..The specific effects of LMP2A on an integrin with a diverse repertoire of ligand specificities could promote migration of different cell types and be initiated by multiple chemoattractants...
  6. pmc The role of miRNAs and EBV BARTs in NPC
    Aron R Marquitz
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
    Semin Cancer Biol 22:166-72. 2012
    ..This article will focus on the nature of this complicated set of transcripts and the evidence that they contribute to the development of nasopharyngeal carcinoma...
  7. pmc Human tumor virus utilizes exosomes for intercellular communication
    David G Meckes
    The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Proc Natl Acad Sci U S A 107:20370-5. 2010
    ..The exosomes may manipulate the tumor microenvironment to influence the growth of neighboring cells through the intercellular transfer of LMP1, signaling molecules, and viral miRNAs...
  8. pmc Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta
    Che Pei Kung
    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Virol 85:4399-408. 2011
    ..These findings indicate that LMP1 activates multiple distinct signaling pathways and suggest that PKCδ functions as a master regulator of EGFR, STAT3, and ERK activation by LMP1-CTAR1...
  9. pmc The Epstein-Barr Virus BART microRNAs target the pro-apoptotic protein Bim
    Aron R Marquitz
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Virology 412:392-400. 2011
    ..These results are consistent with the BART miRNAs downregulating Bim post-transcriptionally in part through the 3'UTR and suggest that there are miRNA recognition sites within other areas of the Bim mRNA...
  10. pmc Microvesicles and viral infection
    David G Meckes
    Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 85:12844-54. 2011
    ..This review focuses on aspects of the biology of microvesicles with an emphasis on their potential contributions to viral infection and pathogenesis...
  11. pmc Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) and LMP2A function cooperatively to promote carcinoma development in a mouse carcinogenesis model
    Kathy H Y Shair
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 86:5352-65. 2012
    ..This study is the first to characterize the effects of LMP2 on tumor initiation and promotion and to identify an effect of the combined expression of LMP1 and LMP2 on the increase of carcinoma development...
  12. pmc Epstein-Barr virus latent membrane protein-2A-induced DeltaNp63alpha expression is associated with impaired epithelial-cell differentiation
    J A Fotheringham
    Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Oncogene 29:4287-96. 2010
    ..By associating with and being regulated by LMP2A, DeltaNp63alpha may function as a unique regulator of LMP2A effects on epithelial differentiation and contribute to EBV-associated epithelial cancers...
  13. pmc Epstein-Barr virus latent membrane protein 1 modulates distinctive NF- kappaB pathways through C-terminus-activating region 1 to regulate epidermal growth factor receptor expression
    Che Pei Kung
    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 84:6605-14. 2010
    ..These findings suggest that this novel NF-kappaB pathway is differentially regulated by TRAF2 and TRAF3, and that distinct interactions of LMP1 and its effectors regulate LMP1-mediated gene expression...
  14. ncbi Epstein-Barr virus latent membrane protein 1 CTAR1 mediates rodent and human fibroblast transformation through activation of PI3K
    Bernardo A Mainou
    Department of Microbiology Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Oncogene 24:6917-24. 2005
    ..These findings indicate that LMP1-mediated rodent fibroblast transformation is dependent upon activation of PI3K and Akt and is independent of activation of NF-kappaB...
  15. ncbi Multiple Epstein-Barr virus strains in patients with infectious mononucleosis: comparison of ex vivo samples with in vitro isolates by use of heteroduplex tracking assays
    Rosemary J Tierney
    Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
    J Infect Dis 193:287-97. 2006
    ....
  16. pmc LMP1 strain variants: biological and molecular properties
    Bernardo A Mainou
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 80:6458-68. 2006
    ..These findings indicate that the signature amino acid changes of the LMP1 variants do not hinder or enhance their in vitro transforming potentials or affect their signaling properties...
  17. pmc Unique signaling properties of CTAR1 in LMP1-mediated transformation
    Bernardo A Mainou
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 81:9680-92. 2007
    ..These findings identify a new signaling pathway that is uniquely activated by the TRAF-binding domain of LMP1 and is required for transformation...
  18. pmc Induction of epidermal growth factor receptor expression by Epstein-Barr virus latent membrane protein 1 C-terminal-activating region 1 is mediated by NF-kappaB p50 homodimer/Bcl-3 complexes
    Natalie J Thornburg
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 81:12954-61. 2007
    ..The distinct forms of NF-kappaB that are induced by LMP1 CTAR1 likely activate distinct cellular genes...
  19. pmc Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor through effects on Bcl-3 and STAT3
    Che Pei Kung
    Department of Microbiology Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Virol 82:5486-93. 2008
    ..The increased nuclear Bcl-3 and p50 homodimer complexes positively regulate EGFR expression. These results indicate that LMP1 likely regulates distinct cellular genes by activating specific NF-kappaB pathways...
  20. pmc The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation
    David N Everly
    Lineberger Comprehensive Cancer Center, CB 7295, University of North Carolina Chapel Hill, 450 West Drive, Chapel Hill, NC 27599 7295, USA
    Virology 376:258-69. 2008
    ..These data indicate that overexpression of the Id proteins is not sufficient for the effects of LMP1 on the cell cycle but that inhibition of Id expression does affect the growth of LMP1-transformed and parental Rat1 cells...
  21. pmc Epstein-Barr virus BART microRNAs are produced from a large intron prior to splicing
    Rachel Hood Edwards
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 82:9094-106. 2008
    ..These findings indicate that multiple factors contribute to the production of the BART miRNAs and to the apparent differences in abundance between the individual miRNAs of the cluster...
  22. pmc EBV latent membrane protein 1 effects on plakoglobin, cell growth, and migration
    Kathy H Y Shair
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
    Cancer Res 68:6997-7005. 2008
    ....
  23. pmc Epstein-Barr virus latent membrane protein-1 effects on junctional plakoglobin and induction of a cadherin switch
    Kathy H Y Shair
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Cancer Res 69:5734-42. 2009
    ..Low levels of plakoglobin were also detected in human NPC tissues. These findings reveal that the effects of LMP1 on junctional plakoglobin and the initiation of a cadherin switch likely contribute to metastasis of NPC...
  24. pmc Transcriptional downregulation of p27KIP1 through regulation of E2F function during LMP1-mediated transformation
    David N Everly
    Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA
    J Virol 83:12671-9. 2009
    ..These findings indicate that LMP1 decreases p27 transcription through effects on E2F family transcription factors. This property likely contributes to the ability of LMP1 to stimulate cell cycle progression...
  25. pmc Roles of the ITAM and PY motifs of Epstein-Barr virus latent membrane protein 2A in the inhibition of epithelial cell differentiation and activation of {beta}-catenin signaling
    Jennifer A Morrison
    Department of Microbiology and Immunology, University of North Carolina Chapel Hill, Mason Farm Rd, Chapel Hill, NC 27599, USA
    J Virol 79:2375-82. 2005
    ..LMP2A is expressed in the EBV-associated epithelial malignancies nasopharyngeal carcinoma and gastric carcinoma, and these data indicate that LMP2A affects cellular processes that likely contribute to carcinogenesis...