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. ncbi 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
  2. ncbi 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
  3. ncbi 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
  4. ncbi 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
  5. ncbi 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
  6. ncbi 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
  7. ncbi 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
  8. ncbi 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
  9. ncbi 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
  10. 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

Scientific Experts

  • David N Everly
  • Nancy Raab-Traub
  • Bernardo A Mainou
  • Kathy H Y Shair
  • Rachel Hood Edwards
  • Caroline I Schnegg
  • Che Pei Kung
  • Natalie J Thornburg
  • Rosemary J Tierney
  • Jennifer A Morrison
  • Che-Pei Kung
  • Aron R Marquitz
  • Alan B Rickinson
  • Deborah Croom-Carter
  • Diane Sitki-Green
  • Sushmita Roy
  • Qing-yun Yao

Detail Information

Publications12

  1. ncbi 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...
  2. ncbi 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...
  3. ncbi 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
    ....
  4. ncbi 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...
  5. ncbi 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...
  6. ncbi 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...
  7. ncbi 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...
  8. ncbi 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...
  9. ncbi 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...
  10. 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
    ....
  11. 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...
  12. ncbi 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...