Cell growth and matrix invasion of EBV-immortalized human B lymphocytes is regulated by expression of alpha(v) integrins.
alpha(v) integrins have been shown to play an important role in epithelial-derived cell migration, cell growth and tumor invasion/metastasis, however their role on cells of hematopoietic origin is less clear. Epstein-Barr virus (EBV), a human herpesvirus associated with several lymphoproliferative disorders in man, induces expression of alpha(v) integrins on transformed B lymphocytes. In the studies reported here, we show that EBV infection increases alpha(v), beta3 and beta5 integrin subunit mRNAs as well as upregulates the expression of the alphavbeta3 integrin protein on human B cells. Among the nine different EBV proteins expressed in latently infected B cells (nuclear and plasma membrane-associated), only LMP1, LMP2A and EBNA2 were shown to selectively transactivate the alpha(v) integrin promoter. Treatment of EBV-transformed B cells with alpha(v) antisense oligonucleotides specifically reduced cell surface expression of alpha(v) integrins, inhibited cell growth in low serum, reduced cell invasion in matrigels and decreased expression of metalloprotease, MMP9. These studies indicate that alpha(v) integrins play a significant role in EBV-induced B-lymphocyte proliferation and invasion. Strategies to interfere with alphav integrin expression and/or function may therefore be of potential value in the treatment of EBV-associated lymphoproliferative disorders.
Huang
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S
Department of Immunology, IMM19 The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, CA 92037, USA.
Stupack
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D
Liu
A
A
Cheresh
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D
Nemerow
G R
GR
D015703:Antigens, CD / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division; D002461:Cell Line, Transformed; D019309:Epstein-Barr Virus Nuclear Antigens; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D039564:Integrin alphaV; D016023:Integrins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D015533:Transcriptional Activation; D014763:Viral Matrix Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D015703:Antigens, CD; C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D039564:Integrin alphaV; D016023:Integrins; D016376:Oligonucleotides, Antisense; D014763:Viral Matrix Proteins; D014764:Viral Proteins