Epstein-Barr-virus-encoded LMP2A induces primary epithelial cell migration and invasion: possible role in nasopharyngeal carcinoma metastasis.
Nonkeratinizing nasopharyngeal carcinomas (NPC) are >95% associated with the expression of the Epstein-Barr virus (EBV) LMP2A latent protein. However, the role of EBV, in particular, LMP2A, in tumor progression is not well understood. Using Affymetrix chips and a pattern-matching computational technique (neighborhood analysis), we show that the level of LMP2A expression in NPC biopsy samples correlates with that of a cellular protein, integrin-alpha-6 (ITGalpha6), that is associated with cellular migration in vitro and metastasis in vivo. We have recently developed a primary epithelial model from tonsil tissue to study EBV infection in epithelial cells. Here we report that LMP2A expression in primary tonsil epithelial cells causes them to become migratory and invasive, that ITGalpha6 RNA levels are up-regulated in epithelial cells expressing LMP2, and that ITGalpha6 protein levels are increased in the migrating cells. Blocking antibodies against ITGalpha6 abrogated LMP2-induced invasion through Matrigel by primary epithelial cells. Our results provide a link between LMP2A expression, ITGalpha6 expression, epithelial cell migration, and NPC metastasis and suggest that EBV infection may contribute to the high incidence of metastasis in NPC progression.
Pegtel
Dirk M
DM
Department of Pathology, Tufts University School of Medicine, Jaharis Building, 150 Harrison Ave., Boston, MA 02111, USA.
Subramanian
Aravind
A
Sheen
Tzung-Shiahn
TS
Tsai
Ching-Hwa
CH
Golub
Todd R
TR
Thorley-Lawson
David A
DA
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000737:chemistry*; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000503:physiopathology* / Q000821:virology; D009305:Nasopharynx / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000503:physiopathology; D014763:Viral Matrix Proteins / Q000494:pharmacology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins