Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma.
To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC.
Sengupta
Srikumar
S
Institute for Molecular Virology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
den Boon
Johan A
JA
Chen
I-How
IH
Newton
Michael A
MA
Dahl
David B
DB
Chen
Meng
M
Cheng
Yu-Juen
YJ
Westra
William H
WH
Chen
Chien-Jen
CJ
Hildesheim
Allan
A
Sugden
Bill
B
Ahlquist
Paul
P
D001706:Biopsy; D020869:Gene Expression Profiling; D005814:Genes, Viral; D015894:Genome, Human; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D015994:Incidence; D009303:Nasopharyngeal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012016:Reference Values; D014481:United States / Q000453:epidemiology
D015395:Histocompatibility Antigens Class I