Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma

Abstract

To identify the molecular mechanisms by which EBVassociated 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 oncogenemediated 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. (Cancer Res 2006; 66(16): 7999-8006)

MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins

“…In a recent report on cholangiocytes/cholangiocarcinoma, mir-29b was shown to regulate expression of the antiapoptotic protein Mcl-1 by inhibiting its translation without affecting Mcl-1 mRNA levels (26). Consistent with these observations, despite a 4-fold decrease in mir-29b levels in NPC tumor cells (Table S2), Mcl-1 mRNA levels also remained unchanged in NPC (17). It is feasible that the level of Mcl-1 protein is likewise increased in NPC tumor cells because of the reduced action of mir-29b, contributing to suppression of apoptosis.…”

“…teins in the studied tumor samples might have come from the stromal cells supporting those tumors (38). Our use of laser capture to isolate tumor cells essentially free of stromal contaminants (17) indicates that NPC tumor cells themselves upregulate mRNAs encoding collagens and laminins. mir-29c is a member of the mir-29 family that also includes the closely related mir-29a and mir-29b.…”

“…Using bioinformatic approaches, we identified candidate target genes of these eight miRNAs. Next, we analyzed our previous mRNA expression profiling data of these same specimens (17) to identify candidate target genes that were differentially expressed, possibly because of action of these miRNAs. Among the differentially expressed candidate target genes of the eight miRNAs, those of mir-29c showed a group of 15 genes, 10 of which were extracellular matrix components involved in cell migration and metastasis (Table 2).…”

“…We previously analyzed differential gene expression in NPC relative to normal nasopharyngeal epithelium that could underlie the properties of this tumor, which elucidated the contribution of EBV genes toward immune evasion of tumor cells in this cancer and further implicated DNA repair and nitrosamine metabolism mechanisms in NPC pathogenesis (17,18). For the current study, we developed a sensitive method to measure miRNAs to determine whether they, too, could contribute to the properties of NPC.…”

CD24 blunts oral squamous cancer development and dampens the functional expansion of myeloid-derived suppressor cells

“…19,20 Oncomine Ò Power Tools 21 was used to analyze the relationship between CD24 gene expression and oral cancer progression as well as patient outcome based on publically available datasets. 22,23 We found that oral cavity squamous cell carcinoma cancer patients with regional lymph node metastasis showed lower expression of CD24 mRNA compared to patients without metastasis (Fig. 1A).…”