Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways.
Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[+]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV(+)DLBCL-E, gene expression profiling of five EBV(+)DLBCL-E and seven EBV-negative DLBCL (EBV[-]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-κB) pathways were enriched in EBV(+)DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-κB pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-κB pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV-infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL-E clinical samples using immunohistochemistry (EBV[+]DLBCL-E: 80.0% [n = 20/25] versus EBV[-]DLBCL: 38.9% [n = 14/36]; P = 0.001). The results of the present study suggest that activation of the JAK-STAT and NF-κB pathways was characteristic of EBV(+)DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL-E.
['Kato|Harumi|H|', 'Karube|Kennosuke|K|', 'Yamamoto|Kazuhito|K|', 'Takizawa|Jun|J|', 'Tsuzuki|Shinobu|S|', 'Yatabe|Yasushi|Y|', 'Kanda|Teru|T|', 'Katayama|Miyuki|M|', 'Ozawa|Yukiyasu|Y|', 'Ishitsuka|Kenji|K|', 'Okamoto|Masataka|M|', 'Kinoshita|Tomohiro|T|', 'Ohshima|Koichi|K|', 'Nakamura|Shigeo|S|', 'Morishima|Yasuo|Y|', 'Seto|Masao|M|']
D000328:Adult D000368:Aged D000375:Aging D014408:Biomarkers, Tumor D024202:Electrophoretic Mobility Shift Assay D004789:Enzyme Activation D020031:Epstein-Barr Virus Infections D005260:Female D020869:Gene Expression Profiling D004854:Herpesvirus 4, Human D006801:Humans D053612:Janus Kinases D016403:Lymphoma, Large B-Cell, Diffuse D008297:Male D008875:Middle Aged D016328:NF-kappa B D020411:Oligonucleotide Array Sequence Analysis D050796:STAT3 Transcription Factor
gene expression profiling lymphoma Epstein-Barr virus NF-κB STAT3