title: Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways.
abstract: 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.
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan; Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kato
authors.forename: Kennosuke
authors.initials: K
authors.lastname: Karube
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Takizawa
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Teru
authors.initials: T
authors.lastname: Kanda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Katayama
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Masataka
authors.initials: M
authors.lastname: Okamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging; D014408:Biomarkers, Tumor / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053612:Janus Kinases
keywords: Epstein-Barr virus; NF-κB; STAT3; gene expression profiling; lymphoma