Gene expression profiling of Epstein–Barr virus‐positive diffuse large B‐cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways

Cancer Science

Harumi Kato³  Kennosuke Karube³  Kazuhito Yamamoto¹⁰  Jun Takizawa⁸  Shinobu Tsuzuki³  Yasushi Yatabe⁴  Teru Kanda⁵  Miyuki Katayama³  Yukiyasu Ozawa⁶  Kenji Ishitsuka²  Masataka Okamoto¹  Tomohiro Kinoshita¹⁰  Koichi Ohshima⁷  Shigeo Nakamura⁴  Yasuo Morishima^3,9 

[1] Department of Hematology and Oncology, Fujita-Health University School of Medicine, Toyoake, Aichi, Japan;Division of Medical Oncology, Hematology and Infectious Disease, Fukuoka University, Fukuoka, Japan;Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan;Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan;Division of Virology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan;Department of Transfusion Medicine, Japanese Red Cross Nagoya First Hospital, Nagoya, Aichi, Japan;Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan;Division of Hematology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan;Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan;Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan

关键词: Epstein–Barr virus;    gene expression profiling;    lymphoma;    NF‐κB;    STAT3;   

DOI  :  10.1111/cas.12389

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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