Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways.
Gene expression profiling of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly reveals alterations of characteristic oncogenetic pathways.
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DOI：
10.1111/cas.12389
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发表时间：
2014-05
期刊：
影响因子：
5.7
通讯作者：
Seto M
中科院分区：
文献类型：
--
作者：
Kato H;Karube K;Yamamoto K;Takizawa J;Tsuzuki S;Yatabe Y;Kanda T;Katayama M;Ozawa Y;Ishitsuka K;Okamoto M;Kinoshita T;Ohshima K;Nakamura S;Morishima Y;Seto M
EB病毒（EBV）阳性的老年弥漫性大B细胞淋巴瘤（DLBCL）（EBV[+]DLBCL-E）被归类为DLBCL的一种亚型。到目前为止，其分子发病机制仍不清楚。为了鉴定EBV（+）DLBCL-E的特征性途径，使用人寡核苷酸微阵列分析对5例EBV（+）DLBCL-E和7例EBV阴性DLBCL（EBV[−]DLBCL）病例进行基因表达谱分析。基因集富集分析和基因本体分析显示，Janus激酶-信号转导子和转录激活子（JAK-STAT）通路和核因子κ B（NF-κB）通路的基因集在EBV（+）DLBCL-E病例中富集。为了确认表达谱的结果，进行了体外分析。表达谱分析显示，EBV感染DLBCL细胞后，JAK-STAT和NF-κB通路高度活化。使用电泳迁移率变动分析证实了EBV感染细胞系中NF-κB通路的激活。Western印迹分析显示，在EBV感染的细胞系中，磷酸化信号转导子和转录激活子3（STAT 3）的蛋白表达水平增加。使用免疫组织化学，在EBV（+）DLBCL-E临床样本的淋巴瘤细胞中经常观察到磷酸化STAT 3的蛋白表达（EBV[+] DLBCL-E：80. 0%[n = 20/25] vs EBV[−]DLBCL：38. 9%[n = 14/36]; P = 0. 001）。本研究结果提示，JAK-STAT和NF-κB通路的激活是EBV（+）DLBCL-E的特征，这可能反映了EBV阳性肿瘤细胞的性质。靶向这些途径作为治疗可能会改善EBV（+）DLBCL-E的临床结局。
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.
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通讯作者：
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