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

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 - Cancer Sci. (2014)

Bottom Line: To confirm the results of the expression profiles, in vitro analysis was performed.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.

View Article: PubMed Central - PubMed

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.

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Gene Set Enrichment Analysis (GSEA) using a signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signature, and a model depicting the molecular pathways. (a, b) A GSEA was performed to compare Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV[+]DLBCL-E) and EBV-negative DLBCL (EBV[−]DLBCL) cases using (a) STAT323 and (b) NF-κB29 gene sets. The graph at the bottom of each panel shows the ranked list metric (signal-to-noise ratio) for each gene as a function of the rank in the ordered dataset.19 The two gene sets were overexpressed in EBV(+)DLBCL-E compared with EBV(−)DLBCL. Activation of these pathways is suggested to be characteristic of EBV(+)DLBCL-E. (c) NF-κB is downstream of the TOLL-like receptor (TLR) pathway and NF-κB is also activated with nucleotide-binding oligomerization domain (NOD)-like receptor signals.27 JAK-STAT, triggered by interleukin-6 (IL6), has a cross-talk with NF-κB pathway activation.28
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fig02: Gene Set Enrichment Analysis (GSEA) using a signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signature, and a model depicting the molecular pathways. (a, b) A GSEA was performed to compare Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV[+]DLBCL-E) and EBV-negative DLBCL (EBV[−]DLBCL) cases using (a) STAT323 and (b) NF-κB29 gene sets. The graph at the bottom of each panel shows the ranked list metric (signal-to-noise ratio) for each gene as a function of the rank in the ordered dataset.19 The two gene sets were overexpressed in EBV(+)DLBCL-E compared with EBV(−)DLBCL. Activation of these pathways is suggested to be characteristic of EBV(+)DLBCL-E. (c) NF-κB is downstream of the TOLL-like receptor (TLR) pathway and NF-κB is also activated with nucleotide-binding oligomerization domain (NOD)-like receptor signals.27 JAK-STAT, triggered by interleukin-6 (IL6), has a cross-talk with NF-κB pathway activation.28

Mentions: For greater characterization, we then performed Gene Ontology Analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the WebGestalt website. The differentially expressed probes with an average expression level of more than 0.5 log fold-change (268 probes in EBV[+]DLBCL-E and 275 probes in EBV[−]DLBCL) were used in both analyses. Additionally, GSEA was carried out using the KEGG pathway-associated gene sets from the Molecular Signatures Database (186 gene sets) (Table S2). These analyses revealed that JAK-STAT, nucleotide-binding oligomerization domain (NOD)-like receptor and Toll-like receptor pathways were characteristic of EBV(+)DLBCL-E. Tables2, S4 and S5 show the results of the pathway analyses. The protein of STAT3 encoded by this gene is a member of the STAT protein family and the protein of STAT3 is activated through phosphorylation in response to IL6. It is known that STAT3 is activated in B-cell lymphoma. Therefore, we focused on the analysis of STAT3 and performed GSEA analysis using STAT3 and the STAT3 target gene set (Table S2) reported previously23 and found that the gene sets were enriched in EBV(+)DLBCL-E cases (Fig.2a, Table S6). Constitutive activation of STAT3 was indicated as a characteristic of EBV(+)DLBCL-E.


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

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 - Cancer Sci. (2014)

Gene Set Enrichment Analysis (GSEA) using a signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signature, and a model depicting the molecular pathways. (a, b) A GSEA was performed to compare Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV[+]DLBCL-E) and EBV-negative DLBCL (EBV[−]DLBCL) cases using (a) STAT323 and (b) NF-κB29 gene sets. The graph at the bottom of each panel shows the ranked list metric (signal-to-noise ratio) for each gene as a function of the rank in the ordered dataset.19 The two gene sets were overexpressed in EBV(+)DLBCL-E compared with EBV(−)DLBCL. Activation of these pathways is suggested to be characteristic of EBV(+)DLBCL-E. (c) NF-κB is downstream of the TOLL-like receptor (TLR) pathway and NF-κB is also activated with nucleotide-binding oligomerization domain (NOD)-like receptor signals.27 JAK-STAT, triggered by interleukin-6 (IL6), has a cross-talk with NF-κB pathway activation.28
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getmorefigures.php?uid=PMC4317839&req=5

fig02: Gene Set Enrichment Analysis (GSEA) using a signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signature, and a model depicting the molecular pathways. (a, b) A GSEA was performed to compare Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV[+]DLBCL-E) and EBV-negative DLBCL (EBV[−]DLBCL) cases using (a) STAT323 and (b) NF-κB29 gene sets. The graph at the bottom of each panel shows the ranked list metric (signal-to-noise ratio) for each gene as a function of the rank in the ordered dataset.19 The two gene sets were overexpressed in EBV(+)DLBCL-E compared with EBV(−)DLBCL. Activation of these pathways is suggested to be characteristic of EBV(+)DLBCL-E. (c) NF-κB is downstream of the TOLL-like receptor (TLR) pathway and NF-κB is also activated with nucleotide-binding oligomerization domain (NOD)-like receptor signals.27 JAK-STAT, triggered by interleukin-6 (IL6), has a cross-talk with NF-κB pathway activation.28
Mentions: For greater characterization, we then performed Gene Ontology Analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the WebGestalt website. The differentially expressed probes with an average expression level of more than 0.5 log fold-change (268 probes in EBV[+]DLBCL-E and 275 probes in EBV[−]DLBCL) were used in both analyses. Additionally, GSEA was carried out using the KEGG pathway-associated gene sets from the Molecular Signatures Database (186 gene sets) (Table S2). These analyses revealed that JAK-STAT, nucleotide-binding oligomerization domain (NOD)-like receptor and Toll-like receptor pathways were characteristic of EBV(+)DLBCL-E. Tables2, S4 and S5 show the results of the pathway analyses. The protein of STAT3 encoded by this gene is a member of the STAT protein family and the protein of STAT3 is activated through phosphorylation in response to IL6. It is known that STAT3 is activated in B-cell lymphoma. Therefore, we focused on the analysis of STAT3 and performed GSEA analysis using STAT3 and the STAT3 target gene set (Table S2) reported previously23 and found that the gene sets were enriched in EBV(+)DLBCL-E cases (Fig.2a, Table S6). Constitutive activation of STAT3 was indicated as a characteristic of EBV(+)DLBCL-E.

Bottom Line: To confirm the results of the expression profiles, in vitro analysis was performed.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.

View Article: PubMed Central - PubMed

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.

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Related in: MedlinePlus