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Article: Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling
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TitleActivated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling
 
AuthorsNg, SB2
Selvarajan, V2
Huang, G7
Zhou, J7
Feldman, AL1
Law, M1
Kwong, YL5
Shimizu, N6
Kagami, Y4
Aozasa, K3
SaltoTellez, M2 7
Chng, WJ7
 
Issue Date2011
 
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
 
CitationJournal Of Pathology, 2011, v. 223 n. 4, p. 496-510 [How to Cite?]
DOI: http://dx.doi.org/10.1002/path.2823
 
AbstractWe performed comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed, paraffin-embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle-related genes and pathways, such as PLK1, CDK1, and Aurora-A. Furthermore, our results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF-κB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c-Myc (45.4%), p53 (87.9%), and NF-κB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF-κB, possibly driven by EBV LMP-1, results in the cumulative up-regulation of survivin. Down-regulation of survivin with Terameprocol (EM-1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL. © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
 
ISSN0022-3417
2013 Impact Factor: 7.330
 
DOIhttp://dx.doi.org/10.1002/path.2823
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorNg, SB
 
dc.contributor.authorSelvarajan, V
 
dc.contributor.authorHuang, G
 
dc.contributor.authorZhou, J
 
dc.contributor.authorFeldman, AL
 
dc.contributor.authorLaw, M
 
dc.contributor.authorKwong, YL
 
dc.contributor.authorShimizu, N
 
dc.contributor.authorKagami, Y
 
dc.contributor.authorAozasa, K
 
dc.contributor.authorSaltoTellez, M
 
dc.contributor.authorChng, WJ
 
dc.date.accessioned2012-09-05T05:30:33Z
 
dc.date.available2012-09-05T05:30:33Z
 
dc.date.issued2011
 
dc.description.abstractWe performed comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed, paraffin-embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle-related genes and pathways, such as PLK1, CDK1, and Aurora-A. Furthermore, our results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF-κB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c-Myc (45.4%), p53 (87.9%), and NF-κB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF-κB, possibly driven by EBV LMP-1, results in the cumulative up-regulation of survivin. Down-regulation of survivin with Terameprocol (EM-1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL. © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Pathology, 2011, v. 223 n. 4, p. 496-510 [How to Cite?]
DOI: http://dx.doi.org/10.1002/path.2823
 
dc.identifier.citeulike8511490
 
dc.identifier.doihttp://dx.doi.org/10.1002/path.2823
 
dc.identifier.epage510
 
dc.identifier.issn0022-3417
2013 Impact Factor: 7.330
 
dc.identifier.issue4
 
dc.identifier.pmid21294123
 
dc.identifier.scopuseid_2-s2.0-79551696483
 
dc.identifier.spage496
 
dc.identifier.urihttp://hdl.handle.net/10722/163360
 
dc.identifier.volume223
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofJournal of Pathology
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAdolescent
 
dc.subject.meshAdult
 
dc.subject.meshAged
 
dc.subject.meshAged, 80 And Over
 
dc.subject.meshApoptosis - Drug Effects
 
dc.subject.meshFemale
 
dc.subject.meshGene Expression Profiling - Methods
 
dc.subject.meshGene Regulatory Networks
 
dc.subject.meshGenome-Wide Association Study
 
dc.subject.meshHumans
 
dc.subject.meshInhibitor Of Apoptosis Proteins
 
dc.subject.meshKiller Cells, Natural - Metabolism
 
dc.subject.meshLymphoma, Extranodal Nk-T-Cell - Genetics - Immunology - Metabolism - Pathology
 
dc.subject.meshMale
 
dc.subject.meshMicrotubule-Associated Proteins - Antagonists & Inhibitors - Metabolism - Physiology
 
dc.subject.meshMiddle Aged
 
dc.subject.meshNf-Kappa B - Metabolism
 
dc.subject.meshNeoplasm Proteins - Metabolism
 
dc.subject.meshNordihydroguaiaretic Acid - Analogs & Derivatives - Pharmacology
 
dc.subject.meshNose Neoplasms - Genetics - Immunology - Metabolism - Pathology
 
dc.subject.meshOncogenes - Physiology
 
dc.subject.meshProto-Oncogene Proteins C-Myc - Metabolism
 
dc.subject.meshTumor Cells, Cultured
 
dc.subject.meshTumor Suppressor Protein P53 - Metabolism
 
dc.subject.meshYoung Adult
 
dc.titleActivated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling
 
dc.typeArticle
 
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<description.abstract>We performed comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed, paraffin-embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle-related genes and pathways, such as PLK1, CDK1, and Aurora-A. Furthermore, our results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF-&#954;B), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c-Myc (45.4%), p53 (87.9%), and NF-&#954;B p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF-&#954;B, possibly driven by EBV LMP-1, results in the cumulative up-regulation of survivin. Down-regulation of survivin with Terameprocol (EM-1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL. &#169; 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.</description.abstract>
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Author Affiliations
  1. Mayo Clinic
  2. Yong Loo Lin School of Medicine
  3. Osaka University
  4. Toyota Kosei Hospital
  5. Queen Mary Hospital Hong Kong
  6. Tokyo Medical and Dental University
  7. National University of Singapore