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Article: Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling

TitleActivated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling
Authors
Issue Date2011
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal Of Pathology, 2011, v. 223 n. 4, p. 496-510 How to Cite?
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-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.
Persistent Identifierhttp://hdl.handle.net/10722/163360
ISSN
2013 Impact Factor: 7.330
ISI Accession Number ID
References

 

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
DC FieldValueLanguage
dc.contributor.authorNg, SBen_US
dc.contributor.authorSelvarajan, Ven_US
dc.contributor.authorHuang, Gen_US
dc.contributor.authorZhou, Jen_US
dc.contributor.authorFeldman, ALen_US
dc.contributor.authorLaw, Men_US
dc.contributor.authorKwong, YLen_US
dc.contributor.authorShimizu, Nen_US
dc.contributor.authorKagami, Yen_US
dc.contributor.authorAozasa, Ken_US
dc.contributor.authorSaltoTellez, Men_US
dc.contributor.authorChng, WJen_US
dc.date.accessioned2012-09-05T05:30:33Z-
dc.date.available2012-09-05T05:30:33Z-
dc.date.issued2011en_US
dc.identifier.citationJournal Of Pathology, 2011, v. 223 n. 4, p. 496-510en_US
dc.identifier.issn0022-3417en_US
dc.identifier.urihttp://hdl.handle.net/10722/163360-
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.en_US
dc.languageengen_US
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130en_US
dc.relation.ispartofJournal of Pathologyen_US
dc.subject.meshAdolescenten_US
dc.subject.meshAdulten_US
dc.subject.meshAgeden_US
dc.subject.meshAged, 80 And Overen_US
dc.subject.meshApoptosis - Drug Effectsen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Expression Profiling - Methodsen_US
dc.subject.meshGene Regulatory Networksen_US
dc.subject.meshGenome-Wide Association Studyen_US
dc.subject.meshHumansen_US
dc.subject.meshInhibitor Of Apoptosis Proteinsen_US
dc.subject.meshKiller Cells, Natural - Metabolismen_US
dc.subject.meshLymphoma, Extranodal Nk-T-Cell - Genetics - Immunology - Metabolism - Pathologyen_US
dc.subject.meshMaleen_US
dc.subject.meshMicrotubule-Associated Proteins - Antagonists & Inhibitors - Metabolism - Physiologyen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshNf-Kappa B - Metabolismen_US
dc.subject.meshNeoplasm Proteins - Metabolismen_US
dc.subject.meshNordihydroguaiaretic Acid - Analogs & Derivatives - Pharmacologyen_US
dc.subject.meshNose Neoplasms - Genetics - Immunology - Metabolism - Pathologyen_US
dc.subject.meshOncogenes - Physiologyen_US
dc.subject.meshProto-Oncogene Proteins C-Myc - Metabolismen_US
dc.subject.meshTumor Cells, Cultureden_US
dc.subject.meshTumor Suppressor Protein P53 - Metabolismen_US
dc.subject.meshYoung Adulten_US
dc.titleActivated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profilingen_US
dc.typeArticleen_US
dc.identifier.emailKwong, YL:ylkwong@hku.hken_US
dc.identifier.authorityKwong, YL=rp00358en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/path.2823en_US
dc.identifier.pmid21294123en_US
dc.identifier.scopuseid_2-s2.0-79551696483en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79551696483&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume223en_US
dc.identifier.issue4en_US
dc.identifier.spage496en_US
dc.identifier.epage510en_US
dc.identifier.isiWOS:000287672100006-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridNg, SB=7403358752en_US
dc.identifier.scopusauthoridSelvarajan, V=37075646500en_US
dc.identifier.scopusauthoridHuang, G=7403424897en_US
dc.identifier.scopusauthoridZhou, J=7405551697en_US
dc.identifier.scopusauthoridFeldman, AL=7202334040en_US
dc.identifier.scopusauthoridLaw, M=35329862900en_US
dc.identifier.scopusauthoridKwong, YL=7102818954en_US
dc.identifier.scopusauthoridShimizu, N=7403575308en_US
dc.identifier.scopusauthoridKagami, Y=7006467850en_US
dc.identifier.scopusauthoridAozasa, K=35381404000en_US
dc.identifier.scopusauthoridSaltoTellez, M=7003434917en_US
dc.identifier.scopusauthoridChng, WJ=8717348700en_US
dc.identifier.citeulike8511490-

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