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, SB1
Selvarajan, V1
Huang, G6
Zhou, J6
Feldman, AL2
Law, M2
Kwong, YL5
Shimizu, N7
Kagami, Y4
Aozasa, K3
SaltoTellez, M1 6
Chng, WJ6
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
2011 Impact Factor: 6.318
2011 SCImago Journal Rankings: 0.946
DOIhttp://dx.doi.org/10.1002/path.2823
ReferencesReferences in Scopus
DC Field
Value
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
2011 Impact Factor: 6.318
2011 SCImago Journal Rankings: 0.946
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
Author Affiliations
  1. Yong Loo Lin School of Medicine
  2. Mayo Clinic
  3. Osaka University
  4. Toyota Kosei Hospital
  5. Queen Mary Hospital Hong Kong
  6. National University of Singapore
  7. Tokyo Medical and Dental University