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Article: Inhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV-associated nasopharyngeal carcinoma

TitleInhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV-associated nasopharyngeal carcinoma
Authors
Issue Date2012
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal Of Pathology, 2012, v. 226 n. 3, p. 471-481 How to Cite?
AbstractNasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy which is prevalent in south-east Asia and southern China. Despite the multiple genetic and epigenetic changes reported, the contribution of dysregulated signalling pathways to this distinct type of head and neck cancer is not well understood. Here we demonstrate the up-regulation of NOTCH ligands (JAG1 or DLL4) and effector (HEY1) in the majority of EBV-positive tumour lines and primary tumours. Among the NOTCH receptors, NOTCH3 was over-expressed in all EBV-positive tumour lines and 92.5% of primary tumours. Aberrant activation of NOTCH3 signalling was consistently detected in all these samples. These findings imply that NOTCH3 may play an crucial role in the development of NPC. By NOTCH3 specific siRNA, NOTCH3 signalling was suppressed and thereby significant growth inhibition and apoptosis induction occurred in NPC cells. Down-regulation of a number of targets involved in cell proliferation, eg CCND1, C-MYC,NFKB1, and survival, eg BCL2, BCL-XL, SURVIVIN, was confirmed in the NOTCH3 knockdown NPC cells. Importantly, NOTCH3 knockdown highly enhanced the sensitivity of NPC cells to cisplatin treatment. Furthermore, we revealed that the ability of NPC cells to form spheroids in vitro and tumours in nude mice was also significantly decreased after knockdown of NICD3 expression. These findings indicate that activation of NOTCH3 pathway is a critical oncogenic event in NPC tumourigenesis. Targeting NOTCH3 signalling may serve as a potential therapeutic approach for treating patients suffering from EBV-associated NPC. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/149777
ISSN
2015 Impact Factor: 7.381
2015 SCImago Journal Rankings: 4.176
ISI Accession Number ID
Funding AgencyGrant Number
Michael and Betty Kadoorie Cancer Genetics Research Program IIMBKCGRPII
Li Ka Shing Institute of Health Science
Hong Kong Research Grant Council471709
471407
HKU779810
CUHK4/CRF/08
RGC AoEAoE/M-06/08
Funding Information:

This work was supported by the Michael and Betty Kadoorie Cancer Genetics Research Program II (Grant No. MBKCGRPII), the Li Ka Shing Institute of Health Science and the Hong Kong Research Grant Council (Grant Nos 471709, 471407, HKU779810 and CUHK4/CRF/08). SW Tsao and TT Yip were supported by the RGC AoE Funding (Grant No. AoE/M-06/08). The authors would like to express their gratitude to Professor CK Wong for his assistance in flow cytometry analysis.

References
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DC FieldValueLanguage
dc.contributor.authorMan, CHen_US
dc.contributor.authorLun, SWMen_US
dc.contributor.authorHui, JWYen_US
dc.contributor.authorTo, KFen_US
dc.contributor.authorChoy, KWen_US
dc.contributor.authorChan, AWHen_US
dc.contributor.authorChow, Cen_US
dc.contributor.authorChung, GTYen_US
dc.contributor.authorTsao, SWen_US
dc.contributor.authorYip, TTCen_US
dc.contributor.authorBusson, Pen_US
dc.contributor.authorLo, KWen_US
dc.creatorjt 130815-
dc.date.accessioned2012-06-26T05:58:28Z-
dc.date.available2012-06-26T05:58:28Z-
dc.date.issued2012en_US
dc.identifier.citationJournal Of Pathology, 2012, v. 226 n. 3, p. 471-481en_US
dc.identifier.issn0022-3417en_US
dc.identifier.urihttp://hdl.handle.net/10722/149777-
dc.description.abstractNasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy which is prevalent in south-east Asia and southern China. Despite the multiple genetic and epigenetic changes reported, the contribution of dysregulated signalling pathways to this distinct type of head and neck cancer is not well understood. Here we demonstrate the up-regulation of NOTCH ligands (JAG1 or DLL4) and effector (HEY1) in the majority of EBV-positive tumour lines and primary tumours. Among the NOTCH receptors, NOTCH3 was over-expressed in all EBV-positive tumour lines and 92.5% of primary tumours. Aberrant activation of NOTCH3 signalling was consistently detected in all these samples. These findings imply that NOTCH3 may play an crucial role in the development of NPC. By NOTCH3 specific siRNA, NOTCH3 signalling was suppressed and thereby significant growth inhibition and apoptosis induction occurred in NPC cells. Down-regulation of a number of targets involved in cell proliferation, eg CCND1, C-MYC,NFKB1, and survival, eg BCL2, BCL-XL, SURVIVIN, was confirmed in the NOTCH3 knockdown NPC cells. Importantly, NOTCH3 knockdown highly enhanced the sensitivity of NPC cells to cisplatin treatment. Furthermore, we revealed that the ability of NPC cells to form spheroids in vitro and tumours in nude mice was also significantly decreased after knockdown of NICD3 expression. These findings indicate that activation of NOTCH3 pathway is a critical oncogenic event in NPC tumourigenesis. Targeting NOTCH3 signalling may serve as a potential therapeutic approach for treating patients suffering from EBV-associated NPC. Copyright © 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.meshAnimalsen_US
dc.subject.meshAntineoplastic Agents - Pharmacologyen_US
dc.subject.meshApoptosis - Physiologyen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Proliferationen_US
dc.subject.meshCell Transformation, Neoplastic - Drug Effectsen_US
dc.subject.meshCisplatin - Pharmacologyen_US
dc.subject.meshEpstein-Barr Virus Infections - Complicationsen_US
dc.subject.meshGene Knockdown Techniquesen_US
dc.subject.meshGenes, Neoplasm - Physiologyen_US
dc.subject.meshHumansen_US
dc.subject.meshInhibitor Of Apoptosis Proteins - Metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Nudeen_US
dc.subject.meshNasopharyngeal Neoplasms - Drug Therapy - Virologyen_US
dc.subject.meshNeoplasm Transplantationen_US
dc.subject.meshRna, Small Interfering - Metabolismen_US
dc.subject.meshReceptors, Notch - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshSignal Transduction - Physiologyen_US
dc.subject.meshSpheroids, Cellular - Physiologyen_US
dc.subject.meshTransfectionen_US
dc.subject.meshTransplantation, Heterologousen_US
dc.titleInhibition of NOTCH3 signalling significantly enhances sensitivity to cisplatin in EBV-associated nasopharyngeal carcinomaen_US
dc.typeArticleen_US
dc.identifier.emailTsao, SW:gswtsao@hkucc.hku.hken_US
dc.identifier.authorityTsao, SW=rp00399en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/path.2997en_US
dc.identifier.pmid22009689-
dc.identifier.scopuseid_2-s2.0-84856057486en_US
dc.identifier.hkuros217820-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84856057486&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume226en_US
dc.identifier.issue3en_US
dc.identifier.spage471en_US
dc.identifier.epage481en_US
dc.identifier.isiWOS:000299158400010-
dc.publisher.placeUnited Kingdomen_US
dc.relation.projectCentre for MicroRNA Study - Basic Research and Clinical Potentials in Cancer-
dc.relation.projectCentre for Nasopharyngeal Carcinoma Research-
dc.identifier.scopusauthoridMan, CH=53463664800en_US
dc.identifier.scopusauthoridWeiMan Lun, S=53464585700en_US
dc.identifier.scopusauthoridHui, JWY=54908059400en_US
dc.identifier.scopusauthoridTo, KF=36785812800en_US
dc.identifier.scopusauthoridChoy, KW=43261131500en_US
dc.identifier.scopusauthoridWingHung Chan, A=53464538900en_US
dc.identifier.scopusauthoridChow, C=35739799700en_US
dc.identifier.scopusauthoridTinYun Chung, G=53464252800en_US
dc.identifier.scopusauthoridTsao, SW=7102813116en_US
dc.identifier.scopusauthoridTakChun Yip, T=53464410900en_US
dc.identifier.scopusauthoridBusson, P=35739803700en_US
dc.identifier.scopusauthoridLo, KW=34872774800en_US
dc.identifier.citeulike9927734-

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