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Article: STAT3 activation contributes directly to Epstein-Barr virus-mediated invasiveness of nasopharyngeal cancer cells in vitro

TitleSTAT3 activation contributes directly to Epstein-Barr virus-mediated invasiveness of nasopharyngeal cancer cells in vitro
Authors
KeywordsEBV
Invasion
Nasopharyngeal cancer (NPC)
STAT3
Issue Date2009
PublisherJohn Wiley & Sons, Inc.. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home
Citation
International Journal Of Cancer, 2009, v. 125 n. 8, p. 1884-1893 How to Cite?
AbstractNasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-associated head and neck cancer prevalent in Asia. Although with reasons not fully understood, the intrinsic invasiveness of NPC is believed to be EBV-linked. Recently, EBV was found to induce STAT3 activation. Constitutive STAT3 activation correlated with advanced clinical staging in NPC. We hypothesized that STAT3 activation by EBV directly contributes to the intrinsic invasiveness of NPC cells. Phospho-STAT3-Tyr705 was detected in high percentage of NPC tumors (7/10 cases). Using a paired NPC cell line model, HONE-1 and the EBV-infected counterpart, HONE-1-EBV, we found that HONE-1-EBV expressed a higher level of phospho-STAT3-Tyr705 and was ∼11-fold more invasive than HONE-1. In HONE-1-EBV, STAT3 siRNA targeting inhibited both spontaneous and serum-induced invasion, as well as cell growth. Conversely, activation of STAT3 (by expressing an activated STAT3 mutant, namely STAT3C) in the parental HONE-1, mimicking EBV-induced STAT3 activation, significantly enhanced its invasiveness and proliferation, which was accompanied by increased expression of markers of mesenchymal status, proliferation and anti-apoptosis. Our results demonstrated that EBV-induced STAT3 activation is responsible for NPC cell proliferation and invasion. This was further confirmed by a small molecule inhibitor of JAK/STAT3, JSI-124. JSI-124 inhibited STAT3 activation in HONE-1-EBV, with subsequent growth inhibition, induction of PARP cleavage, abrogation of anchorage-independent growth and invasion. We found that EBV-independent activation of STAT3 by a growth factor, EGF, also contributed to NPC invasion. In conclusion, EBV-induced STAT3 activation directly contributes to the intrinsic invasiveness of NPC cells and STAT3 targeting may be beneficial in treating aggressive NPC. © 2009 UICC.
Persistent Identifierhttp://hdl.handle.net/10722/124472
ISSN
2015 Impact Factor: 5.531
2015 SCImago Journal Rankings: 2.657
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLui, VWYen_HK
dc.contributor.authorWong, EYLen_HK
dc.contributor.authorHo, Yen_HK
dc.contributor.authorHong, Ben_HK
dc.contributor.authorWong, SCCen_HK
dc.contributor.authorTao, Qen_HK
dc.contributor.authorChoi, GCGen_HK
dc.contributor.authorAu, TCCen_HK
dc.contributor.authorHo, Ken_HK
dc.contributor.authorYau, DMSen_HK
dc.contributor.authorMa, BBYen_HK
dc.contributor.authorHui, EPen_HK
dc.contributor.authorChan, ASKen_HK
dc.contributor.authorTsang, CMen_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorGrandis, JRen_HK
dc.contributor.authorChan, ATCen_HK
dc.date.accessioned2010-10-31T10:36:19Z-
dc.date.available2010-10-31T10:36:19Z-
dc.date.issued2009en_HK
dc.identifier.citationInternational Journal Of Cancer, 2009, v. 125 n. 8, p. 1884-1893en_HK
dc.identifier.issn0020-7136en_HK
dc.identifier.urihttp://hdl.handle.net/10722/124472-
dc.description.abstractNasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-associated head and neck cancer prevalent in Asia. Although with reasons not fully understood, the intrinsic invasiveness of NPC is believed to be EBV-linked. Recently, EBV was found to induce STAT3 activation. Constitutive STAT3 activation correlated with advanced clinical staging in NPC. We hypothesized that STAT3 activation by EBV directly contributes to the intrinsic invasiveness of NPC cells. Phospho-STAT3-Tyr705 was detected in high percentage of NPC tumors (7/10 cases). Using a paired NPC cell line model, HONE-1 and the EBV-infected counterpart, HONE-1-EBV, we found that HONE-1-EBV expressed a higher level of phospho-STAT3-Tyr705 and was ∼11-fold more invasive than HONE-1. In HONE-1-EBV, STAT3 siRNA targeting inhibited both spontaneous and serum-induced invasion, as well as cell growth. Conversely, activation of STAT3 (by expressing an activated STAT3 mutant, namely STAT3C) in the parental HONE-1, mimicking EBV-induced STAT3 activation, significantly enhanced its invasiveness and proliferation, which was accompanied by increased expression of markers of mesenchymal status, proliferation and anti-apoptosis. Our results demonstrated that EBV-induced STAT3 activation is responsible for NPC cell proliferation and invasion. This was further confirmed by a small molecule inhibitor of JAK/STAT3, JSI-124. JSI-124 inhibited STAT3 activation in HONE-1-EBV, with subsequent growth inhibition, induction of PARP cleavage, abrogation of anchorage-independent growth and invasion. We found that EBV-independent activation of STAT3 by a growth factor, EGF, also contributed to NPC invasion. In conclusion, EBV-induced STAT3 activation directly contributes to the intrinsic invasiveness of NPC cells and STAT3 targeting may be beneficial in treating aggressive NPC. © 2009 UICC.en_HK
dc.languageengen_HK
dc.publisherJohn Wiley & Sons, Inc.. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/homeen_HK
dc.relation.ispartofInternational Journal of Canceren_HK
dc.rightsInternational Journal of Cancer. Copyright © John Wiley & Sons, Inc..-
dc.subjectEBVen_HK
dc.subjectInvasionen_HK
dc.subjectNasopharyngeal cancer (NPC)en_HK
dc.subjectSTAT3en_HK
dc.titleSTAT3 activation contributes directly to Epstein-Barr virus-mediated invasiveness of nasopharyngeal cancer cells in vitroen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0020-7136&volume=125&issue=8&spage=1884&epage=1893&date=2009&atitle=STAT3+activation+contributes+directly+to+Epstein-Barr+virus-mediated+invasiveness+of+nasopharyngeal+cancer+cells+in+vitroen_HK
dc.identifier.emailTsao, SW:gswtsao@hkucc.hku.hken_HK
dc.identifier.authorityTsao, SW=rp00399en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/ijc.24567en_HK
dc.identifier.pmid19588483-
dc.identifier.scopuseid_2-s2.0-70349256524en_HK
dc.identifier.hkuros182759en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70349256524&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume125en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1884en_HK
dc.identifier.epage1893en_HK
dc.identifier.isiWOS:000270011000018-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLui, VWY=7004231347en_HK
dc.identifier.scopusauthoridWong, EYL=8234468400en_HK
dc.identifier.scopusauthoridHo, Y=26654872400en_HK
dc.identifier.scopusauthoridHong, B=7202125896en_HK
dc.identifier.scopusauthoridWong, SCC=26039647800en_HK
dc.identifier.scopusauthoridTao, Q=7102578359en_HK
dc.identifier.scopusauthoridChoi, GCG=26644787500en_HK
dc.identifier.scopusauthoridAu, TCC=24597501100en_HK
dc.identifier.scopusauthoridHo, K=34971221500en_HK
dc.identifier.scopusauthoridYau, DMS=19639624800en_HK
dc.identifier.scopusauthoridMa, BBY=7403301016en_HK
dc.identifier.scopusauthoridHui, EP=7005081895en_HK
dc.identifier.scopusauthoridChan, ASK=18435746400en_HK
dc.identifier.scopusauthoridTsang, CM=24831236400en_HK
dc.identifier.scopusauthoridTsao, SW=7102813116en_HK
dc.identifier.scopusauthoridGrandis, JR=7005746142en_HK
dc.identifier.scopusauthoridChan, ATC=13404833700en_HK

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