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Article: The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

TitleThe tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas
Authors
Keywordsβ-catenin
Esophageal carcinoma
Methylation
Nasopharyngeal carcinoma
Tumor suppressor gene
WIF1
Issue Date2007
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/
Citation
Laboratory Investigation, 2007, v. 87 n. 7, p. 644-650 How to Cite?
AbstractAberrant activation of the wingless-type- (Wnt)-signaling pathway is common in many cancers including nasopharyngeal (NPC) and esophageal squamous cell (ESCC) carcinomas, both prevalent in Southern China and Southeast Asia. However, the molecular mechanism leading to this abnormality is still obscure. Wnt inhibitory factor-1 (WIF1) is a secreted antagonist of the Wnt pathway, and is recently shown to be inactivated by epigenetic mechanism in some tumors. Here, we examined whether WIF1 is also inactivated epigenetically in NPC and ESCC. With semiquantitative reverse transcription-PCR and methylation-specific PCR, we detected WIF1 downregulation or silencing in 6/6 of NPC and 12/19 of ESCC cell lines, which is well correlated with its methylation status. Methylation was further confirmed by high-resolution bisulfite genomic sequencing. Methylation was also frequently observed in a large collection of primary tumors of NPC (85%, 55/65) and ESCC (27%, 25/92), with WIF1 expressed and unmethylated in normal NPC and esophageal cell lines and normal tissues. Treatment of 5-aza-2′-deoxycytidine demethylated WIF1 and induced its expression in NPC and ESCC cell lines, highlighting a direct role of epigenetic inactivation. Ectopic expression of WIF1 in NPC and ESCC tumor cells resulted in significant inhibition of tumor cell colony formation, similar to TP53, and also significant downregulation of β-catenin protein level in NPC cells. Thus, WIF1 functions as a tumor suppressor for both NPC and ESCC through suppressing the Wnt-signaling pathway, but is frequently silenced by epigenetic mechanism in a tumor-specific way. Our study indicates that epigenetic inactivation of WIF1 contributes to the aberrant activation of Wnt pathway and is involved in the pathogenesis of both tumors. WIF1 methylation could also serve as a specific biomarker for these tumors. © 2007 USCAP, Inc All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/67685
ISSN
2014 Impact Factor: 3.676
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChan, SLen_HK
dc.contributor.authorCui, Yen_HK
dc.contributor.authorVan Hasselt, Aen_HK
dc.contributor.authorLi, Hen_HK
dc.contributor.authorSrivastava, Gen_HK
dc.contributor.authorJin, Hen_HK
dc.contributor.authorNg, KMen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorLee, KYen_HK
dc.contributor.authorTsao, GSWen_HK
dc.contributor.authorZhong, Sen_HK
dc.contributor.authorRobertson, KDen_HK
dc.contributor.authorRha, SYen_HK
dc.contributor.authorChan, ATCen_HK
dc.contributor.authorTao, Qen_HK
dc.date.accessioned2010-09-06T05:57:20Z-
dc.date.available2010-09-06T05:57:20Z-
dc.date.issued2007en_HK
dc.identifier.citationLaboratory Investigation, 2007, v. 87 n. 7, p. 644-650en_HK
dc.identifier.issn0023-6837en_HK
dc.identifier.urihttp://hdl.handle.net/10722/67685-
dc.description.abstractAberrant activation of the wingless-type- (Wnt)-signaling pathway is common in many cancers including nasopharyngeal (NPC) and esophageal squamous cell (ESCC) carcinomas, both prevalent in Southern China and Southeast Asia. However, the molecular mechanism leading to this abnormality is still obscure. Wnt inhibitory factor-1 (WIF1) is a secreted antagonist of the Wnt pathway, and is recently shown to be inactivated by epigenetic mechanism in some tumors. Here, we examined whether WIF1 is also inactivated epigenetically in NPC and ESCC. With semiquantitative reverse transcription-PCR and methylation-specific PCR, we detected WIF1 downregulation or silencing in 6/6 of NPC and 12/19 of ESCC cell lines, which is well correlated with its methylation status. Methylation was further confirmed by high-resolution bisulfite genomic sequencing. Methylation was also frequently observed in a large collection of primary tumors of NPC (85%, 55/65) and ESCC (27%, 25/92), with WIF1 expressed and unmethylated in normal NPC and esophageal cell lines and normal tissues. Treatment of 5-aza-2′-deoxycytidine demethylated WIF1 and induced its expression in NPC and ESCC cell lines, highlighting a direct role of epigenetic inactivation. Ectopic expression of WIF1 in NPC and ESCC tumor cells resulted in significant inhibition of tumor cell colony formation, similar to TP53, and also significant downregulation of β-catenin protein level in NPC cells. Thus, WIF1 functions as a tumor suppressor for both NPC and ESCC through suppressing the Wnt-signaling pathway, but is frequently silenced by epigenetic mechanism in a tumor-specific way. Our study indicates that epigenetic inactivation of WIF1 contributes to the aberrant activation of Wnt pathway and is involved in the pathogenesis of both tumors. WIF1 methylation could also serve as a specific biomarker for these tumors. © 2007 USCAP, Inc All rights reserved.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/en_HK
dc.relation.ispartofLaboratory Investigationen_HK
dc.subjectβ-cateninen_HK
dc.subjectEsophageal carcinomaen_HK
dc.subjectMethylationen_HK
dc.subjectNasopharyngeal carcinomaen_HK
dc.subjectTumor suppressor geneen_HK
dc.subjectWIF1en_HK
dc.subject.meshAdaptor Proteins, Signal Transducing - drug effects - genetics - metabolismen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshAzacitidine - analogs & derivatives - pharmacologyen_HK
dc.subject.meshCarcinoma - genetics - metabolism - pathologyen_HK
dc.subject.meshCell Lineen_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshCell Proliferation - drug effectsen_HK
dc.subject.meshDNA Methylation - drug effectsen_HK
dc.subject.meshDown-Regulationen_HK
dc.subject.meshEsophageal Neoplasms - genetics - metabolism - pathologyen_HK
dc.subject.meshGene Expression Regulation, Neoplasticen_HK
dc.subject.meshGene Silencingen_HK
dc.subject.meshHumansen_HK
dc.subject.meshNasopharyngeal Neoplasms - genetics - metabolism - pathologyen_HK
dc.subject.meshPromoter Regions, Genetic - geneticsen_HK
dc.subject.meshRepressor Proteins - drug effects - genetics - metabolismen_HK
dc.subject.meshTumor Markers, Biologicalen_HK
dc.subject.meshTumor Suppressor Proteins - drug effects - genetics - metabolismen_HK
dc.subject.meshWnt1 Protein - genetics - metabolismen_HK
dc.titleThe tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomasen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0023-6837&volume=87&issue=7&spage=644&epage=50&date=2007&atitle=The+tumor+suppressor+Wnt+inhibitory+factor+1+is+frequently+methylated+in+nasopharyngeal+and+esophageal+carcinomasen_HK
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_HK
dc.identifier.emailTsao, GSW:gswtsao@hkucc.hku.hken_HK
dc.identifier.authoritySrivastava, G=rp00365en_HK
dc.identifier.authorityTsao, GSW=rp00399en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1038/labinvest.3700547en_HK
dc.identifier.pmid17384664en_HK
dc.identifier.scopuseid_2-s2.0-34250310905en_HK
dc.identifier.hkuros132901en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34250310905&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume87en_HK
dc.identifier.issue7en_HK
dc.identifier.spage644en_HK
dc.identifier.epage650en_HK
dc.identifier.isiWOS:000247344700003-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridChan, SL=34973871600en_HK
dc.identifier.scopusauthoridCui, Y=55196756600en_HK
dc.identifier.scopusauthoridVan Hasselt, A=6603932076en_HK
dc.identifier.scopusauthoridLi, H=24468545300en_HK
dc.identifier.scopusauthoridSrivastava, G=7202242238en_HK
dc.identifier.scopusauthoridJin, H=24577511700en_HK
dc.identifier.scopusauthoridNg, KM=16053249400en_HK
dc.identifier.scopusauthoridWang, Y=36062525200en_HK
dc.identifier.scopusauthoridLee, KY=35080729700en_HK
dc.identifier.scopusauthoridTsao, GSW=7102813116en_HK
dc.identifier.scopusauthoridZhong, S=7202152664en_HK
dc.identifier.scopusauthoridRobertson, KD=35994002600en_HK
dc.identifier.scopusauthoridRha, SY=7006023235en_HK
dc.identifier.scopusauthoridChan, ATC=13404833700en_HK
dc.identifier.scopusauthoridTao, Q=7102578359en_HK
dc.identifier.citeulike1190114-

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