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

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TitleThe tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas
AuthorsChan, SL
Cui, Y
Van Hasselt, A
Li, H
Srivastava, G1
Jin, H
Ng, KM
Wang, Y
Lee, KY
Tsao, GSW1
Zhong, S
Robertson, KD
Rha, SY
Chan, ATC
Tao, Q
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/
CitationLaboratory Investigation, 2007, v. 87 n. 7, p. 644-650 [How to Cite?]
DOI: http://dx.doi.org/10.1038/labinvest.3700547
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.
ISSN0023-6837
2011 Impact Factor: 3.641
2011 SCImago Journal Rankings: 0.516
DOIhttp://dx.doi.org/10.1038/labinvest.3700547
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorChan, SL
dc.contributor.authorCui, Y
dc.contributor.authorVan Hasselt, A
dc.contributor.authorLi, H
dc.contributor.authorSrivastava, G
dc.contributor.authorJin, H
dc.contributor.authorNg, KM
dc.contributor.authorWang, Y
dc.contributor.authorLee, KY
dc.contributor.authorTsao, GSW
dc.contributor.authorZhong, S
dc.contributor.authorRobertson, KD
dc.contributor.authorRha, SY
dc.contributor.authorChan, ATC
dc.contributor.authorTao, Q
dc.date.accessioned2010-09-06T05:57:20Z
dc.date.available2010-09-06T05:57:20Z
dc.date.issued2007
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.
dc.description.naturelink_to_OA_fulltext
dc.identifier.citationLaboratory Investigation, 2007, v. 87 n. 7, p. 644-650 [How to Cite?]
DOI: http://dx.doi.org/10.1038/labinvest.3700547
dc.identifier.citeulike1190114
dc.identifier.doihttp://dx.doi.org/10.1038/labinvest.3700547
dc.identifier.epage650
dc.identifier.hkuros132901
dc.identifier.isiWOS:000247344700003
dc.identifier.issn0023-6837
2011 Impact Factor: 3.641
2011 SCImago Journal Rankings: 0.516
dc.identifier.issue7
dc.identifier.openurl
dc.identifier.pmid17384664
dc.identifier.scopuseid_2-s2.0-34250310905
dc.identifier.spage644
dc.identifier.urihttp://hdl.handle.net/10722/67685
dc.identifier.volume87
dc.languageeng
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/
dc.publisher.placeUnited Kingdom
dc.relation.ispartofLaboratory Investigation
dc.relation.referencesReferences in Scopus
dc.subject.meshAdaptor Proteins, Signal Transducing - drug effects - genetics - metabolism
dc.subject.meshAnimals
dc.subject.meshAzacitidine - analogs & derivatives - pharmacology
dc.subject.meshCarcinoma - genetics - metabolism - pathology
dc.subject.meshCell Line
dc.subject.meshCell Line, Tumor
dc.subject.meshCell Proliferation - drug effects
dc.subject.meshDNA Methylation - drug effects
dc.subject.meshDown-Regulation
dc.subject.meshEsophageal Neoplasms - genetics - metabolism - pathology
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshGene Silencing
dc.subject.meshHumans
dc.subject.meshNasopharyngeal Neoplasms - genetics - metabolism - pathology
dc.subject.meshPromoter Regions, Genetic - genetics
dc.subject.meshRepressor Proteins - drug effects - genetics - metabolism
dc.subject.meshTumor Markers, Biological
dc.subject.meshTumor Suppressor Proteins - drug effects - genetics - metabolism
dc.subject.meshWnt1 Protein - genetics - metabolism
dc.subjectβ-catenin
dc.subjectEsophageal carcinoma
dc.subjectMethylation
dc.subjectNasopharyngeal carcinoma
dc.subjectTumor suppressor gene
dc.subjectWIF1
dc.titleThe tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong
  2. Yonsei University College of Medicine
  3. Prince of Wales Hospital Hong Kong
  4. University of Florida
  5. The Johns Hopkins School of Medicine
  6. Chinese University of Hong Kong