File Download
 
Links for fulltext
(May Require Subscription)
 
Supplementary

Article: The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas
  • Basic View
  • Metadata View
  • XML View
TitleThe tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas
 
AuthorsChan, SL3
Cui, Y3
Van Hasselt, A6
Li, H3
Srivastava, G1
Jin, H3
Ng, KM3
Wang, Y3
Lee, KY3
Tsao, GSW1
Zhong, S4
Robertson, KD4
Rha, SY2
Chan, ATC3
Tao, Q3 5 6
 
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
2012 Impact Factor: 3.961
2012 SCImago Journal Rankings: 1.448
 
DOIhttp://dx.doi.org/10.1038/labinvest.3700547
 
ISI Accession Number IDWOS:000247344700003
 
ReferencesReferences in Scopus
 
DC FieldValue
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
2012 Impact Factor: 3.961
2012 SCImago Journal Rankings: 1.448
 
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
 
<?xml encoding="utf-8" version="1.0"?>
<item><contributor.author>Chan, SL</contributor.author>
<contributor.author>Cui, Y</contributor.author>
<contributor.author>Van Hasselt, A</contributor.author>
<contributor.author>Li, H</contributor.author>
<contributor.author>Srivastava, G</contributor.author>
<contributor.author>Jin, H</contributor.author>
<contributor.author>Ng, KM</contributor.author>
<contributor.author>Wang, Y</contributor.author>
<contributor.author>Lee, KY</contributor.author>
<contributor.author>Tsao, GSW</contributor.author>
<contributor.author>Zhong, S</contributor.author>
<contributor.author>Robertson, KD</contributor.author>
<contributor.author>Rha, SY</contributor.author>
<contributor.author>Chan, ATC</contributor.author>
<contributor.author>Tao, Q</contributor.author>
<date.accessioned>2010-09-06T05:57:20Z</date.accessioned>
<date.available>2010-09-06T05:57:20Z</date.available>
<date.issued>2007</date.issued>
<identifier.citation>Laboratory Investigation, 2007, v. 87 n. 7, p. 644-650</identifier.citation>
<identifier.issn>0023-6837</identifier.issn>
<identifier.uri>http://hdl.handle.net/10722/67685</identifier.uri>
<description.abstract>Aberrant 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&#8242;-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 &#946;-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. &#169; 2007 USCAP, Inc All rights reserved.</description.abstract>
<language>eng</language>
<publisher>Nature Publishing Group. The Journal&apos;s web site is located at http://www.nature.com/labinvest/</publisher>
<relation.ispartof>Laboratory Investigation</relation.ispartof>
<subject>&#946;-catenin</subject>
<subject>Esophageal carcinoma</subject>
<subject>Methylation</subject>
<subject>Nasopharyngeal carcinoma</subject>
<subject>Tumor suppressor gene</subject>
<subject>WIF1</subject>
<subject.mesh>Adaptor Proteins, Signal Transducing - drug effects - genetics - metabolism</subject.mesh>
<subject.mesh>Animals</subject.mesh>
<subject.mesh>Azacitidine - analogs &amp; derivatives - pharmacology</subject.mesh>
<subject.mesh>Carcinoma - genetics - metabolism - pathology</subject.mesh>
<subject.mesh>Cell Line</subject.mesh>
<subject.mesh>Cell Line, Tumor</subject.mesh>
<subject.mesh>Cell Proliferation - drug effects</subject.mesh>
<subject.mesh>DNA Methylation - drug effects</subject.mesh>
<subject.mesh>Down-Regulation</subject.mesh>
<subject.mesh>Esophageal Neoplasms - genetics - metabolism - pathology</subject.mesh>
<subject.mesh>Gene Expression Regulation, Neoplastic</subject.mesh>
<subject.mesh>Gene Silencing</subject.mesh>
<subject.mesh>Humans</subject.mesh>
<subject.mesh>Nasopharyngeal Neoplasms - genetics - metabolism - pathology</subject.mesh>
<subject.mesh>Promoter Regions, Genetic - genetics</subject.mesh>
<subject.mesh>Repressor Proteins - drug effects - genetics - metabolism</subject.mesh>
<subject.mesh>Tumor Markers, Biological</subject.mesh>
<subject.mesh>Tumor Suppressor Proteins - drug effects - genetics - metabolism</subject.mesh>
<subject.mesh>Wnt1 Protein - genetics - metabolism</subject.mesh>
<title>The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas</title>
<type>Article</type>
<identifier.openurl>http://library.hku.hk:4550/resserv?sid=HKU:IR&amp;issn=0023-6837&amp;volume=87&amp;issue=7&amp;spage=644&amp;epage=50&amp;date=2007&amp;atitle=The+tumor+suppressor+Wnt+inhibitory+factor+1+is+frequently+methylated+in+nasopharyngeal+and+esophageal+carcinomas</identifier.openurl>
<description.nature>link_to_OA_fulltext</description.nature>
<identifier.doi>10.1038/labinvest.3700547</identifier.doi>
<identifier.pmid>17384664</identifier.pmid>
<identifier.scopus>eid_2-s2.0-34250310905</identifier.scopus>
<identifier.hkuros>132901</identifier.hkuros>
<relation.references>http://www.scopus.com/mlt/select.url?eid=2-s2.0-34250310905&amp;selection=ref&amp;src=s&amp;origin=recordpage</relation.references>
<identifier.volume>87</identifier.volume>
<identifier.issue>7</identifier.issue>
<identifier.spage>644</identifier.spage>
<identifier.epage>650</identifier.epage>
<identifier.isi>WOS:000247344700003</identifier.isi>
<publisher.place>United Kingdom</publisher.place>
<identifier.citeulike>1190114</identifier.citeulike>
<bitstream.url>http://hub.hku.hk/bitstream/10722/67685/1/re01.htm</bitstream.url>
</item>
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