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Article: The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation
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TitleThe major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation
 
AuthorsSeng, TJ5
Low, JSW5
Li, H5 4
Cui, Y4
Goh, HK5
Wong, MLY1
Srivastava, G1
Sidransky, D6
Califano, J6
Steenbergen, RDM2
Rha, SY3
Tan, J5
Hsieh, WS5 6
Ambinder, RF5 6
Lin, X4
Chan, ATC4
Tao, Q5 6 4 7
 
Issue Date2007
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
CitationOncogene, 2007, v. 26 n. 6, p. 934-944 [How to Cite?]
DOI: http://dx.doi.org/10.1038/sj.onc.1209839
 
AbstractIdentification of tumor suppressor genes (TSG) silenced by methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic tumor markers for early cancer detection. Both nasopharyngeal carcinoma (NPC) and esophageal carcinoma are major tumors in Southern China and Southeast Asia. Through expression subtraction of NPC, we identified Deleted in Liver Cancer 1 (DLC1)/ARHGAP7 (NM_006094) - an 8p22 TSG as a major downregulated gene. Although expressed in all normal tissues, DLC1 was silenced or downregulated in 11/12 (91%) NPC, 6/15 (40%) esophageal, 5/8 (63%) cervical and 3/9 (33%) breast carcinoma cell lines. No genetic deletion of DLC1 was detected in NPC although a hemizygous deletion at 8p22-11 was found by 1-Mb array-CGH in some cell lines. We then located the functional DLC1 promoter by 5′-RACE and promoter activity assays. This promoter was frequently methylated in all downregulated cell lines and in a large collection of primary tumors including 89% (64/72) NPC (endemic and sporadic types), 51% (48/94) esophageal, 87% (7/8) cervical and 36% (5/14) breast carcinomas, but seldom in paired surgical marginal tissues and not in any normal epithelial tissue. The transcriptional silencing of DLC1 could be reversed by 5-aza-2′-deoxycytidine or genetic double knock-out of DNMT1 and DNMT3B. Furthermore, ectopic expression of DLC1 in NPC and esophageal carcinoma cells strongly inhibited their colony formation. We thus found frequent epigenetic silencing of DLC1 in NPC, esophageal and cervical carcinomas, and a high correlation of methylation with its downregulation, suggesting a predominant role of epigenetic inactivation. DLC1 appears to be a major TSG implicated in the pathogenesis of these tumors, and should be further tested as a molecular biomarker in patients with these cancers. © 2007 Nature Publishing Group All rights reserved.
 
ISSN0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
DOIhttp://dx.doi.org/10.1038/sj.onc.1209839
 
ISI Accession Number IDWOS:000244063800013
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorSeng, TJ
 
dc.contributor.authorLow, JSW
 
dc.contributor.authorLi, H
 
dc.contributor.authorCui, Y
 
dc.contributor.authorGoh, HK
 
dc.contributor.authorWong, MLY
 
dc.contributor.authorSrivastava, G
 
dc.contributor.authorSidransky, D
 
dc.contributor.authorCalifano, J
 
dc.contributor.authorSteenbergen, RDM
 
dc.contributor.authorRha, SY
 
dc.contributor.authorTan, J
 
dc.contributor.authorHsieh, WS
 
dc.contributor.authorAmbinder, RF
 
dc.contributor.authorLin, X
 
dc.contributor.authorChan, ATC
 
dc.contributor.authorTao, Q
 
dc.date.accessioned2010-09-06T09:41:57Z
 
dc.date.available2010-09-06T09:41:57Z
 
dc.date.issued2007
 
dc.description.abstractIdentification of tumor suppressor genes (TSG) silenced by methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic tumor markers for early cancer detection. Both nasopharyngeal carcinoma (NPC) and esophageal carcinoma are major tumors in Southern China and Southeast Asia. Through expression subtraction of NPC, we identified Deleted in Liver Cancer 1 (DLC1)/ARHGAP7 (NM_006094) - an 8p22 TSG as a major downregulated gene. Although expressed in all normal tissues, DLC1 was silenced or downregulated in 11/12 (91%) NPC, 6/15 (40%) esophageal, 5/8 (63%) cervical and 3/9 (33%) breast carcinoma cell lines. No genetic deletion of DLC1 was detected in NPC although a hemizygous deletion at 8p22-11 was found by 1-Mb array-CGH in some cell lines. We then located the functional DLC1 promoter by 5′-RACE and promoter activity assays. This promoter was frequently methylated in all downregulated cell lines and in a large collection of primary tumors including 89% (64/72) NPC (endemic and sporadic types), 51% (48/94) esophageal, 87% (7/8) cervical and 36% (5/14) breast carcinomas, but seldom in paired surgical marginal tissues and not in any normal epithelial tissue. The transcriptional silencing of DLC1 could be reversed by 5-aza-2′-deoxycytidine or genetic double knock-out of DNMT1 and DNMT3B. Furthermore, ectopic expression of DLC1 in NPC and esophageal carcinoma cells strongly inhibited their colony formation. We thus found frequent epigenetic silencing of DLC1 in NPC, esophageal and cervical carcinomas, and a high correlation of methylation with its downregulation, suggesting a predominant role of epigenetic inactivation. DLC1 appears to be a major TSG implicated in the pathogenesis of these tumors, and should be further tested as a molecular biomarker in patients with these cancers. © 2007 Nature Publishing Group All rights reserved.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationOncogene, 2007, v. 26 n. 6, p. 934-944 [How to Cite?]
DOI: http://dx.doi.org/10.1038/sj.onc.1209839
 
dc.identifier.citeulike771102
 
dc.identifier.doihttp://dx.doi.org/10.1038/sj.onc.1209839
 
dc.identifier.epage944
 
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dc.identifier.isiWOS:000244063800013
 
dc.identifier.issn0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
dc.identifier.issue6
 
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dc.identifier.urihttp://hdl.handle.net/10722/88329
 
dc.identifier.volume26
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofOncogene
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshBase Sequence
 
dc.subject.meshCell Line
 
dc.subject.meshCell Line, Tumor
 
dc.subject.meshCell Proliferation
 
dc.subject.meshChromosomes, Human, Pair 8 - genetics
 
dc.subject.meshDNA Methylation
 
dc.subject.meshEsophageal Neoplasms - genetics - metabolism
 
dc.subject.meshFemale
 
dc.subject.meshGTPase-Activating Proteins
 
dc.subject.meshGene Expression Regulation, Neoplastic
 
dc.subject.meshGene Silencing
 
dc.subject.meshHumans
 
dc.subject.meshMolecular Sequence Data
 
dc.subject.meshNasopharyngeal Neoplasms - genetics - metabolism - pathology
 
dc.subject.meshPromoter Regions, Genetic - genetics
 
dc.subject.meshTumor Suppressor Proteins - genetics - metabolism
 
dc.subject.meshUterine Cervical Neoplasms - genetics - metabolism
 
dc.titleThe major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. VU University Medical Center
  3. Yonsei University
  4. Prince of Wales Hospital Hong Kong
  5. Johns Hopkins Singapore
  6. The Johns Hopkins School of Medicine
  7. Chinese University of Hong Kong