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, H4 5
Cui, Y4
Goh, HK5
Wong, MLY1
Srivastava, G1
Sidransky, D6
Califano, J6
Steenbergen, RDM3
Rha, SY2
Tan, J5
Hsieh, WS5 6
Ambinder, RF5 6
Lin, X4
Chan, ATC4
Tao, Q4 5 6 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
2011 Impact Factor: 6.373
2011 SCImago Journal Rankings: 1.216
DOIhttp://dx.doi.org/10.1038/sj.onc.1209839
ISI Accession Number IDWOS:000244063800013
ReferencesReferences in Scopus
DC Field
Value
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
dc.identifier.hkuros132803
dc.identifier.isiWOS:000244063800013
dc.identifier.issn0950-9232
2011 Impact Factor: 6.373
2011 SCImago Journal Rankings: 1.216
dc.identifier.issue6
dc.identifier.openurl
dc.identifier.pmid16862168
dc.identifier.scopuseid_2-s2.0-33846941189
dc.identifier.spage934
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
Author Affiliations
  1. The University of Hong Kong
  2. Yonsei University
  3. VU University Medical Center
  4. Prince of Wales Hospital Hong Kong
  5. Johns Hopkins Singapore
  6. The Johns Hopkins School of Medicine
  7. Chinese University of Hong Kong