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Article: Epigenetic disruption of interferon-γ response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas
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TitleEpigenetic disruption of interferon-γ response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas
 
AuthorsLee, KY4
Geng, H4
Ng, KM4
Yu, J8
Van Hasselt, A8
Cao, Y7
Zeng, YX1
Wong, AHY4
Wang, X4
Ying, J4
Srivastava, G2
Lung, ML5
Wang, LD3
Kwok, TT8
Levi, BZ6
Chan, ATC4
Sung, JJY8
Tao, Q4
 
KeywordsCarcinoma
CpG island
IRF8
Methylation
Tumor suppressor gene
 
Issue Date2008
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
CitationOncogene, 2008, v. 27 n. 39, p. 5267-5276 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2008.147
 
Abstract16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal and 18-78% in other carcinoma cell lines) and in a large collection of primary carcinomas (78% in NPC, 36-71% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-γ stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas. © 2008 Macmillan Publishers Limited All rights reserved.
 
ISSN0950-9232
2012 Impact Factor: 7.357
2012 SCImago Journal Rankings: 3.558
 
DOIhttp://dx.doi.org/10.1038/onc.2008.147
 
ISI Accession Number IDWOS:000258915100011
Funding AgencyGrant Number
Michael and Betty Kadoorie Cancer Genetics Research Program (MBKCGRP)
Hong Kong RGC Central Allocation GrantCA06/07.SC03
Funding Information:

This project was supported by a Michael and Betty Kadoorie Cancer Genetics Research Program (MBKCGRP) Grant to QT and a Hong Kong RGC Central Allocation Grant (CA06/07.SC03, QT). We thank Drs Bert Vogelstein, George Tsao (Dolly Huang), Sun Young Rha and Kaitai Yao for some cell lines, DSMZ (German Collection of Microorganisms and Cell Cultures) for the KYSE cell lines [Shimada et al., Cancer 69: 277-284 (1992)], Dr C Langford at the Wellcome Trust Sanger Institute, Cambridge, UK for aCGH slides, and Tzer- Jing Seng (Johns Hopkins Singapore) for her valuable help in aCGH analysis.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLee, KY
 
dc.contributor.authorGeng, H
 
dc.contributor.authorNg, KM
 
dc.contributor.authorYu, J
 
dc.contributor.authorVan Hasselt, A
 
dc.contributor.authorCao, Y
 
dc.contributor.authorZeng, YX
 
dc.contributor.authorWong, AHY
 
dc.contributor.authorWang, X
 
dc.contributor.authorYing, J
 
dc.contributor.authorSrivastava, G
 
dc.contributor.authorLung, ML
 
dc.contributor.authorWang, LD
 
dc.contributor.authorKwok, TT
 
dc.contributor.authorLevi, BZ
 
dc.contributor.authorChan, ATC
 
dc.contributor.authorSung, JJY
 
dc.contributor.authorTao, Q
 
dc.date.accessioned2012-05-29T06:13:51Z
 
dc.date.available2012-05-29T06:13:51Z
 
dc.date.issued2008
 
dc.description.abstract16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal and 18-78% in other carcinoma cell lines) and in a large collection of primary carcinomas (78% in NPC, 36-71% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-γ stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas. © 2008 Macmillan Publishers Limited All rights reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationOncogene, 2008, v. 27 n. 39, p. 5267-5276 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2008.147
 
dc.identifier.citeulike2791205
 
dc.identifier.doihttp://dx.doi.org/10.1038/onc.2008.147
 
dc.identifier.epage5276
 
dc.identifier.hkuros150716
 
dc.identifier.isiWOS:000258915100011
Funding AgencyGrant Number
Michael and Betty Kadoorie Cancer Genetics Research Program (MBKCGRP)
Hong Kong RGC Central Allocation GrantCA06/07.SC03
Funding Information:

This project was supported by a Michael and Betty Kadoorie Cancer Genetics Research Program (MBKCGRP) Grant to QT and a Hong Kong RGC Central Allocation Grant (CA06/07.SC03, QT). We thank Drs Bert Vogelstein, George Tsao (Dolly Huang), Sun Young Rha and Kaitai Yao for some cell lines, DSMZ (German Collection of Microorganisms and Cell Cultures) for the KYSE cell lines [Shimada et al., Cancer 69: 277-284 (1992)], Dr C Langford at the Wellcome Trust Sanger Institute, Cambridge, UK for aCGH slides, and Tzer- Jing Seng (Johns Hopkins Singapore) for her valuable help in aCGH analysis.

 
dc.identifier.issn0950-9232
2012 Impact Factor: 7.357
2012 SCImago Journal Rankings: 3.558
 
dc.identifier.issue39
 
dc.identifier.pmid18469857
 
dc.identifier.scopuseid_2-s2.0-51349083104
 
dc.identifier.spage5267
 
dc.identifier.urihttp://hdl.handle.net/10722/148578
 
dc.identifier.volume27
 
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.meshCell Line, Tumor
 
dc.subject.meshDna Methylation
 
dc.subject.meshDown-Regulation
 
dc.subject.meshEpigenesis, Genetic
 
dc.subject.meshEsophageal Neoplasms - Genetics
 
dc.subject.meshGene Silencing
 
dc.subject.meshHumans
 
dc.subject.meshInterferon Regulatory Factors - Genetics
 
dc.subject.meshInterferon-Gamma - Physiology
 
dc.subject.meshNasopharyngeal Neoplasms - Genetics
 
dc.subject.meshPromoter Regions, Genetic
 
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
 
dc.subjectCarcinoma
 
dc.subjectCpG island
 
dc.subjectIRF8
 
dc.subjectMethylation
 
dc.subjectTumor suppressor gene
 
dc.titleEpigenetic disruption of interferon-γ response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas
 
dc.typeArticle
 
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<description.abstract>16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal and 18-78% in other carcinoma cell lines) and in a large collection of primary carcinomas (78% in NPC, 36-71% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-&#947; stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas. &#169; 2008 Macmillan Publishers Limited All rights reserved.</description.abstract>
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Author Affiliations
  1. Sun Yat-Sen University Cancer Center
  2. The University of Hong Kong
  3. Zhengzhou University
  4. Prince of Wales Hospital Hong Kong
  5. Hong Kong University of Science and Technology
  6. Technion - Israel Institute of Technology
  7. Central South University China
  8. Chinese University of Hong Kong