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Article: Functional role of the KLF6 tumour suppressor gene in gastric cancer

TitleFunctional role of the KLF6 tumour suppressor gene in gastric cancer
Authors
Issue Date2009
PublisherPergamon. The Journal's web site is located at http://www.elsevier.com/locate/ejca
Citation
European Journal Of Cancer, 2009, v. 45 n. 4, p. 666-676 How to Cite?
AbstractGastric cancer is the second most common cancer and a leading cause of cancer-related death worldwide. The Kruppel-like factor 6 (KLF6) tumour suppressor gene had been previously shown to be inactivated in a number of human cancers through loss of heterozygosity (LOH), somatic mutation, decreased expression and increased alternative splicing into a dominant negative oncogenic splice variant, KLF6-SV1. In the present study, 37 gastric cancer samples were analysed for the presence of loss of heterozygosity (LOH) of the KLF6 locus and somatic mutation. In total, 18 of 34 (53%) of the gastric cancer samples analysed demonstrated KLF6 locus specific loss. Four missense mutations, such as T179I, R198G, R71Q and S180L, were detected. Interestingly, two of these mutations R71Q and S180L have been identified independently by several groups in various malignancies including prostate, colorectal and gastric cancers. In addition, decreased wild-type KLF6 (wtKLF6) expression was associated with loss of the KLF6 locus and was present in 48% of primary gastric tumour samples analysed. Functional studies confirmed that wtKLF6 suppressed proliferation of gastric cancer cells via transcriptional regulation of the cyclin-dependent kinase inhibitor p21 and the oncogene c-myc. Functional characterisation of the common tumour-derived mutants demonstrated that the mutant proteins fail to suppress proliferation and function as dominant negative regulators of wtKLF6 function. Furthermore, stable overexpression of the R71Q and S180L tumour-derived mutants in the gastric cancer cell line, Hs746T, resulted in an increased tumourigenicity in vivo. Combined, these findings suggest an important role for the KLF6 tumour suppressor gene in gastric cancer development and progression and identify several highly cancer-relevant signalling pathways regulated by the KLF6 tumour suppressor gene. © 2008 Elsevier Ltd. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/163226
ISSN
2015 Impact Factor: 6.163
2015 SCImago Journal Rankings: 3.152
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorSangodkar, Jen_US
dc.contributor.authorShi, Jen_US
dc.contributor.authorDifeo, Aen_US
dc.contributor.authorSchwartz, Ren_US
dc.contributor.authorBromberg, Ren_US
dc.contributor.authorChoudhri, Aen_US
dc.contributor.authorMcclinch, Ken_US
dc.contributor.authorHatami, Ren_US
dc.contributor.authorScheer, Een_US
dc.contributor.authorKremerTal, Sen_US
dc.contributor.authorMartignetti, JAen_US
dc.contributor.authorHui, Aen_US
dc.contributor.authorLeung, WKen_US
dc.contributor.authorFriedman, SLen_US
dc.contributor.authorNarla, Gen_US
dc.date.accessioned2012-09-05T05:28:56Z-
dc.date.available2012-09-05T05:28:56Z-
dc.date.issued2009en_US
dc.identifier.citationEuropean Journal Of Cancer, 2009, v. 45 n. 4, p. 666-676en_US
dc.identifier.issn0959-8049en_US
dc.identifier.urihttp://hdl.handle.net/10722/163226-
dc.description.abstractGastric cancer is the second most common cancer and a leading cause of cancer-related death worldwide. The Kruppel-like factor 6 (KLF6) tumour suppressor gene had been previously shown to be inactivated in a number of human cancers through loss of heterozygosity (LOH), somatic mutation, decreased expression and increased alternative splicing into a dominant negative oncogenic splice variant, KLF6-SV1. In the present study, 37 gastric cancer samples were analysed for the presence of loss of heterozygosity (LOH) of the KLF6 locus and somatic mutation. In total, 18 of 34 (53%) of the gastric cancer samples analysed demonstrated KLF6 locus specific loss. Four missense mutations, such as T179I, R198G, R71Q and S180L, were detected. Interestingly, two of these mutations R71Q and S180L have been identified independently by several groups in various malignancies including prostate, colorectal and gastric cancers. In addition, decreased wild-type KLF6 (wtKLF6) expression was associated with loss of the KLF6 locus and was present in 48% of primary gastric tumour samples analysed. Functional studies confirmed that wtKLF6 suppressed proliferation of gastric cancer cells via transcriptional regulation of the cyclin-dependent kinase inhibitor p21 and the oncogene c-myc. Functional characterisation of the common tumour-derived mutants demonstrated that the mutant proteins fail to suppress proliferation and function as dominant negative regulators of wtKLF6 function. Furthermore, stable overexpression of the R71Q and S180L tumour-derived mutants in the gastric cancer cell line, Hs746T, resulted in an increased tumourigenicity in vivo. Combined, these findings suggest an important role for the KLF6 tumour suppressor gene in gastric cancer development and progression and identify several highly cancer-relevant signalling pathways regulated by the KLF6 tumour suppressor gene. © 2008 Elsevier Ltd. All rights reserved.en_US
dc.languageengen_US
dc.publisherPergamon. The Journal's web site is located at http://www.elsevier.com/locate/ejcaen_US
dc.relation.ispartofEuropean Journal of Canceren_US
dc.subject.meshAgeden_US
dc.subject.meshAnimalsen_US
dc.subject.meshCell Cycleen_US
dc.subject.meshCell Proliferationen_US
dc.subject.meshCell Transformation, Neoplastic - Geneticsen_US
dc.subject.meshDna Mutational Analysis - Methodsen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Silencingen_US
dc.subject.meshGenes, Tumor Suppressoren_US
dc.subject.meshHumansen_US
dc.subject.meshKruppel-Like Transcription Factors - Genetics - Metabolismen_US
dc.subject.meshLoss Of Heterozygosityen_US
dc.subject.meshMaleen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred Balb Cen_US
dc.subject.meshMicrosatellite Repeatsen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshMutationen_US
dc.subject.meshNeoplasm Stagingen_US
dc.subject.meshNeoplasm Transplantationen_US
dc.subject.meshProto-Oncogene Proteins - Genetics - Metabolismen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction - Methodsen_US
dc.subject.meshStomach Neoplasms - Genetics - Metabolism - Pathologyen_US
dc.subject.meshTumor Cells, Cultureden_US
dc.titleFunctional role of the KLF6 tumour suppressor gene in gastric canceren_US
dc.typeArticleen_US
dc.identifier.emailLeung, WK:waikleung@hku.hken_US
dc.identifier.authorityLeung, WK=rp01479en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.ejca.2008.11.009en_US
dc.identifier.pmid19101139en_US
dc.identifier.scopuseid_2-s2.0-60149105042en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-60149105042&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume45en_US
dc.identifier.issue4en_US
dc.identifier.spage666en_US
dc.identifier.epage676en_US
dc.identifier.isiWOS:000264606100030-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridSangodkar, J=24492414400en_US
dc.identifier.scopusauthoridShi, J=7404495210en_US
dc.identifier.scopusauthoridDiFeo, A=6603187042en_US
dc.identifier.scopusauthoridSchwartz, R=7404170457en_US
dc.identifier.scopusauthoridBromberg, R=7004894940en_US
dc.identifier.scopusauthoridChoudhri, A=25924137700en_US
dc.identifier.scopusauthoridMcClinch, K=25924454800en_US
dc.identifier.scopusauthoridHatami, R=22835180300en_US
dc.identifier.scopusauthoridScheer, E=25924457200en_US
dc.identifier.scopusauthoridKremerTal, S=8246611100en_US
dc.identifier.scopusauthoridMartignetti, JA=35417611400en_US
dc.identifier.scopusauthoridHui, A=7102453670en_US
dc.identifier.scopusauthoridLeung, WK=7201504523en_US
dc.identifier.scopusauthoridFriedman, SL=35406698100en_US
dc.identifier.scopusauthoridNarla, G=6602545784en_US

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