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Article: Overexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21 WAF1/CIP1 expression in ovarian cancer

TitleOverexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21 WAF1/CIP1 expression in ovarian cancer
Authors
KeywordsFOXG1
Ovarian cancer
P21WAF1/CIP1
TGF-β
Issue Date2009
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjc
Citation
British Journal Of Cancer, 2009, v. 101 n. 8, p. 1433-1443 How to Cite?
AbstractBackground:Loss of growth inhibitory response to transforming growth factor-Β (TGF-Β) is a common feature of epithelial cancers. Recent studies have reported that genetic lesions and overexpression of oncoproteins in TGF-Β/Smads signalling cascade contribute to the TGF-Β resistance. Here, we showed that the overexpressed FOXG1 was involved in attenuating the anti-proliferative control of TGF-Β/Smads signalling in ovarian cancer.Methods:FOXG1 and p21 WAF1/CIP1 expressions were evaluated by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR), western blot and immunohistochemical analyses. The effect of FOXG1 on p21 WAF1/CIP1 transcriptional activity was examined by luciferase reporter assays. Cell lines stably expressing or short hairpin RNA interference-mediated knockdown FOXG1 were established for studying the gain-or-loss functional effects of FOXG1. XTT cell proliferation assay was used to measure cell growth of ovarian cancer cells.Results:Quantitative RT-PCR and western blot analyses showed that FOXG1 was upregulated and inversely associated with the expression levels of p21 WAF1/CIP1 in ovarian cancer. The overexpression of FOXG1 was significantly correlated with high-grade ovarian cancer (P0.025). Immunohistochemical analysis on ovarian cancer tissue array was further evidenced that FOXG1 was highly expressed and significantly correlated with high-grade ovarian cancer (P0.048). Functionally, enforced expression of FOXG1 selectively blocked the TGF-Β-induced p21 WAF1/CIP1 expressions and increased cell proliferation in ovarian cancer cells. Conversely, FOXG1 knockdown resulted in a 20-26% decrease in cell proliferation together with 16-33% increase in p21 WAF1/CIP1 expression. Notably, FOXG1 was able to inhibit the p21 WAF1/CIP1 promoter activity in a p53-independent manner by transient reporter assays.ConclusionOur results suggest that FOXG1 acts as an oncoprotein inhibiting TGF-Β-mediated anti-proliferative responses in ovarian cancer cells through suppressing p21 WAF1/CIP1 transcription. © 2009 Cancer Research UK All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/68131
ISSN
2014 Impact Factor: 4.836
2014 SCImago Journal Rankings: 2.205
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
HKU Seed Funding Programme for Basic Research200711159085
Wong Check She Charitable Foundation
Funding Information:

We thank Prof Benjamin Tsang from the Department of Obstetrics and Gynaecology, University of Ottawa, Canada for providing four ovarian cancer cell lines, OV2008, C13*, A2780s, A2780cp; Professor George Tsao from the Department of Anatomy, the University of Hong Kong for providing four HOSEs cell lines; Dr Stefano Stifani from McGill University, Montreal, Quebec, Canada for providing the pCMV2-Flag-FOXG1-expressing plasmid; Dr Mark Feitelson from Mercer Laboratory, Thomas Jefferson University, Philadelphia, PA, USA for providing the human mutant p21WAF1/CIP1 promoter luciferase construct (pWWP). This study was supported by HKU Seed Funding Programme for Basic Research (200711159085) and Wong Check She Charitable Foundation.

References

 

DC FieldValueLanguage
dc.contributor.authorChan, DWen_HK
dc.contributor.authorLiu, VWSen_HK
dc.contributor.authorTo, RMYen_HK
dc.contributor.authorChiu, PMen_HK
dc.contributor.authorLee, WYWen_HK
dc.contributor.authorYao, KMen_HK
dc.contributor.authorCheung, ANYen_HK
dc.contributor.authorNgan, HYSen_HK
dc.date.accessioned2010-09-06T06:01:39Z-
dc.date.available2010-09-06T06:01:39Z-
dc.date.issued2009en_HK
dc.identifier.citationBritish Journal Of Cancer, 2009, v. 101 n. 8, p. 1433-1443en_HK
dc.identifier.issn0007-0920en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68131-
dc.description.abstractBackground:Loss of growth inhibitory response to transforming growth factor-Β (TGF-Β) is a common feature of epithelial cancers. Recent studies have reported that genetic lesions and overexpression of oncoproteins in TGF-Β/Smads signalling cascade contribute to the TGF-Β resistance. Here, we showed that the overexpressed FOXG1 was involved in attenuating the anti-proliferative control of TGF-Β/Smads signalling in ovarian cancer.Methods:FOXG1 and p21 WAF1/CIP1 expressions were evaluated by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR), western blot and immunohistochemical analyses. The effect of FOXG1 on p21 WAF1/CIP1 transcriptional activity was examined by luciferase reporter assays. Cell lines stably expressing or short hairpin RNA interference-mediated knockdown FOXG1 were established for studying the gain-or-loss functional effects of FOXG1. XTT cell proliferation assay was used to measure cell growth of ovarian cancer cells.Results:Quantitative RT-PCR and western blot analyses showed that FOXG1 was upregulated and inversely associated with the expression levels of p21 WAF1/CIP1 in ovarian cancer. The overexpression of FOXG1 was significantly correlated with high-grade ovarian cancer (P0.025). Immunohistochemical analysis on ovarian cancer tissue array was further evidenced that FOXG1 was highly expressed and significantly correlated with high-grade ovarian cancer (P0.048). Functionally, enforced expression of FOXG1 selectively blocked the TGF-Β-induced p21 WAF1/CIP1 expressions and increased cell proliferation in ovarian cancer cells. Conversely, FOXG1 knockdown resulted in a 20-26% decrease in cell proliferation together with 16-33% increase in p21 WAF1/CIP1 expression. Notably, FOXG1 was able to inhibit the p21 WAF1/CIP1 promoter activity in a p53-independent manner by transient reporter assays.ConclusionOur results suggest that FOXG1 acts as an oncoprotein inhibiting TGF-Β-mediated anti-proliferative responses in ovarian cancer cells through suppressing p21 WAF1/CIP1 transcription. © 2009 Cancer Research UK All rights reserved.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjcen_HK
dc.relation.ispartofBritish Journal of Canceren_HK
dc.subjectFOXG1en_HK
dc.subjectOvarian canceren_HK
dc.subjectP21WAF1/CIP1en_HK
dc.subjectTGF-βen_HK
dc.subject.meshCyclin-Dependent Kinase Inhibitor p21 - antagonists and inhibitors - genetics-
dc.subject.meshForkhead Transcription Factors - analysis - genetics - physiology-
dc.subject.meshNerve Tissue Proteins - analysis - genetics - physiology-
dc.subject.meshOvarian Neoplasms - drug therapy - pathology-
dc.subject.meshTransforming Growth Factor beta - pharmacology-
dc.titleOverexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21 WAF1/CIP1 expression in ovarian canceren_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0007-0920&volume=101&issue=8&spage=1433&epage=1443&date=2009&atitle=Overexpression+of+FOXG1+contributes+to+TGF-beta+resistance+through+inhibition+of+p21(WAF1/CIP1)+expression+in+ovarian+canceren_HK
dc.identifier.emailChan, DW: dwchan@hku.hken_HK
dc.identifier.emailLiu, VWS: vwsliu@hkusua.hku.hken_HK
dc.identifier.emailYao, KM: kmyao@hku.hken_HK
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.authorityChan, DW=rp00543en_HK
dc.identifier.authorityLiu, VWS=rp00341en_HK
dc.identifier.authorityYao, KM=rp00344en_HK
dc.identifier.authorityCheung, ANY=rp00542en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/sj.bjc.6605316en_HK
dc.identifier.pmid19755996en_HK
dc.identifier.pmcidPMC2768441-
dc.identifier.scopuseid_2-s2.0-70349973752en_HK
dc.identifier.hkuros168066en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70349973752&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume101en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1433en_HK
dc.identifier.epage1443en_HK
dc.identifier.eissn1532-1827-
dc.identifier.isiWOS:000270767200028-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridChan, DW=26533900600en_HK
dc.identifier.scopusauthoridLiu, VWS=7006405113en_HK
dc.identifier.scopusauthoridTo, RMY=35192199100en_HK
dc.identifier.scopusauthoridChiu, PM=24463308700en_HK
dc.identifier.scopusauthoridLee, WYW=7407088222en_HK
dc.identifier.scopusauthoridYao, KM=7403234578en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK
dc.identifier.citeulike5809580-

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