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Article: Overexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21 WAF1/CIP1 expression in ovarian cancer
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TitleOverexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21 WAF1/CIP1 expression in ovarian cancer
 
AuthorsChan, DW1
Liu, VWS1
To, RMY1
Chiu, PM1
Lee, WYW1
Yao, KM1
Cheung, ANY1
Ngan, HYS1 2
 
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
 
CitationBritish Journal Of Cancer, 2009, v. 101 n. 8, p. 1433-1443 [How to Cite?]
DOI: http://dx.doi.org/10.1038/sj.bjc.6605316
 
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.
 
ISSN0007-0920
2012 Impact Factor: 5.082
2012 SCImago Journal Rankings: 2.311
 
DOIhttp://dx.doi.org/10.1038/sj.bjc.6605316
 
PubMed Central IDPMC2768441
 
ISI Accession Number IDWOS:000270767200028
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorChan, DW
 
dc.contributor.authorLiu, VWS
 
dc.contributor.authorTo, RMY
 
dc.contributor.authorChiu, PM
 
dc.contributor.authorLee, WYW
 
dc.contributor.authorYao, KM
 
dc.contributor.authorCheung, ANY
 
dc.contributor.authorNgan, HYS
 
dc.date.accessioned2010-09-06T06:01:39Z
 
dc.date.available2010-09-06T06:01:39Z
 
dc.date.issued2009
 
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.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationBritish Journal Of Cancer, 2009, v. 101 n. 8, p. 1433-1443 [How to Cite?]
DOI: http://dx.doi.org/10.1038/sj.bjc.6605316
 
dc.identifier.citeulike5809580
 
dc.identifier.doihttp://dx.doi.org/10.1038/sj.bjc.6605316
 
dc.identifier.eissn1532-1827
 
dc.identifier.epage1443
 
dc.identifier.hkuros168066
 
dc.identifier.isiWOS:000270767200028
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.

 
dc.identifier.issn0007-0920
2012 Impact Factor: 5.082
2012 SCImago Journal Rankings: 2.311
 
dc.identifier.issue8
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2768441
 
dc.identifier.pmid19755996
 
dc.identifier.scopuseid_2-s2.0-70349973752
 
dc.identifier.spage1433
 
dc.identifier.urihttp://hdl.handle.net/10722/68131
 
dc.identifier.volume101
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjc
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofBritish Journal of Cancer
 
dc.relation.referencesReferences in Scopus
 
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.subjectFOXG1
 
dc.subjectOvarian cancer
 
dc.subjectP21WAF1/CIP1
 
dc.subjectTGF-β
 
dc.titleOverexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21 WAF1/CIP1 expression in ovarian cancer
 
dc.typeArticle
 
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<contributor.author>Liu, VWS</contributor.author>
<contributor.author>To, RMY</contributor.author>
<contributor.author>Chiu, PM</contributor.author>
<contributor.author>Lee, WYW</contributor.author>
<contributor.author>Yao, KM</contributor.author>
<contributor.author>Cheung, ANY</contributor.author>
<contributor.author>Ngan, HYS</contributor.author>
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<description.abstract>Background:Loss of growth inhibitory response to transforming growth factor-&#914; (TGF-&#914;) is a common feature of epithelial cancers. Recent studies have reported that genetic lesions and overexpression of oncoproteins in TGF-&#914;/Smads signalling cascade contribute to the TGF-&#914; resistance. Here, we showed that the overexpressed FOXG1 was involved in attenuating the anti-proliferative control of TGF-&#914;/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-&#914;-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-&#914;-mediated anti-proliferative responses in ovarian cancer cells through suppressing p21 WAF1/CIP1 transcription. &#169; 2009 Cancer Research UK All rights reserved.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Queen Mary Hospital Hong Kong