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Article: Downregulation of ASPP1 in gestational trophoblastic disease: Correlation with hypermethylation, apoptotic activity and clinical outcome
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TitleDownregulation of ASPP1 in gestational trophoblastic disease: Correlation with hypermethylation, apoptotic activity and clinical outcome
 
AuthorsMak, VCY1
Lee, L1
Siu, MKY1
Wong, OGW1
Lu, X2
Ngan, HYS1
Wong, ESY1
Cheung, ANY1
 
Keywordsapoptotic activity
ASPP1
choriocarcinomas
gestational trophoblastic disease
hypermethylation
methylation
 
Issue Date2011
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/modpathol/
 
CitationModern Pathology, 2011, v. 24 n. 4, p. 522-532 [How to Cite?]
DOI: http://dx.doi.org/10.1038/modpathol.2010.216
 
AbstractGestational trophoblastic disease encompasses a spectrum of trophoblastic lesions including true neoplasms such as choriocarcinomas and the potentially malignant hydatidiform moles, which may develop persistent disease requiring chemotherapy. ASPP1, a member of apoptosis-stimulating proteins of p53 (ASPPs), is a proapoptotic protein that can stimulate apoptosis through its interaction with p53. We evaluated the promoter methylation and expression profiles of ASPP1 in different trophoblastic tissues and its in vitro functional effect on two choriocarcinoma cell lines, namely JEG-3 and JAR. Significant downregulation of ASPP1 mRNA and protein levels was demonstrated in hydatidiform moles and choriocarcinomas, when compared with normal placentas by quantitative-PCR and immunohistochemistry. The ASPP1 mRNA level was significantly correlated with its hypermethylation status, evaluated with methylation-specific PCR, in placenta and gestational trophoblastic disease samples (P=0.024). Moreover, lower ASPP1 immunoreactivity was shown in hydatidiform moles that progressed to persistent gestational trophoblastic neoplasms than in those that regressed (P=0.045). A significant correlation was also found between expression of ASPP1 and proliferative indices (assessed by Ki67 and MCM7), apoptotic activity (M30 CytoDeath antibody), p53 and caspase-8 immunoreactivities. An in vitro study showed that ectopic expression of ASPP1 could trigger apoptosis through intrinsic and extrinsic pathways as indicated by an increase in cleaved caspase-9 and Fas ligand protein expression. The latter suggests a hitherto unreported novel link between ASPP1 and the extrinsic pathway of apoptosis. Our findings suggest that downregulation of ASPP1 by hypermethylation may be involved in the pathogenesis and progress of gestational trophoblastic disease, probably through its effect on apoptosis. © 2011 USCAP, Inc. All rights reserved.
 
ISSN0893-3952
2012 Impact Factor: 5.253
2012 SCImago Journal Rankings: 2.127
 
DOIhttp://dx.doi.org/10.1038/modpathol.2010.216
 
ISI Accession Number IDWOS:000289072100006
Funding AgencyGrant Number
Research Grants Council of the Hong Kong Special Administrative RegionAoE/M-04/06
Funding Information:

This study was supported by grants from the 'Centre for Research into Circulating Fetal Nucleic Acids' (AoE/M-04/06) funded by the Research Grants Council of the Hong Kong Special Administrative Region.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorMak, VCY
 
dc.contributor.authorLee, L
 
dc.contributor.authorSiu, MKY
 
dc.contributor.authorWong, OGW
 
dc.contributor.authorLu, X
 
dc.contributor.authorNgan, HYS
 
dc.contributor.authorWong, ESY
 
dc.contributor.authorCheung, ANY
 
dc.date.accessioned2011-09-23T06:01:43Z
 
dc.date.available2011-09-23T06:01:43Z
 
dc.date.issued2011
 
dc.description.abstractGestational trophoblastic disease encompasses a spectrum of trophoblastic lesions including true neoplasms such as choriocarcinomas and the potentially malignant hydatidiform moles, which may develop persistent disease requiring chemotherapy. ASPP1, a member of apoptosis-stimulating proteins of p53 (ASPPs), is a proapoptotic protein that can stimulate apoptosis through its interaction with p53. We evaluated the promoter methylation and expression profiles of ASPP1 in different trophoblastic tissues and its in vitro functional effect on two choriocarcinoma cell lines, namely JEG-3 and JAR. Significant downregulation of ASPP1 mRNA and protein levels was demonstrated in hydatidiform moles and choriocarcinomas, when compared with normal placentas by quantitative-PCR and immunohistochemistry. The ASPP1 mRNA level was significantly correlated with its hypermethylation status, evaluated with methylation-specific PCR, in placenta and gestational trophoblastic disease samples (P=0.024). Moreover, lower ASPP1 immunoreactivity was shown in hydatidiform moles that progressed to persistent gestational trophoblastic neoplasms than in those that regressed (P=0.045). A significant correlation was also found between expression of ASPP1 and proliferative indices (assessed by Ki67 and MCM7), apoptotic activity (M30 CytoDeath antibody), p53 and caspase-8 immunoreactivities. An in vitro study showed that ectopic expression of ASPP1 could trigger apoptosis through intrinsic and extrinsic pathways as indicated by an increase in cleaved caspase-9 and Fas ligand protein expression. The latter suggests a hitherto unreported novel link between ASPP1 and the extrinsic pathway of apoptosis. Our findings suggest that downregulation of ASPP1 by hypermethylation may be involved in the pathogenesis and progress of gestational trophoblastic disease, probably through its effect on apoptosis. © 2011 USCAP, Inc. All rights reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationModern Pathology, 2011, v. 24 n. 4, p. 522-532 [How to Cite?]
DOI: http://dx.doi.org/10.1038/modpathol.2010.216
 
dc.identifier.citeulike8335420
 
dc.identifier.doihttp://dx.doi.org/10.1038/modpathol.2010.216
 
dc.identifier.epage532
 
dc.identifier.hkuros192466
 
dc.identifier.isiWOS:000289072100006
Funding AgencyGrant Number
Research Grants Council of the Hong Kong Special Administrative RegionAoE/M-04/06
Funding Information:

This study was supported by grants from the 'Centre for Research into Circulating Fetal Nucleic Acids' (AoE/M-04/06) funded by the Research Grants Council of the Hong Kong Special Administrative Region.

 
dc.identifier.issn0893-3952
2012 Impact Factor: 5.253
2012 SCImago Journal Rankings: 2.127
 
dc.identifier.issue4
 
dc.identifier.openurl
 
dc.identifier.pmid21102414
 
dc.identifier.scopuseid_2-s2.0-79953305430
 
dc.identifier.spage522
 
dc.identifier.urihttp://hdl.handle.net/10722/139929
 
dc.identifier.volume24
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/modpathol/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofModern Pathology
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAdaptor Proteins, Signal Transducing - genetics - metabolism
 
dc.subject.meshApoptosis Regulatory Proteins - genetics - metabolism
 
dc.subject.meshChoriocarcinoma - genetics - metabolism - pathology
 
dc.subject.meshDNA Methylation
 
dc.subject.meshHydatidiform Mole - genetics - metabolism - pathology
 
dc.subjectapoptotic activity
 
dc.subjectASPP1
 
dc.subjectchoriocarcinomas
 
dc.subjectgestational trophoblastic disease
 
dc.subjecthypermethylation
 
dc.subjectmethylation
 
dc.titleDownregulation of ASPP1 in gestational trophoblastic disease: Correlation with hypermethylation, apoptotic activity and clinical outcome
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. University of Oxford