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http://hdl.handle.net/10773/26893
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DC Field | Value | Language |
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dc.contributor.author | Carvalho, Joana | pt_PT |
dc.contributor.author | van Grieken, Nicole C. | pt_PT |
dc.contributor.author | Pereira, Patrícia M. | pt_PT |
dc.contributor.author | Sousa, Sónia | pt_PT |
dc.contributor.author | Tijssen, Marianne | pt_PT |
dc.contributor.author | Buffart, Tineke E. | pt_PT |
dc.contributor.author | Diosdado, Begoña | pt_PT |
dc.contributor.author | Grabsch, Heike | pt_PT |
dc.contributor.author | Santos, Manuel A. S. | pt_PT |
dc.contributor.author | Meijer, Gerrit | pt_PT |
dc.contributor.author | Seruca, Raquel | pt_PT |
dc.contributor.author | Carvalho, Beatriz | pt_PT |
dc.contributor.author | Oliveira, Carla | pt_PT |
dc.date.accessioned | 2019-10-30T12:45:04Z | - |
dc.date.available | 2019-10-30T12:45:04Z | - |
dc.date.issued | 2012-09 | - |
dc.identifier.issn | 0022-3417 | pt_PT |
dc.identifier.uri | http://hdl.handle.net/10773/26893 | - |
dc.description.abstract | E-cadherin expression disruption is commonly observed in metastatic epithelial cancers and is a crucial step in gastric cancer (GC) initiation and progression. As aberrant expression of microRNAs often perturb the normal expression/function of pivotal cancer-related genes, we characterized and dissected a pathway that causes E-cadherin dysfunction via loss of microRNA-101 and up-regulation of EZH2 expression in GC. MicroRNA microarray expression profiling and array-CGH were used to reinforce miR-101 involvement in GC. By using quantitative real-time PCR and quantitative SNaPshot genomic PCR, we confirmed that miR-101 was significantly down-regulated in GC (p < 0.0089) in comparison with normal gastric mucosas and, at least in 65% of the GC cases analysed, this down-regulation was caused by deletions and/or microdeletions at miR-101 genomic loci. Moreover, around 40% of cases showing miR-101 down-regulation displayed concomitant EZH2 over-expression (at the RNA and protein levels), which, in turn, was associated with loss/aberrant expression of E-cadherin. Interestingly, this occurred preferentially in intestinal-type GCs, retaining allele(s) untargeted by classical CDH1-inactivating mechanisms. We also demonstrated that miR-101 gain of function or direct inhibition of EZH2 in Kato III GC cells led to a strong depletion of endogenous EZH2 and consequent rescue of E-cadherin membranous localization, mimicking results obtained in clinical GC samples. In conclusion, we show that deletions and/or microdeletions at both miR-101 genomic loci cause mature miR-101 down-regulation, subsequent EZH2 over-expression and E-cadherin dysfunction, specifically in intestinal-type GC. | pt_PT |
dc.language.iso | eng | pt_PT |
dc.publisher | John Wiley & Sons | pt_PT |
dc.relation | PTDCSAUGMG/72168/2006 | pt_PT |
dc.relation | info:eu-repo/grantAgreement/FCT/5876-PPCDTI/64745/PT | pt_PT |
dc.relation | info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F44074%2F2008/PT | pt_PT |
dc.rights | restrictedAccess | pt_PT |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | pt_PT |
dc.subject | Gastric cancer | pt_PT |
dc.subject | E-cadherin (CDH1) | pt_PT |
dc.subject | Enhancer of Zeste homologue 2 (EZH2) | pt_PT |
dc.subject | MicroRNA-101 | pt_PT |
dc.title | Lack of microRNA-101 causes E-cadherin functional deregulation through EZH2 up-regulation in intestinal gastric cancer | pt_PT |
dc.type | article | pt_PT |
dc.description.version | published | pt_PT |
dc.peerreviewed | yes | pt_PT |
degois.publication.firstPage | 31 | pt_PT |
degois.publication.issue | 1 | pt_PT |
degois.publication.lastPage | 34 | pt_PT |
degois.publication.title | Journal of Pathology | pt_PT |
degois.publication.volume | 228 | pt_PT |
dc.identifier.doi | 10.1002/path.4032 | pt_PT |
dc.identifier.essn | 1096-9896 | pt_PT |
Appears in Collections: | CESAM - Artigos DBio - Artigos |
Files in This Item:
File | Description | Size | Format | |
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Carvalho et al. - 2012 - Lack of microRNA-101 causes E-cadherin functional .pdf | 3.96 MB | Adobe PDF |
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