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Title: Lack of microRNA-101 causes E-cadherin functional deregulation through EZH2 up-regulation in intestinal gastric cancer
Author: Carvalho, Joana
van Grieken, Nicole C.
Pereira, Patrícia M.
Sousa, Sónia
Tijssen, Marianne
Buffart, Tineke E.
Diosdado, Begoña
Grabsch, Heike
Santos, Manuel A. S.
Meijer, Gerrit
Seruca, Raquel
Carvalho, Beatriz
Oliveira, Carla
Keywords: Gastric cancer
E-cadherin (CDH1)
Enhancer of Zeste homologue 2 (EZH2)
Issue Date: Sep-2012
Publisher: John Wiley & Sons
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.
Peer review: yes
DOI: 10.1002/path.4032
ISSN: 0022-3417
Appears in Collections:CESAM - Artigos
DBio - Artigos

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