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Transcription initiation arising from E-cadherin/CDH1 intron2: a novel protein isoform that increases gastric cancer cell invasion and angiogenesis

2012-06Journal article Open access
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dc.contributor.authorPinheiro, Hugo
dc.contributor.authorCarvalho, Joana
dc.contributor.authorOliveira, Patrícia
dc.contributor.authorFerreira, Daniel
dc.contributor.authorTeixeira Pinto, Marta
dc.contributor.authorOsório, Hugo
dc.contributor.authorLicastro, Danilo
dc.contributor.authorBordeira-Carriço, Renata
dc.contributor.authorJordan, Peter
dc.contributor.authorLazarevic, Dejan
dc.contributor.authorSanges, Remo
dc.contributor.authorStupka, Elia
dc.contributor.authorHuntsman, David
dc.contributor.authorSeruca, Raquel
dc.contributor.authorOliveira, Carla
dc.date.accessioned2012-07-10T16:22:15Z
dc.date.available2012-07-10T16:22:15Z
dc.date.issued2012-06
dc.description.abstractDisruption of E-cadherin (CDH1 gene) expression, subcellular localization or function arises during initiation and progression of almost 90% of all epithelial carcinomas. Nevertheless, the mechanisms through which this occurs are largely unknown. Previous studies showed the importance of CDH1 intron 2 sequences for proper gene and protein expression, supporting these as E-cadherin cis-modulators. Through RACE and RT-PCR, we searched for transcription events arising from CDH1 intron 2 and discovered several new transcripts. One, named CDH1a, with high expression in spleen and absent from normal stomach, was demonstrated to be translated into a novel isoform, differing from canonical E-cadherin in its N-terminal, as determined by mass-spectrometry. Quantitative and functional assays showed that when overexpressed in an E-cadherin negative context, CDH1a replaced canonical protein interactions and functions. However, when co-expressed with canonical E-cadherin, CDH1a increased cell invasion and angiogenesis. Further, interferon-induced genes IFITM1 and IFI27 levels were increased upon CDH1a overexpression. Effects on invasion and IFITM1 and IFI27 expression were reverted upon CDH1a specific knockdown. Importantly, CDH1a was de novo expressed in gastric cancer cell lines. This study presents a new mechanism by which E-cadherin functions are impaired by cis-regulatory mechanisms possibly with the involvement of inflammatory machinery. If confirmed in other cancer models, our data encloses potential for designing targeted therapies to rescue E-cadherin function.por
dc.description.sponsorshipFundação para a Ciência e Tecnologiapor
dc.identifier.citationHum Mol Genet. 2012 Oct 1;21(19):4253-69. Epub 2012 Jun 29.por
dc.identifier.issn0964-6906
dc.identifier.otherdoi:10.1093/hmg/dds248
dc.identifier.urihttp://hdl.handle.net/10400.18/919
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherOxford University Presspor
dc.subjectVias de Transdução de Sinal e Patologias Associadaspor
dc.subjecte-cadherinpor
dc.subjectGastric Cancerpor
dc.subjectTranscriptionpor
dc.titleTranscription initiation arising from E-cadherin/CDH1 intron2: a novel protein isoform that increases gastric cancer cell invasion and angiogenesispor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titleHuman Molecular Geneticspor
rcaap.rightsopenAccesspor
rcaap.typearticlepor

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