title: Transcription initiation arising from E-cadherin/CDH1 intron2: a novel protein isoform that increases gastric cancer cell invasion and angiogenesis.
abstract: Disruption 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 gene 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 enclose potential for designing targeted therapies to rescue E-cadherin function.
authors: IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-465, Portugal.
authors: Hugo
authors: H
authors: Pinheiro
authors: Joana
authors: J
authors: Carvalho
authors: Patrícia
authors: P
authors: Oliveira
authors: Daniel
authors: D
authors: Ferreira
authors: Marta Teixeira
authors: MT
authors: Pinto
authors: Hugo
authors: H
authors: Osório
authors: Danilo
authors: D
authors: Licastro
authors: Renata
authors: R
authors: Bordeira-Carriço
authors: Peter
authors: P
authors: Jordan
authors: Dejan
authors: D
authors: Lazarevic
authors: Remo
authors: R
authors: Sanges
authors: Elia
authors: E
authors: Stupka
authors: David
authors: D
authors: Huntsman
authors: Raquel
authors: R
authors: Seruca
authors: Carla
authors: C
authors: Oliveira
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002642:Chick Embryo; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D020033:Protein Isoforms