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

Hugo Pinheiro, Joana Carvalho, Patrícia Oliveira, Daniel Ferreira, Marta Teixeira Pinto, Hugo Osoquot;rio, Danilo Licastro, Renata Bordeira-carricquot;o, Peter Jordan, Dejan Lazarevic, Remo Sanges, Elia Stupka, David Huntsman, Raquel Seruca, Carla Oliveira

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Article numberdds248
Pages (from-to)4253-4269
Number of pages17
JournalHuman Molecular Genetics
Volume21
Issue number19
DOIs
Publication statusPublished - Oct 2012

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Cadherins
Stomach Neoplasms
Protein Isoforms
Introns
Gene Expression
Interferons
Mass Spectrometry
Stomach
Proteins
Spleen
Carcinoma
Cell Line
Polymerase Chain Reaction
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Pinheiro, H., Carvalho, J., Oliveira, P., Ferreira, D., Pinto, M. T., Osoquot;rio, H., ... Oliveira, C. (2012). Transcription initiation arising from E-cadherin/CDH1 intron2: A novel protein isoform that increases gastric cancer cell invasion and angiogenesis. Human Molecular Genetics, 21(19), 4253-4269. [dds248]. https://doi.org/10.1093/hmg/dds248

Transcription initiation arising from E-cadherin/CDH1 intron2 : A novel protein isoform that increases gastric cancer cell invasion and angiogenesis. / Pinheiro, Hugo; Carvalho, Joana; Oliveira, Patrícia; Ferreira, Daniel; Pinto, Marta Teixeira; Osoquot;rio, Hugo; Licastro, Danilo; Bordeira-carricquot;o, Renata; Jordan, Peter; Lazarevic, Dejan; Sanges, Remo; Stupka, Elia; Huntsman, David; Seruca, Raquel; Oliveira, Carla.

In: Human Molecular Genetics, Vol. 21, No. 19, dds248, 10.2012, p. 4253-4269.

Research output: Contribution to journalArticle

Pinheiro, H, Carvalho, J, Oliveira, P, Ferreira, D, Pinto, MT, Osoquot;rio, H, Licastro, D, Bordeira-carricquot;o, R, Jordan, P, Lazarevic, D, Sanges, R, Stupka, E, Huntsman, D, Seruca, R & Oliveira, C 2012, 'Transcription initiation arising from E-cadherin/CDH1 intron2: A novel protein isoform that increases gastric cancer cell invasion and angiogenesis', Human Molecular Genetics, vol. 21, no. 19, dds248, pp. 4253-4269. https://doi.org/10.1093/hmg/dds248
Pinheiro, Hugo ; Carvalho, Joana ; Oliveira, Patrícia ; Ferreira, Daniel ; Pinto, Marta Teixeira ; Osoquot;rio, Hugo ; Licastro, Danilo ; Bordeira-carricquot;o, Renata ; Jordan, Peter ; Lazarevic, Dejan ; Sanges, Remo ; Stupka, Elia ; Huntsman, David ; Seruca, Raquel ; Oliveira, Carla. / Transcription initiation arising from E-cadherin/CDH1 intron2 : A novel protein isoform that increases gastric cancer cell invasion and angiogenesis. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 19. pp. 4253-4269.
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