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: Hugo Pinheiro, Joana Carvalho, Patrícia Oliveira, Daniel Ferreira, Marta Teixeira Pinto, Hugo Osório, Danilo Licastro, Renata Bordeira-Carriço, Peter Jordan, Dejan Lazarevic, Remo Sanges, Elia Stupka, David Huntsman, Raquel Seruca, Carla Oliveira
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 21 Issue 19 Pg. 4253-69 (Oct 01 2012) ISSN: 1460-2083 [Electronic] England
• PMID: 22752307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins
• Protein Isoforms

Topics

• Animals
• Antigens, CD
• Cadherins (genetics, metabolism)
• Cell Line, Tumor
• Chick Embryo
• Gene Expression Regulation, Neoplastic
• Humans
• Introns
• Neoplasm Invasiveness
• Neovascularization, Pathologic
• Protein Isoforms (genetics, metabolism)
• Stomach Neoplasms (genetics, metabolism, pathology)
• Transcription, Genetic
• Up-Regulation