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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.

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