A novel member of the human frizzled (Fz) gene family was cloned and found to be specifically expressed compared to the adjacent uninvolved normal mucosa in 28 of 47 (60%) squamous cell esophageal carcinomas. The FzE3 cDNA encodes a protein of 574 amino acids and shares high sequence homology with other frizzled genes, particularly in the putative ligand-binding region of the cysteine-rich extracellular domain. Functional analysis revealed that transfection and expression of the FzE3 cDNA in esophageal carcinoma cells stimulates complex formation between APC and β-catenin followed by nuclear translocation of β-catenin, which mediates cell:cell attachment with E- cadherin. Furthermore, cotransfection of a mutant construct encoding a FzE3 protein with a C-terminal truncation completely inhibited the interaction of APC with β-catenin in the cells. These observations suggest that FzE3 gene expression may downregulate APC function and enhance β-catenin mediated signals in human esophageal carcinomas.
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