A NOVEL FRIZZLED GENE IDENTIFIED IN HUMAN ESOPHAGEAL-CARCINOMA MEDIATES APC BETA-CATENIN SIGNALS/

A novel member of the human frizzled (Fz) gene family was cloned and f ound to be specifically expressed in 3 of 13 well differentiated (23%) , 13 of 20 moderately differentiated (62%), and 12 of 14 poorly differ entiated (86%) squamous cell esophageal carcinomas compared with the a djacent uninvolved normal mucosa. The FzE3 cDNA encodes a protein of 5 74 amino acids and shares high sequence homology with the human FzD2 g ene particularly in the putative ligand binding region of the cysteine -rich extracellular domain, Functional analysis revealed that transfec tion and expression of the FzE3 cDNA in esophageal carcinoma cells sti mulates complex formation between adenomatous polyposis coli (APC) and beta-catenin followed by nuclear translocation of beta-catenin, Furth ermore, cotransfection of a mutant construct encoding a FzE3 protein w ith a C-terminal truncation completely inhibited the interaction of AP C with beta-catenin in cells. Finally, coexpression of FzE3 with Lef-1 transcription factor enhanced beta-catenin translocation to the nucle us. These observations suggest that FzE3 gene expression may down-regu late APC function and enhance beta-catenin mediated signals in poorly differentiated human esophageal carcinomas.