Transcriptional repression of TFF1 in gastric epithelial cells by CCAAT/enhancer binding protein-beta.

TFF1 is a member of a unique family of gastrointestinal peptides. Loss of TFF1 expression has been observed in the majority of human gastric cancers and the biological significance of this loss has been demonstrated in a Tff1 knockout mouse model. However, few TFF1 gene mutations or allelic loss have also been documented. To understand the molecular mechanism repressing the TFF1 gene expression, the 5'-flanking region of the human TFF1 gene was characterized. We found a repressor region (-241 to -84), which is active in MKN45 and IMGE5 cells expressing endogenous TFF1 gene. A consensus binding site for C/EBPbeta was identified and EMSA analysis demonstrated specific binding of CEBPbeta. Mutation of this C/EBPbeta element potentiated the transactivation of TFF1 by 50% and 145% for MKN45 and IMGE5 cells respectively. Furthermore, co-transfection of C/EBPbeta isoforms specifically decreased TFF1 promoter activity. These findings suggest that C/EBPbeta is involved in the down-regulating of TFF1 gene expression and this mode of repression may account at least in part for the loss of TFF1 gene expression in transformed human and mice gastric epithelial cells.