Lef‐1 isoforms regulate different target genes and reduce cellular adhesion

Abstract The lymphoid enhancer factor 1 (Lef‐1) belongs to the nuclear transducers of canonical Wnt‐signalling in embryogenesis and cancer. Lef‐1 acts, in cooperation with β‐catenin, as a context‐dependent transcriptional activator or repressor, thereby influencing multiple cellular functions such as proliferation, differentiation and migration. Here we report that an increased Lef‐1 expression in human pancreatic cancer correlates with advanced tumour stages. In pancreatic tumours, two different transcripts of Lef‐1 have been detected in various stages, as demonstrated by RT‐PCR analysis. One transcript was identified as the full length Lef‐1 (Lef‐1 FL), whereas the second, shorter transcript lacked exon VI (Lef‐1 Δexon VI) compared to the published sequence. Comparative analysis of these two Lef‐1 variants revealed that they exhibit different cellular effects after transient expression in pancreatic carcinoma cells. Forced expression of Lef‐1 Δexon VI inhibited E‐cadherin expression in a β‐catenin‐independent way. Increased amounts of Lef‐1 Δexon VI resulted in reduced cellular aggregation and increased cell migration. Expression of Lef‐1 FL, but not the newly identified Lef‐1 Δexon VI, induced the expression of the cell cycle regulating proteins c‐myc and cyclin D1 in cooperation with β‐catenin and it enhanced cell proliferation. Our findings indicate that expression of alternatively spliced Lef‐1 isoforms is involved in the determination of proliferative or migratory characteristics of pancreatic carcinoma cells.