The first two authors contributed equally to this work
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Cancer Cell Biology
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Lef-1 isoforms regulate different target genes and reduce cellular adhesion
Article first published online: 3 AUG 2009
DOI: 10.1002/ijc.24802
Copyright © 2009 UICC
Additional Information
How to Cite
Jesse, S., Koenig, A., Ellenrieder, V. and Menke, A. (2010), Lef-1 isoforms regulate different target genes and reduce cellular adhesion. Int. J. Cancer, 126: 1109–1120. doi: 10.1002/ijc.24802
Publication History
- Issue published online: 27 DEC 2009
- Article first published online: 3 AUG 2009
- Accepted manuscript online: 3 AUG 2009 12:00AM EST
- Manuscript Accepted: 23 JUL 2009
- Manuscript Received: 28 OCT 2008
Funded by
- The Deutsche Forschungsgemeinschaft. Grant Number: SFB 518, B4
- The MD program of the medical faculty of the University Ulm
Keywords:
- Lef-1;
- splice variants;
- regulation of gene expression;
- cell migration;
- pancreatic cancer
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.