Constitutive activation of Wnt/beta-catenin signaling pathway in migration-active melanoma cells: Role of LEF-1 in melanoma with increased metastaticpotential

A constitutive complex of beta -catenin and LEF-1 has been detected in mela noma cell lines expressing either mutant beta -catenin or mutant APC (Rubin feld et al., Science, 275, 1790-1792, 1997). However, it has been recently reported that beta -catenin mutations are rare in primary malignant melanom a, but its nuclear and/or cytoplasmic localization, a potential indicator o f Wnt/beta -catenin pathway activation, is frequently observed in melanoma (Rimm et al., Am. J. Pathol., 154,325-329, 1999). In human malignant melano ma, the appearance of the tumorigenic phase represents a capacity for metas tasis and is the significant phenotypic step in disease progression. Cell m otility in invasive melanoma is thought to play a crucial role in metastati c behavior. In this work, we sought to determine which transcription factor of the LEF/TCF family was preferentially involved in human melanoma from d ifferent stages of tumor progression. We show that LEF-1 mRNA expression is predominant in highly migrating cells from metastatic melanomas. These act ively migrating melanoma cells showed nuclear and cytoplasmic accumulation of beta -catenin and active transcription from a reporter plasmid of the LE F/TCF binding site. These results may provide a new insight into the role o f the Wnt/beta -catenin signaling pathway in the tumor progression of malig nant melanoma. (C) 2001 Academic Press.