Constitutive activation of Wnt/beta-catenin signaling pathway in migration-active melanoma cells: role of LEF-1 in melanoma with increased metastatic potential.

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