Gene regulation in the progression and metastasis of human malignant melanoma

The molecular changes associated with the transition of melanoma cells from the radial growth phase (RGP) to the vertical growth phase (VGP, metastatic phenotype) are not very well defined. We have previously reported that acquisition of the malignant phenotype is associated with a loss of c-Kit expression and gain in MCAM/MUC18 expression. Here we review our findings which demonstrate that both c-Kit and MCAM/MUC18 are regulated by the transcriptional factor, AP-2. AP-2 is not expressed in metastatic melanoma cells. Forced expression of AP-2 in highly metastatic human melanoma cells decreased their tumorigenicity and metastatic potential in nude mice, whereas expression of a dominant-negative AP-2 gene (AP-2B) augmented their tumor growth in vivo. The AP-2 transfected cells displayed downregulation of MCAM/MUC18 and MMP-2 and re-expression of the c-KIT receptor. AP-2 regulates other genes that are involved in the progression of human melanoma, such as E-cadherin, p21/WAF-1, HER-2, Bcl-2, IGF-R1, and FAS/APO-1 which further suggest that its loss may play a central part in the progression of human melanoma. In contrast to the loss of AP-2 expression, the progression of human melanoma from RGF to VGP is associated with over expression of the transcription factors CREB and ATF-1. Expression of a dominant negative CREB in metastatic melanoma cells resulted in an inhibition of their tumorigenicity and metastatic potential in nude mice. We also found that CREB/ATF-1 acts as a survival factors for melanoma cells. In addition, some of the genes regulated by AP-2 such as MCAM/MUC18, MMP-2 and FAS/APO-1 are also regulated by CREB/ATF-1. Taken together, we propose that the balance between AP-2 and CREB/ATF-1 expression is among the factors determining the acquisition of the metastatic phenotype in human melanoma.