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Gene Regulation in Melanoma Metastasis

  • Chapter
Cancer Metastasis — Related Genes

Part of the book series: Cancer Metastasis — Biology and Treatment ((CMBT,volume 3))

  • 175 Accesses

Abstract

The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP, metastatic phenotype) are not very well defined. We previously demonstrated that expression of the cell surface adhesion molecule MCAM/MUC18 correlates directly with the metastatic potential of human melanoma cells. In addition, the progression of human melanoma towards the metastatic phenotype is associated with loss of expression of the tyrosine-kinase receptor c-KIT. We found that both genes MCAM/MUC18 and c-KIT, are regulated by the transcription factor AP-2 and that metastatic melanoma cells do not express AP-2. Re-expression of AP-2 in highly metastatic cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice, while expression of dominant-negative AP-2 gene (AP- 2B) augmented their tumor growth in vivo. The AP-2 transfected cells displayed down regulation of MCAM/MUC18 and MMP-2 and re-expression of the c-KIT receptor. Because AP-2 also regulates other genes that are involved in the progression of human melanoma, such as E-cadherin, p21/WAF-1, HER-2, Bc1-2, IGF-R1, FAS/APO-1 and the thrombin receptor (PAR-1), we propose that loss of AP-2 is a critical event in the development of malignant melanoma. The progression of human melanoma from RGF to VGP is also associated with over expression of the transcription factors CREB and ATF-1. We found that CREB/ATF-1 may act as 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. It is therefore feasible 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.

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  1. Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

    Menashe Bar-eli

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  1. Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Pennsylvania, USA

    Danny R. Welch

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Bar-eli, M. (2002). Gene Regulation in Melanoma Metastasis. In: Welch, D.R. (eds) Cancer Metastasis — Related Genes. Cancer Metastasis — Biology and Treatment, vol 3. Springer, Dordrecht. https://doi.org/10.1007/0-306-47821-8_8

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  • DOI: https://doi.org/10.1007/0-306-47821-8_8

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-1-4020-0522-0

  • Online ISBN: 978-0-306-47821-5

  • eBook Packages: Springer Book Archive

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