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[Cancer Research 64, 5270-5282, August 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Expression Profiling Reveals Novel Pathways in the Transformation of Melanocytes to Melanomas

Keith Hoek1, David L. Rimm2, Kenneth R. Williams1, Hongyu Zhao3, Stephan Ariyan4, Aiping Lin1, Harriet M. Kluger5, Aaron J. Berger2, Elaine Cheng6, E. Sergio Trombetta7, Terence Wu1, Michio Niinobe8, Kazuaki Yoshikawa8, Gregory E. Hannigan9 and Ruth Halaban6

Departments of 1 Molecular Biophysics and Biochemistry, 2 Pathology, 3 Epidemiology, 4 Surgery, 5 Internal Medicine, 6 Dermatology, and 7 Cell Biology, Yale University School of Medicine, New Haven, Connecticut; 8 Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Osaka, Japan; and 9 Laboratory Medicine and Pathobiology, Cancer Research Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Affymetrix and spotted oligonucleotide microarrays were used to assess global differential gene expression comparing normal human melanocytes with six independent melanoma cell strains from advanced lesions. The data, validated at the protein level for selected genes, confirmed the overexpression in melanoma cells relative to normal melanocytes of several genes in the growth factor/receptor family that confer growth advantage and metastasis. In addition, novel pathways and patterns of associated expression in melanoma cells not reported before emerged, including the following: (a) activation of the NOTCH pathway; (b) increased Twist expression and altered expression of additional transcriptional regulators implicated in embryonic development and epidermal/mesenchymal transition; (c) coordinated activation of cancer/testis antigens; (d) coordinated down-regulation of several immune modulation genes, in particular in the IFN pathways; (e) down-regulation of several genes implicated in membrane trafficking events; and (f) down-regulation of growth suppressors, such as the Prader-Willi gene NECDIN, whose function was confirmed by overexpression of ectopic Flag-necdin. Validation of differential expression using melanoma tissue microarrays showed that reduced ubiquitin COOH-terminal esterase L1 in primary melanoma is associated with worse outcome and that increased expression of the basic helix-loop-helix protein Twist is associated with worse outcome. Some differentially expressed genes reside on chromosomal regions displaying common loss or gain in melanomas or are known to be regulated by CpG promoter methylation. These results provide a comprehensive view of changes in advanced melanoma relative to normal melanocytes and reveal new targets that can be used in assessing prognosis, staging, and therapy of melanoma patients.




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