1. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas.
- Author
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Hoek K, Rimm DL, Williams KR, Zhao H, Ariyan S, Lin A, Kluger HM, Berger AJ, Cheng E, Trombetta ES, Wu T, Niinobe M, Yoshikawa K, Hannigan GE, and Halaban R
- Subjects
- Animals, Cohort Studies, Down-Regulation, Humans, Lymphatic Metastasis pathology, Melanocytes pathology, Melanoma genetics, Melanoma secondary, Mice, Nuclear Proteins metabolism, Oligonucleotide Array Sequence Analysis, Prognosis, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms secondary, Survival Rate, Transcription Factors metabolism, Transfection, Twist-Related Protein 1, Ubiquitin Thiolesterase metabolism, Biomarkers, Tumor metabolism, Cell Transformation, Neoplastic genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Melanocytes metabolism, Melanoma metabolism, Signal Transduction
- Abstract
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.
- Published
- 2004
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