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

作者：Keith S. Hoek, David L. Rimm, Kenneth R. Williams, Hongyu Zhao, Stephan Ariyan, Lin Ai, Harriet M. Kluger, Aaron J. Berger, Enhao Cheng, E. Sergio Trombetta, Terence Wu, Michio Niinobe, Kazuaki Yoshikawa, Gregory E. Hannigan, Ruth Halaban · 发表于：Cancer Research · 年份：2004 · DOI：10.1158/0008-5472.can-04-0731 · 被引用次数：444 · 研究领域：Cutaneous Melanoma Detection and Management、Melanoma and MAPK Pathways、melanin and skin pigmentation

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 expresse...