Carcinogenesis Advance Access originally published online on March 10, 2005
Carcinogenesis 2005 26(7):1224-1232; doi:10.1093/carcin/bgi066
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Carcinogenesis vol.26 no.7 © Oxford University Press 2005; all rights reserved.
Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines
1 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany, 2 Department of Biosciences, Karolinska Institute, 141 57 Huddinge, Sweden and 3 Skin Cancer Unit, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
* To whom correspondence should be addressed. Tel: +49 6221 42 1806; Fax: +49 6221 42 1810; Email: r.kumar{at}dkfz.de
We studied global gene expression in three melanoma cell lines with the most common and potent V600E mutation in the B-RAF gene—four cell lines with a common Q61R mutation in the N-RAS gene and three cell lines with no mutations using human HG-U133A 2.0 micro-arrays with 22 277 transcripts. Data analysis using stringent criteria revealed several upregulated and downregulated genes in cell lines with B-RAF and N-RAS mutations compared with cell lines without mutations. We found 29 genes specifically upregulated and 32 genes downregulated in cell lines with B-RAF mutations, whereas 70 genes were upregulated and 39 downregulated in cell lines with N-RAS mutations; 11 genes showed overlapping upregulation and 45 downregulation. The micro-array data for nine selected genes were validated by the real-time PCR technique. Expression of a large number of genes, that encode members or regulators of the RAS/RAF/MEK/ERK pathways or are involved in metastasis or invasion, was affected in cell lines with mutations in B-RAF and N-RAS. Upregulated genes in cell lines with mutations included dual-specificity phosphatase 6 (DUSP6), sprouty 2 (SPRY2), v-akt murine thymoma viral oncogene homolog 3 (AKT3) and matrix metalloproteinase 14 (MMP14); downregulated genes included interleukin 18 (IL18), Krüppel-like factor 5 (KLF5) and inhibitor of DNA binding 2 (ID2). Our results, though carried on cell lines, provide a novel insight into the effect of mutations in the B-RAF and N-RAS genes on global gene expression in melanoma and highlight the complexity of mechanisms involved in tumour initiation and maintenance.
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