| Autor: |
Hoek, K., Rimm, D., Williams, K., Zhao, H., Ariyan, S., Lin, A., Kluger, H., Berger, A., Cheng, E., Trombetta, E. S., Wu, T., Halaban, R., Niinobe, M., Yoshikawa, K., Hannigan, G. E. |
| Předmět: |
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| Zdroj: |
Pigment Cell Research; Aug2004, Vol. 17 Issue 4, p430-430, 1p |
| Abstrakt: |
To assess the differences in global gene expression in normal melanocytes compared with melanoma cells. The human genome Affymetrix GeneChip system HG-U133A microarray and the OHU16K human library oligonucleotide array were used to monitor for gene expression comparing normal human melanocytes and six independent melanoma cell strains from advanced lesions grown in culture. The largest group of upregulated genes in melanoma cells belonged to receptor activity, including the integrin pathway, insulin like growth factor receptor, and the FGFR1 activated by FGF13. We also found novel pathways and patterns of associated expression in melanoma cells not reported before, including: (a) activation of the NOTCH pathway; (b) increased TWIST expression and altered expression of additional transcriptional regulators implicated in embryonic development and epidermal/mesenchyme transition; (c) coordinated activation of cancer/testis antigens; (d) coordinated downregulation of several immunemodulation genes, in particular the interferon pathways; (d) downregulation of Ras-members small GTP-binding proteins whose products are implicated in membrane trafficking events; and (e) downregulation of growth suppressors, such as the Prader–Willi gene Necdin, whose function was validated by overexpression of ectopic necdin. Probing melanoma tissue microarrays showed an association between worse prognosis and reduced ubiquitin carboxyl-terminal esterase L1 in primary melanoma lesions, and with increased expression of the bHLH protein TWIST in melanomas. 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 compared with normal melanocytes, uncover novel pathways associated with malignant transformation, and reveal targets that can be used in assessing prognosis, staging and therapy of melanoma patients. we have confirmed several known changes in melanoma cells and identified a number of novel genes and pathways that are up- or down-regulated in metastatic melanoma cell strains compared with normal melanocytes. Our data suggest that NOTCH2 is activated, that TWIST might be a clinically valuable prognostic marker, for patients with both primary and metastatic melanomas, and that necdin is a potent melanoma growth suppressor. We demonstrated coordinated expression of several groups of genes, from the receptor activity group, interferon-responsive genes, MAGE and GAGE, Rab family members, and genes involved in embryonic tissue remodeling. These data serve as a basis for further evaluation of these genes and their protein products as pathways leading to malignant transformation, prognostic markers and/or as drug targets. National Institutes of Health and the C.J. Swebilius Award. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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