Unformatted text preview: RAS in these cell lines resulted in decreased proliferation, increased
apoptosis as well as decreased phosphorylation of ERK and AKT, in the NRAS
signaling pathway and reduced expression of NF-κB and cyclin D1. In contrast, RNA
interference directed at wild type NRAS had no significant effect on the proliferation
and apoptosis of 224 cells or two human melanoma cell lines (A375 and 397)
containing wild type NRAS but a codon 600 GTG (V) to GAG (E) mutation in BRAF.
These data suggest that oncogenic NRAS is crucial for proliferation in melanomas that
harbor the codon 61 NRAS mutation and that suppression of oncogenic NRAS in such
melanomas by RNA interference may prove a useful future therapeutic option. Paper ΙΙΙ
Oncogenic NRAS has a Pivotal Role in the Malignant Phenotype of Human
Melanoma Cells. Submitted for publication
One of the major goals of melanoma research is to identify molecular targets for the
development of novel treatment strategies. Activating mutations in the NRAS gene,
which occur predominantly in codon 61 (Q61R, Q61K) can be good therapeutic
targets since these alterations are among the most common genetic events in
malignant melanoma. These mutations affect regulation of cellular growth and
viability, which contribute to the malignant phenotype.
We demonstrated in paper II that suppression of oncogenic NRAS by siRNA inhibited
proliferation and induced apoptosis in human melanoma cells, suggesting that
oncogenic NRAS is crucial for proliferation and resistance to apoptosis in melanomas.
With the aim of improving our understanding of the role of this oncogene in melanoma
biology and to identify possible specific molecular therapeutic targets in this malignant
disease, we used gene expression profiling as a method for global characterization of
gene expression alterations that resulted from treatment of melanoma cells with siRNA
specifically targeting NRASQ61R. Thirty-one probe sets were identified whose
expression was significantly altered by siRNA against NRASQ61R in two melanoma cell
lines. The genes with alte...
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