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Unformatted text preview: red expression are involved in several functions, including
modulation of cell growth, invasion and migration. The results suggest that down 30 regulation of cyclin E2 and cyclin D1 and also up-regulation of a negative cell cycle
regulator (HBP1) in NRASQ61R knockdown cells contribute to the inhibition of cell
proliferation. Moreover, staining these cells with β-galactosidase showed 10% positive
cells indicating premature senescence in some of these transfected cells. Furthermore,
suppression of oncogenic NRAS results in a disability of cells in migration and
invasion, which is accompanied by down-regulation of EphA2 (a receptor tyrosine
kinase), uPAR (urokinase receptor) and cytoskeleton proteins such as leupaxin, αactinin, paxillin, and vinculin.
In summary, these studies provide strong support for the conclusion that suppression
of oncogenic NRAS by siRNA can induce growth arrest and inhibit invasion of human
melanoma cells, which may be the basis of the development of more specific
melanoma therapy in the subset of patients with NRAS mutations. 31 Future perspectives
As in any form of research, the answer to each scientific question leads to additional
novel questions and possibilities. The main directions of future work could be as
Paper Ι :
To extend the project with analysis of NRAS alterations in more melanocytic lesions
from hereditary melanomas carrying germline CDKN2A alterations.
To determine the frequency of NRAS mutations in hereditary melanomas without
germline CDKN2A alterations.
To study the gene expression profiling in melanoma tumors with activating NRAS
To analyze other genes involved in melanoma development in hereditary melanomas
like BRAF, c-kit, PIK3CA, PTEN genes, to define the involvement of such genes in
Paper Ι Ι and Ι Ι Ι :
To analyze the expression of main gene products identified in gene expression profiling
after knockdown of the NRAS oncogene in clinical materials including primary and
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