Thesis

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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 follows: 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 mutations 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 hereditary melanomas. 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 metastatic melanomas. To stud...
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This document was uploaded on 03/06/2014.

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