Molecular genetics of cutaneous malignant melanoma
Author: Eskandarpour, Malihe
Date: 2007-09-14
Location: Radiumhemmets föreläsningssal, Karolinska Universitetssjukhuset, Solna
Time: 10.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
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Abstract
Cutaneous malignant melanoma is an aggressive tumor of melanocytes in the
skin with rapidly increasing incidence. Patients with advanced disease
have a poor prognosis since the tumor is usually resistant to current
therapies. Therefore, the development of novel strategies for preventing
and treating melanoma is important. To explore novel therapies we need to
find appropriate targets and for that knowledge about the biology of
melanoma is important. There is growing evidence suggesting that NRAS has
an important role in tumorigenesis and tumor maintenance in malignant
melanoma and that the RAS-RAF-ERK signaling pathway is constitutively
activated through multiple mechanisms, one of which is activating
mutations in NRAS gene.
In an initial study, we investigated the occurrence of activating
mutation in the NRAS gene in a subset of patients with hereditary
melanoma carrying germ line CDKN2A alterations. From this study we found
differences in the frequency of NRAS mutations between hereditary and
sporadic melanomas. Activating mutations in NRAS codon 61 were found in
95% (20/21) of primary hereditary melanomas but in only 10% (1/10) of
sporadic melanomas. We also detected multiple activating NRAS mutations
in tumor cells from different regions of individual primary hereditary
melanomas. We concluded that the high frequency of NRAS codon 61
mutations detected in these hereditary melanomas may be the result of a
hypermutability phenotype associated with the hereditary predisposition
for melanoma development in patients with germline CDKN2A mutations.
The presence of a mutant NRAS oncogene in sporadic and familial melanomas
implies that the NRAS oncogene may be an important target for prevention
and treatment of melanomas. Therefore, to better define the role of this
oncogene in melanoma development, we specifically targeted this mutant
oncogene using RNAi techniques and studied the effect of suppression of
mutant NRAS on melanoma cell lines. Suppression of oncogenic NRAS in
these cell lines resulted in decreased proliferation, increased apoptosis
as well as decreased phosphorylation of ERK and Akt, and also reduced
expression of NF-kappaB and cyclin D1 downstream in the NRAS signaling
pathway. To follow up this investigation, we studied the effect of siRNA
against mutant NRAS on gene expression profiles in melanoma cell lines
which carry oncogenic NRAS mutations. We could show the impact of
knockdown of the NRAS oncogene on different cellular processes. For
instance, we observed a disability of cells with respect to migration and
invasion, which is accompanied by down-regulation of EphA2, uPAR and
cytoskeleton proteins such as leupaxin, alpha-actinin, paxillin, and
vinculin. These cells also showed inhibition of cell proliferation
accompanied by downregulation of two cyclins, cyclin D1, cyclin E2, and
up-regulation of HBP1 repressor. In summary, we conclude that the use of
siRNAs against NRASQ61R is an important tool in suppressing oncogenic
NRAS signaling, which might contribute to the development of more
specific melanoma therapy in the subset of patients with tumor with NRAS
mutations.
List of papers:
I. Eskandarpour M, Hashemi J, Kanter L, Ringborg U, Platz A, Hansson J (2003). "Frequency of UV-inducible NRAS mutations in melanomas of patients with germline CDKN2A mutations." J Natl Cancer Inst 95(11): 790-8
Pubmed
II. Eskandarpour M, Kiaii S, Zhu C, Castro J, Sakko AJ, Hansson J (2005). "Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells." Int J Cancer 115(1): 65-73
Pubmed
III. Eskandarpour M, Huang F, Reeves KA, Clark E, Hansson J (2007). "Oncogenic NRAS has a pivotal role in the malignant phenotype of human melanoma cells." (Submitted)
I. Eskandarpour M, Hashemi J, Kanter L, Ringborg U, Platz A, Hansson J (2003). "Frequency of UV-inducible NRAS mutations in melanomas of patients with germline CDKN2A mutations." J Natl Cancer Inst 95(11): 790-8
Pubmed
II. Eskandarpour M, Kiaii S, Zhu C, Castro J, Sakko AJ, Hansson J (2005). "Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells." Int J Cancer 115(1): 65-73
Pubmed
III. Eskandarpour M, Huang F, Reeves KA, Clark E, Hansson J (2007). "Oncogenic NRAS has a pivotal role in the malignant phenotype of human melanoma cells." (Submitted)
Issue date: 2007-08-24
Rights:
Publication year: 2007
ISBN: 978-91-7357-277-4
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