thesis - Thesis for doctoral degree(Ph.D 2007 Thesis for...

Thesis for doctoral degree (Ph.D.)
2007
Malihe Eskandarpour
Thesis for doctoral degree (Ph.D.)
2007
Malihe Eskandarpour
Molecular Genetics of Cutaneous
Malignant Melanoma
Molecular Genetics
of Cutaneous
Malignant
Melanoma

Karolinska Institutet, Department of Oncology-Pathology
Stockholm, Sweden
Molecular Genetics of Cutaneous Malignant
Melanoma
Malihe Eskandarpour
Stockholm 2007

2007
Gårdsvägen 4, 169 70 Solna
Published and printed by
Doctoral Dissertation
© Malihe Eskandarpour, 2007
Karolinska Institutet
Department of Oncology-Pathology
Stockholm, Sweden

To
My parents Jalal and Parvin
&
Shahryar and Armin

iv
List of publications
The thesis is based on the following publications, which are referred to in the text by
Roman numerals as follows:
Ι . Eskandarpour M , Hashemi J, Kanter L, Ringborg U, Platz A, Hansson J.
Frequency of UV-Inducible NRAS Mutations in Melanomas of Patients With
Germline CDKN2A Mutations. Journal of the National Cancer Institute 2003;
95(11):790-798.
Ι Ι . Eskandarpour M, Kiaii S, Zhu C, Castro J, Sakko AJ, Hansson J.
Suppression of Oncogenic NRAS by RNA Interference Induces Apoptosis of
Human Melanoma Cells . International Journal of Cancer 2005; 115, 65-73.
Ι Ι Ι . Eskandarpour M , Huang F, Reeves KA, Clark E, Hansson J. Oncogenic
NRAS has a Pivotal Role in the Malignant Phenotype of Human Melanoma
Cells. Submitted for publication.
All published papers are reprinted with permission from the corresponding publishers.

1
Table of contents
List of Publications ................................................................................................ IV
Table of Contents ..................................................................................................... 1
Abbreviations ........................................................................................................... 2
Abstract .................................................................................................................... 3
Cutaneous Malignant Melanoma ............................................................................ 5
Melanoma Tumor Progression ............................................................................... 5
Melanoma Risk Factors ........................................................................................... 7
Pathways Involved in Melanoma Biology ............................................................... 8
RAS Signaling Pathway
....................................................................................................................... 9
RAS-RAF-ERK
SIGNALLING
..................................................................................................................... 10
RAS-PI3K-AKT
SIGNALING
...................................................................................................................... 11
RAS-RAL
SIGNALING
................................................................................................................................ 11
OTHER EFFECTORS OF
RAS
SIGNALING PATHWAY
..................................................................................... 12
RB and p53 Pathways ............................................................................................ 13
Mutations in Oncogenes and Suppressor Genes in Melanoma ............................ 13
Chromosomal Abnormalities in Melanoma ......................................................... 17
Susceptibility Genes in Melanoma ........................................................................ 18
Cooperation of RAS and CDKN2A ...................................................................... 20
RAS and Cell Cycle Regulation ............................................................................ 21
RAS and Cell Invasion .......................................................................................... 22
RAS in Differentiation, Growth Arrest and Senescence ...................................... 23
Oncogenic RAS and Human Cancer ..................................................................... 24
Targeting the RAS Oncogenes
....................................................................................................... 25
Aims ....................................................................................................................... 27
Results and Conclusions
................................................................................................................... 28
P
APER
Ι ..................................................................................................................................................... 28
P
APER
Ι Ι ................................................................................................................................................... 29
P
APER
Ι Ι Ι ................................................................................................................................................. 30
Future Perspectives ............................................................................................... 32
Acknowledgments .................................................................................................. 33
References
................................................................................................................................................ 36

2
Abbreviations
ARF alternative reading frame
bFGF basic fibroblast growth factor
CDK cyclin dependent kinase
CDKN2A cyclin dependent kinase inhibitor 2A
CGH comparative genomic hybridization
CIP1 CDK interacting protein 1 (CDKN1A)
CMM cutaneous malignant melanoma
CPD cyclobutane pyrimidine dimmer
ERK extracellular signal regulated kinase
FAK focal adhesion kinase
FTI farnesyltransferase inhibitors
GEF guanine nucleotide exchange factor
GPCR G-protein-coupled receptor
HDM2 human double minute 2
MAPK mitogen activated protein kinase
MC1R melanocortin 1 receptor
MEK MAP-ERK kinase
MLCK myosin light chain kinase
MMP matrix metalloprotease
NF- κ B nuclear factor-kappa B
NMA neuromedin A
Nore 1 novel ras effector 1
PI3K phosphoinositide 3 kinase
PIP3