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Title: Gene expression alterations in central nervous system neoplasms with EGFR amplification
Author: Moedas, Marco Filipe Semião
Advisor: Roque, Lúcia
Correia, Maria do Céu
Keywords: Biologia celular
Expressão genética
Tumores do sistema nervoso central
Teses de mestrado
Defense Date: 2009
Abstract: Central Nervous System (CNS) Neoplasms are characterized by their cell of origin and their histopathological features. Tumors of glial cell origin (Gliomas) are the most frequent, with Glioblastoma Multiforme (GBM) rising as the most common. GBM tumors of grade IV accordingly with the World Health Organization (WHO), are generally lethal, with a median survival time of 4.9 months, and their most striking histopathological features are the high degree of vascularization and necrosis. The most common genetic alterations in GBM are the amplification, overexpression and mutation of the EGFR gene, and the deletion of the long arm of chromosome 10, where, among others, the PTEN gene is located. These genes are related, respectively, with the activation and inhibition of pathways like the MAPK cascade, the PIP-mediated signaling and STAT signaling which are involved in cellular proliferation and inhibition of apoptosis. Deregulation of these pathways renders them the logical target for inhibition of growth and proliferation of tumoral cells, and some anti-EGFR therapies have been tried, but with relatively poor success. The goal of this work is to analyse the genetic expression of the genes that make up the EGFR-activated signaling pathways in gliomas, and identify those molecules where targeted intervention would make sense in such a way that cellular proliferation would cease, and differentiation and apoptosis would be induced. Tumor samples (n=100) were characterized by Multiplex Ligation-dependent Amplification (MLPA) and Chromosomal Comparative Genomic Hybridization (cGGH). Further analysis of tumors samples (n=15) was done by using Gene Expression Arrays GeneChip® HuGene 1.0ST and data analysis softwares Partek Genomics Suite and Ingenuity Pathway Analysis, in order to determine the expression values of the various genes that make up the EGFR-activated signaling pathways. This allowed us to identify a particular pathway that appears to have its components constantly overexpressed, the STAT signaling pathway, mainly through the STAT3 gene. The STAT3 protein is activated by various receptors and is implicated in tumorigenesis and immune evasion, and as such, may be a suitable target for anti-neoplasic therapies.
Resumo largado em português disponível no documento
Description: Tese de mestrado, Biologia (Biologia Molecular Humana), 2009, Universidade de Lisboa, Faculdade de Ciências
Appears in Collections:FC - Dissertações de Mestrado

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