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Title: Kallmann syndrome-associated protein anosmin-1 contributes to brain tumour malignancy
Author: Choy, Catherine Theresa
ISNI:       0000 0004 5349 821X
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2014
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Anosmin-l, encoded by KALl gene, is an extracellular matrix (ECM)-associated protein, which plays essential roles in the migration of olfactory and gonadotropinreleasing hormone (GnRH) neurons during early brain development. Loss-of-function mutations in KALl result in Kallmann syndrome, a developmental genetic disorder with delayed puberty and anosmia. However, there is little comprehension of its role in the developed brain. Since reactivation of developmental signal pathways often contributes to tumourigenesis, I investigate if anosmin-l-mediated cellular mechanisms are involved in brain tumours. Meta-analysis of public microarray data sets and expression profile analysis of patient biopsy samples revealed that KALl mRNA was significantly upregulated in increasing grades of primary brain tumours compared to normal brain and metastasised tumours. Anosmin-l enhanced motility and proliferation of glioblastoma (GBM) cells via fibroblast growth factor receptor 1 (FGFR 1) and urokinase plasminogen activator (uPA) pathways in vitro. Anosmin-l formed a complex with ~l integrin and co-localised with active ~ 1 at the leading edge of GBM cells, inducing downstream signalling pathways including focal adhesion kinase (F AK), protein kinase B (PKBI AKT) and extracellular signal regulated kinase (ERK). Knockdown of anosmin-l attenuated cellular motility and growth but induced apoptosis. Anosmin-l also modulated fibronectin-mediated cell adhesion and activated extracellular proteinases uPA and matrix metalloproteinases (MMP)-2/9. Anosmin-l showed pro-angiogenic effects in endothelial cell culture. Combined, anosmin-l may promote GBM cell proliferation, migration, invasion, adhesion and survival. In a mouse xenograft model, anosmin-l-expressing tumours grew faster and showed increased vasculature and infiltrations. To predict the localisation of anosmin-l and its interact ants within the tumour architecture, the xenograft tissues were analysed by immunohistological methods. These studies provided novel insights for the function of anosmin-l within the tumour microenvironment, contributing to the neoplastic progression. Therefore, anosmin-l is required for normal GnRH neuronal migration, but inappropriate expression in adult brain may be a potential mechanism of malignant brain tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available