title: ELUCIDATION OF THE POTENTIAL OF SGK1 AS PROGNOSTIC MARKER AND THERAPEUTIC TARGET IN MEDULLOBLASTOMA
creator: Pleier, Sabrina Valesca
subject: ddc-570
subject: 570 Life sciences
description: Medulloblastoma comprises the most common malignant brain tumor in children and one of the leading causes of cancer-related mortality in this age group. Despite significant therapeutic achievements within the last three decades, medulloblastoma is still associated with a comparably poor overall survival rate of only 70%. Moreover, many patients suffer from severe adverse effects from adjuvant chemo- or radiotherapy. A better understanding of the underlying molecular pathomechanisms could reveal more targeted therapeutic approaches for molecular subgroups to enhance individual outcome. In the present study, comparative array-CGH and genome-wide expression profiling analyses (n=64) demonstrated that copy-number aberrations at the genomic locus of serum- and glucocorticoid regulated kinase (SGK1) at 6q23 were tightly correlated with mRNA abundance. Immunohistochemical examinations in an independent patient cohort (n=260) and correlation with follow-up data revealed a significant association of SGK1 immunopositivity with poor overall survival as assessed by Kaplan-Meier analysis (p = 0.0168). Based on this integrative genomics approach, SGK1 was suggested as a novel prognostic marker, and SGK1 immunohistochemistry may serve as a powerful diagnostic tool in medulloblastoma patients. SGK1 encodes a kinase with high sequence- and structural homology to the anti-apoptotic kinase AKT/PKB and, as the name implicates, it is transcriptionally up-regulated by serum and glucocorticoids. SGK1 was previously found to play a role in promoting cell survival and cell-cycle progression by phosphorylating diverse downstream targets such as FOXO3a, GSK-3β, p27, and NDRG1. Functional analyses in vitro conducted in this project demonstrated that loss of SGK1 function causes apoptosis induction and that stable overexpression of SGK1 promotes migration. Furthermore, a presumptive impairment in chemotherapy sensitivity, caused by ectopic SGK1 overexpression, has been observed in medulloblastoma cells. These findings provide in vitro evidence for a crucial role of SGK1 in medulloblastoma biology making it a prime candidate for targeted therapy in high-risk medulloblastoma patients.
date: 2012
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/13676/1/Dissertation_Sabrina_Pleier_Finalversion_120606.pdf
identifier: DOI:10.11588/heidok.00013676
identifier: urn:nbn:de:bsz:16-heidok-136768
identifier:   Pleier, Sabrina Valesca  (2012) ELUCIDATION OF THE POTENTIAL OF SGK1 AS PROGNOSTIC MARKER AND THERAPEUTIC TARGET IN MEDULLOBLASTOMA.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/13676/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng