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|Title: ||The role of p38 mitogen activated protein kinase in glioma pathophysiology|
|Authors: ||YEUNG, Yiu To|
|Issue Date: ||30-Aug-2013|
|Publisher: ||University of Sydney|
Faculty of Pharmacy
|Abstract: ||Glioblastoma Multiforme (GBM) is the most common primary brain tumour. One of the main causes for treatment failure is the high invasiveness of GBM. The EGFRvIII mutation and the inflammatory microenvironment have been reported to promote progression of the cancer. Within the microenvironment, pro-inflammatory cytokines (IL-1β, TNFα, IL-6 and IL-8) generate a communication network between tumour cells and the surrounding environment. p38 MAPK is a crucial kinase that regulates the production of pro-inflammatory cytokines. In this thesis, two main pathways that link cancer and inflammation – oncogene-induced and immune cell-derived – were investigated. Results revealed that activated microglia and GBM cells significantly upregulate pro-inflammatory cytokines expression via p38 MAPK signalling. Using conditioned media from microglia, GBM cell motility was enhanced in response to inflammatory cytokines secreted by microglia. By employing p38 MAPK inhibitors, GBM invasion was attenuated via reduction of the inflammatory microenvironment. These effects were potentiated in glioma cells expressing the EGFRvIII mutation. We also discovered that enhanced IL-6 production and increased sensitivity to p38 MAPK inhibitors in EGFRvIII expressing cells is associated with increased accumulation of human antigen R (HuR) in the cytosol. In summary, we show that p38 MAPK inhibitors could work as an anti-invasive agent in GBM.|
|Access Level: ||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions: ||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
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