This thesis elucidates the crucial role of YKL-40 in enhancing glioma cell migration and invasion in vitro. Increased levels of YKL-40 are specifically associated with the increased invasive capacity of glioma multiforme (GBM) tumors and lower survival rate of GBM patients. In order to examine the effects of YKL-40 on the migration and invasion of GBM cells, we overexpressed YKL-40 in three different glioma cell lines. The overexpression of YKL-40 significantly enhanced glioma cells migration and invasion in vitro and also increased ERK phosphorylation, which is believed to enhance glioma cell survival, and invasiveness. Although receptors for YKL-40 are still unknown, YKL-40 induces interactions between integrin αvβ3 and syndecan-1 in endothelial cells. However, syndecan-1 does not mediate YKL-40-induced migration and invasion of glioma cells since it is expressed at very low levels, in comparison to other syndecans. In contrast, we found that syndecan-4 is expressed at high levels in all glioma cells we tested. Importantly, down-regulation of syndecan-4 dramatically reduced YKL-40-induced migration of U373 cells, suggesting that syndecan-4 may mediate the effect of YKL-40. Since inflammation has been associated with the progression of many cancers, including GBM, we studied the effect of major pro-inflammatory cytokines on the expression of both YKL-40 and syndecans. Interestingly, OSM and IL-1 synergistically enhanced both YKL-40 and syndecan-4 expression in glioma cells. This suggests that this synchronous induction of YKL-40 and syndecan-4 by OSM and IL-1 may enhance invasion of GBM in-vivo. In summary, we propose a mechanism through which YKL-40 may function under pro-inflammatory conditions. Increased expression of YKL-40 and syndecan-4 in glioma cells leads to the subsequent activation of the MAPK/ERK pathway and results in glioma cell invasion.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-3455 |
| Date | 06 May 2011 |
| Creators | Osrah, Bahiya |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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