Defense Date

2011

Document Type

Thesis

Degree Name

Master of Science

Department

Biochemistry

First Advisor

Tomasz Kordula

Second Advisor

Joyce LIoyd

Third Advisor

William Barton

Abstract

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.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2011

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