Date of Award

2012

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biology

First Advisor

Martin, Patrick Dr.

Abstract

Glioblastoma multiforme (GBM) is the most common form of primary brain tumors. It is a highly aggressive tumor, characterized by an increased proliferation rate and a high capacity to invade surrounding tissues. Currently, GBM treatment includes surgical resection followed by chemotherapy and radiation treatment. However, these therapeutic options often do not alter the infiltrative and migratory capacity of GBMs. The invasive migration of glioblastoma multiforme has been associated with CD44, a cell surface glycoprotein and the principle receptor for hyaluronic acid (HA). The molecular basis of CD44 regulation in GBM is not fully understood. However, CD44 regulation has been shown to be associated with an AP-1 transcription factor family member, fos-related antigen 1 (Fra-1), in an equally aggressive cancer, mesothelioma. Recently, it has also been shown that CD44 expression is linked to Fra-1 expression and activity in glioma cells as well. To determine whether malignant brain tumor cell migration is mediated by Fra-1 expression, wound healing assays were conducted using the A172 GBM cell line and its clones. Compared to A172 parental cells, which express normal Fra-1 levels, A172-mw6 cells, express a dominant negative version of Fra-1, which decreases the level of Fra-1. The A172-mw6 cell line exhibits a slower migration rate than the A172-mw12 cell line, which contains a vector resulting in increased Fra-1 expression. This confirmed that increased Fra-1 expression promotes CD44- mediated migration of human GBM cells. This study also demonstrated that the MAPK and AKT/mTOR signaling pathways are involved in regulating the expression and activity of Fra-1 as well as the expression of CD44. Inhibition of both pathways decreases phosphorylated Fra-1 expression; however, only inhibition of the AKT pathway decreases total Fra-1 and CD44 expression. Moreover, AKT inhibition significantly decreases glioma cell migration, whereas 3 MAPK inhibition only slightly decreases the migratory capacity of GBM cells. In conclusion, the results of this study collectively suggest that: (1) Fra-1 and CD44 expression are regulated by the MAPK and/or AKT/mTOR signal transduction pathways in GBM; (2) Fra-1 regulates CD44 expression in human GBM cells, which in turn affects glioma cell migration.

Download

Share

COinS