Date of Graduation
5-2015
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Sadhan Majumder , PhD
Committee Member
Gary Gallick , PhD
Committee Member
Greg Fuller , M.D, PhD
Committee Member
Raymond Grill , PhD
Committee Member
Suyun Huang, PhD
Abstract
Glioblastoma Multiforme (GBM) is the most common and aggressive primary malignant brain tumor in adults. With an average survival of only 12-16 months the prognosis for GBM patients remains dismal, with less than 5% of patients surviving 5 years. New mechanism-based approaches are necessary for the management of patients with GBM. Many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs). These GSCs are resistant to chemo- and radiation therapies, and are believed to be responsible for tumor recurrence. In a recent paper from our lab we have shown that REST, RE1-silencing transcription factor, regulates oncogenic properties such as proliferation, invasion, and apoptosis in GSCs. However, the mechanism by which REST regulates oncogenic properties of GSCs is not clearly understood. Thus, the overall aim of this project is to delineate the mechanism by which REST mediates oncogenic properties of GSCs. Using genome-wide expression analysis followed by biochemical validations, we show that REST targets two microRNAs, miR-124 and miR-203 in High REST GSCs (HR-GSCs). Independent studies were carried out to determine the role of these microRNAs in HR-GSC derived brain tumors. Gain of function of either miR-124 or miR-203 in HR-GSCs leads to increased survival when tumor cells are transplanted into mice. Importantly, the increased survival of tumor-bearing mice caused by knockdown of Rest in HR-GSCs can be reversed by double knockdown of Rest and miR-124 or miR-203, indicating that the REST-miR-124/miR-203 axis controls tumorigenesis. We further show that the REST-miR-124 axis regulates proliferation, invasion and apoptosis of GSCs both in vitro and in vivo, while the REST-miR-203 axis specifically regulates invasion and not proliferation or apoptosis. Our results indicate that invasion is a major hallmark of HR-GSC tumors and that the REST-miR-124/203 axis is critical in this process. These results also suggest that the REST-miR-124/203 axis could potentially be targeted in therapeutic approaches to block invasion in REST-stratified GBM tumors.
Keywords
Glioblastoma, Glioblastoma Stem cells, MicroRNAs, Apoptosis, Invasion, Microarray