Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Celeste Simon

Abstract

Soft tissue sarcomas and glioblastomas are two deadly tumors that are characterized by aggressive overproliferation, and regions of severe intratumoral nutrient and oxygen deprivation. The mechanisms by which tumors evade proliferation control signals and survive in a hostile microenvironment are active areas of investigation. This work describes two projects investigating loss of proliferation control in soft tissue sarcoma, as a result of Hippo pathway deregulation, and mechanisms of survival under stress in glioblastoma, as a result of decreased microRNA-124 (miR-124) levels. First, we demonstrate that the Hippo pathway is deregulated in soft tissue sarcoma patient samples, leading to overexpression of the Hippo effector YAP. YAP, a transcriptional coactivator, binds to TEAD proteins in the nucleus and controls the transcription of multiple pro-proliferation and anti-apoptosis targets, including the transcription factor FOXM1. Interestingly, we show that FOXM1 physically interacts with the TEAD/YAP complex, creating a powerful pro-proliferation complex. FOXM1 genetic deletion and pharmacologic inhibition resulted in decreased sarcoma tumor size, suggesting that FOXM1 inhibition is a viable potential sarcoma treatment. Second, we show that ectopically expressing miR-124 in glioblastoma cells leads to increased cell death. We identify three factors (SERP1, TEAD1, and MAPK14) as direct miR-124 targets and partial effectors of cell survival under stress. Inhibition of these targets recapitulates the miR-124 cell death phenotype under stress, and decreased glioma growth in vivo. Importantly, miR-124 ectopic expression results in increased survival in an in vivo orthotopic intracranial glioma model, suggesting that expression of miR-124, or inhibition of its downstream targets, is an attractive way of targeting glioblastoma cells residing in hypoxic/ischemic regions, and ultimately a method of investigating novel glioblastoma treatments.

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