Glioblastoma Multiforme (GBM) is an aggressive adult brain tumor characterized by inadequately organized vasculature, which results in nutrient and oxygen depleted areas within the tumor. Adaptation to low nutrients and hypoxia supports glioblastoma survival, progression and therapeutic resistance. However, mechanisms controlling survival under nutrient and O2 deprivation remain poorly elucidated. Previous studies have shown that the expression of micro-RNA 124, a brain - enriched micro-RNA, is significantly decreased in glioblastomas, and that overexpression of miR-124 reduces proliferation rates in glioblastoma cell lines. Interestingly, when glioblastoma cells are grown under nutrient and O2 - limited conditions, miR-124 expression leads to a significant increase in cell death. We have identified two novel miR-124 targets involved in adaptation to stress response: Stress-associated Endoplasmic Reticulum Protein 1 (SERP1) and p38/MAPK14. The central hypothesis of this proposal is that miR-124 expression enhances cell death under nutrient/O2 deprivation by downregulating genes responsible for mediating pro-survival stress responses in GBM. Based on this hypothesis, I will pursue two specific aims.
Specific Aim 1 : To determine the effect of miR-124 in counteracting pro-survival Unfolded Protein Response under nutrient and O2 deprivation in glioblastoma.
Specific Aim 2 : To determine the effect of miR-124 in modulating p38-MAPK pathway - mediated responses to nutrient and O2 deprivation in glioblastoma. To complete these studies, I will combine in vitro and in vivo methods of cell biology, gene regulation, immunohistochemistry, microscopy, and animal modeling. The objective of this proposal is to identify new factors involved in adaptation to low nutrients and O2, thus providing important mechanistic clues about how solid tumors respond to their microenvironment. The long-term goal of this project will be to identify novel therapeutic targets which will facilitate new treatments for this deadly disease.
Glioblastoma Multiforme (GBM) is the most common and deadliest adult brain tumor, with a median survival of only 12 months. GBM tumors progress rapidly and are resistant to chemo- and radiotherapy by adapting to various stress responses, which are currently poorly understood. Therefore, I propose to investigate the mechanisms involved in glioblastoma survival under stress response, in order to facilitate the development of novel therapeutic targets for this disease.
|Eisinger-Mathason, T S Karin; Mucaj, Vera; Biju, Kevin M et al. (2015) Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis. Proc Natl Acad Sci U S A 112:E3402-11|
|Mucaj, V; Lee, S S; Skuli, N et al. (2015) MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. Oncogene 34:2204-14|