Malignant glioma (Glioblastoma multiforme, GBM, glioma) is the most common and aggressive primary adult brain tumor. The prognosis of GBM patients remains poor, despite surgery, radiation and chemotherapy. Significantly, genes that play a role in neural stem cell maintenance, including BMI1 and SUZ12, are highly expressed in GBM. BMI1 acts as part of the polycomb repressor complex 1 (PRC1) and SUZ12 as a part of PRC2. These complexes play critical role in epigenetic silencing by modifying chromatin structure. PRC1/2 have been shown to contribute to glioma cells tumorigenicity and glioma """"""""stem-like"""""""" cells (GSCs) self-renewal. Through their regulation of multiple genes, microRNAs (miRNA) orchestrate complex programs of gene expression and act as master regulators of cellular processes. MiRNA-based therapeutics could thus impact broad cellular programs, leading to cancer cell differentiation, cell cycle arrest, apoptosis, inhibition of invasion and sensitization to radio/chemotherapy. Our data show that miR-128 targets BMI1 and SUZ12 in glioma cells and GSCs. This particular miR is weakly expressed in GBM, and, miR-128 directly targets BMI1 and PRC2 component SUZ12. This simultaneous targeting of both PRCs prevents their partially redundant functions. We demonstrated that miR-128 increases radio-sensitivity of GSCs and, using mouse genetic model of glioma, that loss of miR-128 in early event in gliomagenesis. Therefore, our overall hypothesis is that restoration of the expression of this particular miR in GSCs will result in reduced self-renewal and increased radio- sensitivity through a mechanism that involves members of PRC1/2 complexes. To pursue the validity of this overall hypothesis, we thus propose to:
Aim 1 : Characterize in vitro the influence of miR-128 on therapy sensitization and subsequent cell death in extended panel of GSCs;
Aim 2 : Validate the role of miR-128 in regulation of PRC in mouse genetic models of glioblastoma;
Aim 3 : Determine if miR-128 can be exploited to sensitize glioblastoma to conventional therapies in vivo. Successful completion of the proposed experiments will provide additional mechanistic insights into miR based regulation of PRC's role in gliomagenesis and maintenance and a rationale for the clinical translation of a novel therapeutic strategy using miRs that target members of PRC in GSCs for the treatment of gliomas.

Public Health Relevance

This study attempts to determine a link between expression of certain molecules known as microRNA-128 and cancer stem cells (cancer initiating cells) of glioblastoma, the most lethal brain tumors among adult patients. We plan to test our hypotheses by employing series of in vitro and in vivo experiments involving multiple cancer stem cell lines and animal models of glioblastoma. If our study determines that alterations in selected microRNA-128 expression affect glioblastoma pathogenesis, microRNAs replacement therapy can be developed in the future to improve current glioblastoma treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Kondapaka, Sudhir B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Ricklefs, Franz L; Alayo, Quazim; Krenzlin, Harald et al. (2018) Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv 4:eaar2766
Rooj, Arun K; Ricklefs, Franz; Mineo, Marco et al. (2017) MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells. Cell Rep 19:2026-2032
Godlewski, Jakub; Ferrer-Luna, Ruben; Rooj, Arun K et al. (2017) MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer. Stem Cell Reports 8:1497-1505
Rooj, Arun K; Mineo, Marco; Godlewski, Jakub (2016) MicroRNA and extracellular vesicles in glioblastoma: small but powerful. Brain Tumor Pathol 33:77-88
Ricklefs, Franz; Mineo, Marco; Rooj, Arun K et al. (2016) Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity. Cancer Res 76:2876-81
Mineo, Marco; Ricklefs, Franz; Rooj, Arun K et al. (2016) The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches. Cell Rep 15:2500-9
Bronisz, Agnieszka; Godlewski, Jakub; Chiocca, E Antonio (2016) Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors. Cell Mol Neurobiol 36:361-76
Teplyuk, Nadiya M; Uhlmann, Erik J; Gabriely, Galina et al. (2016) Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic. EMBO Mol Med 8:268-87
Rooj, A K; Bronisz, A; Godlewski, J (2016) The role of octamer binding transcription factors in glioblastoma multiforme. Biochim Biophys Acta 1859:805-11
Ansari, Khairul I; Ogawa, Daisuke; Rooj, Arun K et al. (2015) Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor. Cell Rep 11:902-909

Showing the most recent 10 out of 12 publications