Synergism of Proneurogenic miRNAs Provides a More Effective Strategy to Target Glioma Stem Cells.

Adam Kosti,Erzsebet Kokovay,Rodrigo Barreiro,Pedro A F Galante,Luiz O F Penalva,Gabriela D A Guardia,Alexander Pertsemlidis,Shiva Ostadrahimi

doi:10.3390/cancers13020289

Abstract

Simple SummarymiRNAs function as critical regulators of gene expression and have been defined as contributors of cancer phenotypes by acting as oncogenes or tumor suppressors. Based on these findings, miRNA-based therapies have been explored in the treatment of many different malignancies. The use of single miRNAs has faced some challenges and showed limited success. miRNAs cooperate to regulate distinct biological processes and pathways and, therefore, combination of related miRNAs could amplify the repression of oncogenic factors and the effect on cancer relevant pathways. We established that the combination of tumor suppressor miRNAs miR-124, miR-128, and miR-137 is much more effective than single miRNAs in disrupting proliferation and survival of glioma stem cells and neuroblastoma lines and promoting differentiation and response to radiation. Subsequent genomic analyses showed that other combinations of tumor suppressor miRNAs could be equally effective, and its use could provide new routes to target in special cancer-initiating cell populations.Tumor suppressor microRNAs (miRNAs) have been explored as agents to target cancer stem cells. Most strategies use a single miRNA mimic and present many disadvantages, such as the amount of reagent required and the diluted effect on target genes. miRNAs work in a cooperative fashion to regulate distinct biological processes and pathways. Therefore, we propose that miRNA combinations could provide more efficient ways to target cancer stem cells. We have previously shown that miR-124, miR-128, and miR-137 function synergistically to regulate neurogenesis. We used a combination of these three miRNAs to treat glioma stem cells and showed that this treatment was much more effective than single miRNAs in disrupting cell proliferation and survival and promoting differentiation and response to radiation. Transcriptomic analyses indicated that transcription regulation, angiogenesis, metabolism, and neuronal differentiation are among the main biological processes affected by transfection of this miRNA combination. In conclusion, we demonstrated the value of using combinations of neurogenic miRNAs to disrupt cancer phenotypes and glioma stem cell growth. The synergistic effect of these three miRNA amplified the repression of oncogenic factors and the effect on cancer relevant pathways. Future therapeutic approaches would benefit from utilizing miRNA combinations, especially when targeting cancer-initiating cell populations.

Highlights

MicroRNAs are small noncoding RNAs that act as essential post- transcriptional regulators [1] and are implicated in functions ranging from development to homeostasis [2]. miRNAs are especially important in cancers, where many have been identified as oncogenes or tumor suppressors [3]
We have previously shown that miR-124, miR-128, and miR-137 share a large set of target genes and work synergistically to promote neuronal differentiation (Figure 1, Table S1) [18]
We have previously shown that miR-124, miR-128, and miR-137 act synergistically in neurogenesis by targeting a group of common and associated target genes [18]

Summary

Introduction

MicroRNAs (miRNAs) are small noncoding RNAs that act as essential post- transcriptional regulators [1] and are implicated in functions ranging from development to homeostasis [2]. miRNAs are especially important in cancers, where many have been identified as oncogenes or tumor suppressors [3]. MiRNAs are especially important in cancers, where many have been identified as oncogenes or tumor suppressors [3]. Dysregulation of tumor-suppressive miRNAs is associated with the aggressive and undifferentiated nature of neural-derived cancers [4,5]. Glioblastoma multiforme (GBM) and neuroblastoma arise from transformed neural precursors [6,7], where normal stem cell programs are taken over. The use of proneurogenic miRNAs as agents to induce terminal differentiation and turn off oncogenic pathways has been proposed as an option to treat these tumors [8]. MiRNAs control processes such as neuronal differentiation, neuronal processes, and regional specialization [9]. Marked changes in miRNA profiling have been observed during neurogenesis and in comparisons between undifferentiated and differentiated cells [10]

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