Mini-reviewThe emerging role of tumor-suppressive microRNA-218 in targeting glioblastoma stemness
Introduction
Glioblastoma multiforme (GBM) is the most frequently occurring primary tumor of the central nervous system [1]. The term GBM is synonymous with World Health Organization (WHO) grade IV astrocytoma, which is characterized by uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, and rampant genomic instability [2], [3]. Despite measurable advances in cancer treatment, such as surgery, radiation and chemotherapy, the median overall survival of patients with the most malignant glioblastoma is approximately 1 to 2 years [4]. One of the major causes of tumor recurrence is the infiltrative property of GBM cells, because of their highly invasive nature, it is difficult to clear glioblastoma cells with local therapeutic modalities [5].
GBM may arise from cancer stem cells that display neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies [6]. The development of stem cell-like properties is recognized in glioblastoma, and these cancer stem cells can propagate tumors in vivo [7], [8]. Exploring the molecular mechanism through which glioblastoma maintains stemness will allow the development of novel therapies that may promote the differentiation or target the stem cell-like properties of glioblastoma [9]. Recently, miR-218 was newly found to modulate the GBM stemness [10]. In this review, we focus on the novel role of miR-218 in the modulation of the stemness of glioblastoma.
Section snippets
miRNAs are novel epigenetic regulators of glioblastoma stemness
MicroRNAs (miRNA) are endogenous, small, non-coding RNAs that are 19–25 nucleotides in length and regulate gene expression by antisense complementarity to specific mRNAs. Extensive evidence indicates that miRNAs regulate a variety of cellular processes, including cell differentiation, cell proliferation, apoptosis, stress resistance, stem cell maintenance and metabolism [11], [12], [13], [14], [15]. One miRNA may have many targets, and one gene may be targeted by multiple miRNAs; thus, miRNAs
miR-218 regulates glioblastoma migration/invasion, proliferation, and apoptosis by targeting different genes
miRNAs can regulate many targets to affect a variety of cellular processes and tumor growth. miR-218 is downregulated in glioblastoma and regulates tumor growth through numerous direct gene targets in a number of different cell lines. In this section of the manuscript, we review the targets of miR-218 and their functions in glioblastoma migration/invasion, proliferation and apoptosis (Fig. 1).
miR-218 regulates glioblastoma stemness through epigenetic pathways
The overexpression of miR-218 leads to a significant decrease in the volume of glioblastoma neurospheres stably expressing miR-218 and reduces the self-renewal capacity of glioblastoma stem-like cells. The stem cell markers, such as CD133, SOX2, Nestin, and Bmi1, in glioblastoma neurospheres are reduced as a result of miR-218 overexpression [10]. These results suggest that miR-218 regulates glioblastoma stem-like cells in part by blocking Bmi1-associated pathways.
Bmi1 is a polycomb group
Slits/miR-218/Bmi1 epigenetics microcircuitry modulates glioblastoma stemness
Two genes encoding miR-218, namely miR-218–1 and miR-218–2, are located at 4p15.31 and 5q35.1 within the introns of Slit2 and Slit3, respectively [83], [94]. It has been reported that intronic miRNAs are transcribed together with their host gene mRNAs, and a significant positive correlation has been found between Slit2 and pre-miR-218–1 and between Slit3 and pre-miR-218–2 in many cancers [83], [94]. Consistent with its tumor suppressor activity, Slit2 is down-regulated in glioblastoma compared to
Conclusions and outlooks
Recent advances have demonstrated that miR-218 can work as a tumor suppressor by regulating a complex regulatory framework to coordinately downregulate many oncogenes and thereby inhibit the invasion, migration, proliferation, and self-renewal of glioblastoma cancer stem-like cells. miR-218 is downregulated in human glioblastoma, and the restoration of miR-218 expression with a miRNA mimic would inhibit glioblastoma development, particularly glioblastoma stemness. The ability of miR-218 to
Conflict of Interest
The authors declare no conflicts of interest.
Acknowledgments
This work was supported by the National Natural Science Foundation of China-China (No. 81272801), the National Key Basic Research Program of China (“973” Project) (2010CB933900), a scientific research program funded by the Shaanxi Provincial Health Department (Program Nos. 2014D21 and 2014D24), Scientific Research Program Funded by Shaanxi Provincial Education Department (Program No. 14JK1617) and the Program for Youth Science and Technology Star of Shaanxi Province (2014KJXX-76). We apologize
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