Abstract
Glioma-initiating cells (GIC) have stem-like cell properties thought to be sufficient for recurrence, progression, and drug resistance in glioblastomas. In the present study, we defined miRNA (miR)-340 as a differentially expressed miRNA in human GICs that inhibit GIC-mediated tumorigenesis. Furthermore, we defined tissue plasminogen activator (PLAT) as a critical direct target of miR340 for inhibition. Among miRNAs screened, we found that miR340 expression was decreased in all human GICs and in human glioblastoma tissues, compared with human neural stem cells and normal brain tissues. miR340 overexpression in GICs suppressed their proliferative, invasive, and migratory properties in vitro, triggering cell senescence in vitro and inhibiting GIC-induced tumorigenesis in mouse brains. shRNA-mediated silencing of PLAT in GICs phenocopied the effects of miR340 overexpression in vitro and in vivo, suggesting a potential role for tissue factor in stem-like cell function. Taken together, our results identified miR340 as a tumor suppressor that functions in GIC to enforce PLAT blockade and ablate their stem-like functions.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor
Results miR340 is a novel miRNA that is downregulated in glioma-initiating cells (GIC) To identify novel miRNAs that are aberrantly expressed in GICs, we analyzed differences in miRNA expression between mouse and human GICs and control neural stem cells (NSC) using miRNA microarrays
Using qPCR analysis, we confirmed that miR340 expression was significantly decreased in all examined human and mouse GICs and human glioma cell lines compared with NSCs (Fig. 1B)
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. The extremely poor prognosis of patients with GBM is likely because of the presence of glioma-initiating cells (GIC; known as glioma stem-like cells), which are equivalent of the cancer stem cells (CSC) observed in other cancer types [2,3,4]. CSCs are highly resistant to chemo- and radiotherapy [5,6,7] but are highly tumorigenic; these cells are thought to be the primary cause of tumor recurrence and progression. To improve the poor prognosis of patients with GBM, it is important to understand the mechanism that GICs are activated to have high tumorigenesis and invasion. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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