Abstract
Glioblastoma (GBM) is the most frequently diagnosed malignant human glioma, and current median patient survival is less than two years despite maximal surgery followed by temozolomide chemoradiation therapies. Novel microRNA-related therapies are now being developed for cancers such as GBM. Differential microRNA expression profiling revealed that miR-100 expression is down-regulated in GBM compared to normal controls. We report that miR-100 expression reduces GBM tumorigenicity. In vitro, four GBM lines (U87, U251, 22T, and 33T) demonstrated reduced proliferation 24 hours after transient miR100 overexpression via transfection. miR-100 triggered cell death an average 70% more than scrambled miR controls 24 hours after transient transfection (p < 0.01). miR-100 targeted inhibition of the “silencing mediator of retinoid or thyroid hormone receptor-2” (SMRT/NCOR2) gene was confirmed via reporter assays. Ki67 proliferation index was decreased 40% in tumor xenografts generated from stable miR-100 transfected GBM lines versus controls (p < 0.01). Furthermore, treatment of tumor xenografts with a single pre-mir-100 injection (60 pmol) significantly extended survival of mice bearing intracranial GBM xenografts 25% more than scrambled controls (p < 0.01; n=8). These studies establish miR-100’s effect on tumor GBM growth, and suggest clinical potential for microRNA-related GBM therapy.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive primary human brain tumor
Altered miR-100 expression was confirmed with quantitative polymerase chain reaction in four GBM lines (serum cultured patientderived primary GBM lines (22T, 33T) and two standard laboratory GBM lines (U251, U87))
Compared to control astrocyte cells derived from brains free of malignancy, all four GBM lines show an average 70% lower level of miR-100 expression (P < 0.01; n=3/line; Figure 1A)
Summary
In the US, approximately twelve thousand new GBM patients are diagnosed annually [1], accounting for more than fifty percent of all detected malignant brain cancers and twenty percent of all primary intracranial tumors [2,3]. Recent reports suggest that microRNAs play a role in GBM tumorigenesis [11]. Patterns of differential expression of microRNAs have been demonstrated in GBM in recent reports [16,17]. MicroRNA profiling analysis of human GBM against human non-tumor cell lines, miR-100 was one of the top down-regulated microRNAs. Significant miR-100 downregulation was detected in multiple patient-derived and established GBM cell lines compared to control, non-tumor brain cells, suggesting anti-oncogenic role for miR-100. MiR-100 was reported to have anti-angiogenic function through mTOR signaling repression in endothelial cells
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