Glioblastoma multiforme (GBM) is the most common and highly malignant
primary brain tumor, which is virtually incurable due to its therapeutic resistance to radiation and
chemotherapy. To develop novel therapeutic approaches for treatment of GBM, we examined the role of miR-378 on
tumor growth, angiogenesis, and radiation response in ectopic and orthotopic U87
glioblastoma models. Cell and
tumor growth rates, in vitro and in vivo radiation sensitivities, and
tumor vascular density were evaluated in U87-GFP and U87-miR-378
tumor lines. Ectopic
tumor response to radiation was evaluated under normal blood flow and clamp hypoxic conditions. Results show that in vitro, miR-378 expression moderately increased cell growth rate and plating efficiency, but did not alter radiation sensitivity. U87-miR-378
tumors exhibited a higher
transplantation take rate than U87-GFP
tumors. In vivo, under oxygenated condition, subcutaneous U87-miR-378
tumors receiving 25 Gy showed a tendency for longer
tumor growth delay (TGD) than control U87-GFP
tumors. In contrast, under hypoxic condition, U87-miR-378 xenografts exhibited substantially shorter TGD than U87-GFP
tumors, indicating that under normal blood flow conditions, U87-miR-378
tumors were substantially more oxygenated than U87-GFP
tumors. Intracranial multi-photon
laser-scanning microscopy demonstrated increased vascular density of U87-miR-378 versus control U87-GFP
tumors. Finally, miR-378 increased TGD following 12 Gy irradiation in U87 intracranial xenografts, and significantly prolonged survival of U87-miR-378
tumor-bearing mice (P = 0.04). In conclusion, higher miR-378 expression in U87-miR-378 cells promotes
tumor growth, angiogenesis, radiation-induced TGD, and prolongs survival of orthotopic
tumor-bearing hosts. Regulation of VEGFR2 by miR-378 significantly increased vascular density and oxygenation in U87 xenografts.