MicroRNA-588 regulates the invasive, migratory and vasculogenic mimicry-forming abilities of hypoxic glioma cells by targeting ROBO1

Abstract BackgroundGlioma is an intracranial malignancy that is the most challenging tumor to treat. The hypoxic microenvironment is an important factor contributing to tumor development, while the migration, invasion and vasculogenic mimicry (VM) of glioma cells are the main causes of the increasing treatment difficulty.Materials and methodsA microarray was leveraged to identify differentially expressed microRNAs in U251 glioma cells cultured under normoxic and hypoxic conditions. The expression of miR-588 was assessed using quantitative real-time PCR (qRT-PCR). Gain- and loss-of-function studies were used to evaluated the role of miR-588 under hypoxic and normoxic conditions. Cell invasive, migratory, proliferation, as well as VM formation experiments were performed. The relationship between miR-588 and ROBO1 was confirmed using western blot and luciferase reporter assays. Intracranial xenograft tumor mouse models were applied to study the function of miR-588 in vivo.ResultsThe expression of miR-588 was obviously upregulated in hypoxic glioma cells in comparison with normoxic glioma cells. miR-588 inhibited the invasive, migratory and VM-forming abilities of glioma cells in vitro and in vivo. Mechanistically, Roundabout guidance receptor 1 (ROBO1) is a direct, functionally relevant target of miR-588 in glioma. ROBO1 knockdown suppressed the expression of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9), thereby inhibiting the invasive, migratory and VM-forming abilities of glioma.ConclusionsMiR-588 regulated the malignant behaviors of hypoxic glioma cells by targeting ROBO1. miR-588 can be used as a prognostic marker for glioma and has potential implications in glioma gene therapy.