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Human glioblastoma is a malignant and aggressive primary human brain solid tumor characterized by severe hypoxia. Hypoxia can induce autophagy, which may result in chemoresistance and malignant progression of cancer cells. MicroRNAs (miRNAs) have been reported to modulate hypoxia-induced autophagy in various types of cancers. In the present study, we observed that hypoxia-inducible factor (HIF)-1α expression was increased while miR-224-3p expression was decreased under hypoxia in a time-dependent manner in glioma LN229 and astrocytoma U-251MG cell lines, as deteced by western blot analysis and real-time quantitative polymerase chain reaction. In addition, HIF-1α knockout inhibited cell motility and chemosensitivity by negatively regulating the expression of miR-224-3p under a hypoxic condition by Transwell and MTT assay. Moreover, hypoxia increased the relative expression of ATG5 (autophagy-related gene 5) and LC3 II/I with a decreased level of p62. These results were correlated with autophagy in a time-dependent manner, suggesting that hypoxia induced autophagy in glioblastoma and astrocytoma cells. Through bioinformatic prediction and luciferase reporter assay, we confirmed that ATG5 is a target of miR-224-3p and ATG5 expression was negatively regulated by miR-224-3p. Knockdown of ATG5 inhibited cell mobility with increased chemosensitivity of glioblastoma cells under hypoxia. Moreover, overexpression of miR-224-3p also inhibited cell mobility with increased chemosensitivity of glioblastoma cells under hypoxia. However, activation of autophagy was able to counteract these effects of miR-224-3p. Furthermore, in vivo experiments indicated that the miR-224-3p mimic enhanced the chemosensitivity of LN229 cells to temozolomide by immunohistochemistry and TUNEL assay. In summary, our experiments elucidated that the HIF-1α/miR-224-3p/ATG5 axis affects cell mobility and chemosensitivity by regulating hypoxia-induced autophagy in glioblastoma and astrocytoma. Therefore, miR-224-3p could be a novel target against hypoxia-induced autophagy in glioblastoma and astrocytoma.

Spinal cord injury (SCI) is considered to be primarily associated with loss of motor function and leads to activate diverse cellular mechanisms in the central nervous system to attempt to repair the damaged spinal cord tissue. Chemokine Receptor 5 (CCR5), a major co-receptor for macrophage-tropic human immunodeficiency viruses, is expressed on the surface of monocytes/macrophages, dendritic cells, activated T cells, and NK cells. Recent papers have indicated the important role of CCR5 in SCI, but the mechanism is still unknown. In our current study, CCR5 blockade displayed increased myelin sparring and enhanced SC repair process. The number of CD4(+) T cells, CD8(+) T cells, Ly6G(+) neutrophils and CD11b(+) macrophages were all significantly lower in the anti-CCR5 group than that in the control group after SCI. The IL-4 and IL-13 levels in anti-CCR5 group were markedly higher than that in control group after SCI. Correspondingly, the anti-CCR5-treated group showed increased numbers of Arg1- or CD206-expressing macrophages compared with the control IgG group. Furthermore, CCR5 blockade promoted PPARγ activation, and the increased numbers of M2 macrophages induced by CCR5 blockade were both reversed with additional PPARγ antagonist treatment. In conclusion, our present work provides evidence to support the concept that CCR5 blockade promotes M2 macrophage activation and improves locomotor recovery after SCI in mice.

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