miR-124 radiosensitizes human glioma cells by targeting CDK4

• Published in: Journal of neuro-oncology Vol. 114; no. 3; pp. 263 - 274
• Main Authors: Deng, Xubin, Ma, Lei, Wu, Minhua, Zhang, Gong, Jin, Chuan, Guo, Yuping, Liu, Ruilei
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.09.2013; Springer Nature B.V
• Subjects: Adult; Aged; Animals; Apoptosis; Blotting, Western; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 4 - metabolism; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Female; Fluorescent Antibody Technique; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma - radiotherapy; Humans; Immunoenzyme Techniques; In Situ Hybridization; Laboratory Investigation; Luciferases - metabolism; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; Middle Aged; Neurology; Oncology; Radiation Tolerance - genetics; Radiation, Ionizing; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Tumor Cells, Cultured; miR-124; Glioma; Radiotherapy; CDK4; CDA-2
• ISSN: 0167-594X; 1573-7373; 1573-7373
• DOI: 10.1007/s11060-013-1179-2

The aberrant expression of cyclin-dependent kinase-4 (CDK4) has previously been observed in human brain glioma. Furthermore, it is observed that up-regulation of CDK4 is associated with therapy resistance and relapse. However, the mechanisms behind these phenomena remain unclear. Here, we demonstrated that elevated CDK4 expression is correlated with poor prognosis in glioma after radiotherapy and that CDK4 knockdown conferred radiosensitivity in glioma cell lines. CDK4 was identified as potential downstream target of miR-124 through bioinformatics analysis and dual-firefly luciferase reporter assay. Furthermore, restoration of miR-124 could confer radiosensitivity. Cell differentiation agent-2 (CDA-2) mimicked the effect of miR-124 restoration and CDK4 knockdown, and sensitized xenografts to radiation in an animal model. Our findings demonstrated for the first time that CDK4 was a downstream target of miR-124 and that CDA-2 could radiosensitize Glioblastoma multiforme cells through the MiR-124-CDK4 axis.