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J Neurosurg. 2019 Apr 19:1-9. doi: 10.3171/2018.12.JNS181798. [Epub ahead of print]

Effect of glycolysis inhibition by miR-448 on glioma radiosensitivity.

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1Department of Radiation Oncology, National Cancer Center/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen.
2Neuro-oncology Chemotherapy Center, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing.
3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Radiotherapy, Beijing University Cancer Hospital and Institute, Beijing; and.
4Department of Neurosurgery, The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, People's Republic of China.


OBJECTIVEAlthough glucose metabolism reengineering is a typical feature of various tumors, including glioma, key regulators of glycolytic reprogramming are still poorly understood. The authors sought to investigate whether glycolysis inhibition by microRNA (miR)-448 increases radiosensitivity in glioma cells.METHODSThe authors used glioma tissue samples from glioma patients, cells from glioblastoma (GBM) cell lines and normal human astrocyte cells, and subcutaneous tumor-bearing U87 cells in mice to examine the effects of signaling regulation by miR-448 in the response of glioma tissues and cells to radiation treatment. Techniques used for investigation included bioinformatics analyses, biochemical assays, luciferase reporter assays, and establishment of subcutaneous tumors in a mouse model. Glucose consumption, LDH activity, and cellular ATP were measured to determine the ability of glioma cells to perform glycolysis. Expression of HIF-1α was measured as a potential target gene of miR-448 in glycolysis.RESULTSmiR-448 was detected and determined to be significantly downregulated in both glioma tissues from glioma patients and GBM cell lines. Furthermore, miR-448 acted as a tumor-inhibiting factor and suppressed glycolysis in glioma by negatively regulating the activity of HIF-1α signaling and then interfering with its downstream regulators relative to glycolysis, HK1, HK2, and LDHA. Interestingly, overexpression of miR-448 increased the x-radiation sensitivity of glioma cells. Finally, in in vivo experiments, subcutaneous tumor-bearing U87 cells in a mouse model verified that high expression of miR-448 also enhanced glioma radiosensitivity via inhibiting glycolytic factors.CONCLUSIONSmiR-448 can promote radiosensitivity by inhibiting HIF-1α signaling and then negatively controlling the glycolysis process in glioma. A newly identified miR-448-HIF-1α axis acts as a potentially valuable therapeutic target that may be useful in overcoming radioresistance in glioma treatment.


FACS = fluorescence-activated cell sorting; GBM = glioblastoma; HIF-1α; KPS = Karnofsky Performance Status; NHA = normal human astrocyte; NSCLC = non–small cell lung cancer; PCR = polymerase chain reaction; RT-PCR = real-time PCR; UTR = untranslated region; glioma; glycolysis; miR = microRNA; miR-448; miR-NC = miR-448 negative controls; miRNA = microRNA; oncology; qRT-PCR = quantitative RT-PCR; radiosensitivity


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