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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.

Author information

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

Abstract

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.

KEYWORDS:

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

PMID:
31003211
DOI:
10.3171/2018.12.JNS181798

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