期刊
NEURO-ONCOLOGY
卷 16, 期 10, 页码 1341-1353出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/nou084
关键词
carcinogenesis; glioma; miR-124; N-Ras; R-Ras
资金
- National Natural Science Foundation of China [81302182, 81372709, 81071642, 81302184, 81320108019, 30871296]
- Jiangsu Province's Key Discipline of Medicine [XK201117]
- National High Technology Research and Development Program 863 [2012AA02A508]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- National Institutes of Health [R01ES020868]
Background. Glioma is one of the most aggressive and lethal human brain tumors. Accumulating evidence shows that microRNAs play important roles in cancers, including glioma. Previous studies reported that miR-124 levels were downregulated in glioma specimens. Here, we further investigate the potential role of miR-124 in glioma. Methods. The expression levels of miR-124 were detected in glioma specimens by quantitative reverse transcriptase PCR. The direct targets of miR-124 were identified by bioinformatics analysis and were further validated by immunoblotting and luciferase reporter assay. The effects of miR-124 on glioma cell proliferation and chemosensitivity to temozolomide were analyzed by Cell-Counting Kit 8 assay. Apoptosis was evaluated by fluorescence activated cell sorting analysis. A xenograft model was used to study the effect of miR-124 on tumor growth and angiogenesis. Results. Expression levels of miR-124 were greatly downregulated in glioma specimens. related Ras viral oncogene homolog (R-Ras) and neuroblastoma Ras viral oncogene homolog (N-Ras) were identified as direct targets of miR-124. MiR-124 inhibited glioma cell growth, invasion, angiogenesis, and tumor growth and increased chemosensitivity to temozolomide treatment by negatively regulating the Ras family and its downstream signaling pathways: phosphatidylinositol-3 kinase/Akt and Raf/extracellular signal-regulated kinase 1/2. Furthermore, overexpression of R-Ras rescued the inhibitory effects of miR-124. Meanwhile, overexpression of R-Ras and N-Ras restored miR-124-inhibited vascular endothelial growth factor (VEGF) transcription activation. In clinical glioma specimens, protein levels of R-Ras and N-Ras were upregulated and inversely correlated with miR-124 expression levels. Conclusions. Taken together, these results revealed that miR-124 levels in tumor tissues are associated with glioma occurrence, angiogenesis, and chemoresistance and that miR-124 may be used as a new diagnostic marker and therapeutic target for glioma in the future.
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