Zhumei Shi1, Qiudan Chen1, Chongyong Li1, Lin Wang1, Xu Qian1, Chengfei Jiang1, Xue Liu1, Xiefeng Wang1, Hai Li1, Chunsheng Kang1, Tao Jiang1, Ling-Zhi Liu1, Yongping You1, Ning Liu1, Bing-Hua Jiang1. 1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (Z.S., X.W., Y.Y., N.L.); State Key Lab of Reproductive Medicine, Department of Pathology, and Cancer Center, Nanjing Medical University, Nanjing, China (Z.S., Q.C., C.L., L.W., X.Q., C.J., X.L., B.-H.J.); Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China (H.L.); Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China (C.K.); Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China (T.J.); Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (L.-Z.L., B.-H.J.).
Abstract
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.
BACKGROUND:Glioma is one of the most aggressive and lethal humanbrain 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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