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MicroRNA-1301 inhibits proliferation of human glioma cells by directly targeting N-Ras.

ABSTRACT: Glioma is one of the most common, rapidly progressive and fatal brain tumors, and accumulating evidence shows that microRNAs (miRNAs) play important roles in the development of cancers, including glioma. Therapeutic applications of miRNAs in Ras-driven glioma have been proposed; however, their specific functions and mechanisms are poorly understood. Here, we report that miR-1301-3p directly targets the neuroblastoma Ras viral oncogene homolog (N-Ras) and functions as a tumor-suppressor in glioma. Quantitative reverse transcription-PCR was applied to detect the expression of miR-1301-3p in glioma specimens. The direct target genes of miR-1301-3p were predicted by bioinformatic analysis and further verified by immunoblotting and luciferase assays. The effects of miR-1301-3p on the proliferation and cell cycle of glioma cells were analyzed by cell-counting kit 8, colony formation, 5-ethynyl-2-deoxyuridine (EDU) and flow cytometry assays. A xenograft model was used to study the effect of miR-1301-3p on tumor growth and angiogenesis. The expression levels of miR-1301-3p in glioma specimens were significantly downregulated. N-Ras was confirmed as a direct target of miR-1301-3p. MiR-1301-3p inhibited glioma cell growth and blocked the cell cycle to G1 by negatively regulating N-Ras and its downstream signaling pathway, MEK-ERK1/2. Furthermore, the inhibitory effects of miR-1301-3p could be rescued by the overexpression of N-Ras. The protein levels of N-Ras were up-regulated in clinical glioma specimens and were negatively correlated with miR-1301-3p expression levels (r=-056, P=0.0002). In vivo studies revealed that increased levels of miR-1301-3p delayed the growth of intracranial tumors, which was accompanied by decreased Ki67 and CD31 expression. Taken together, our results demonstrate that miR-1301-3p plays a significant role in inactivating the Ras signaling pathway through the inhibition of N-Ras, which may provide a novel therapeutic strategy for treatment of glioma and other Ras-driven cancers.

SUBMITTER: Zhi T

PROVIDER: S-EPMC5411805 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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MicroRNA-1301 inhibits proliferation of human glioma cells by directly targeting N-Ras.

Zhi Tongle T Jiang Kuan K Zhang Chuanzhuo C Xu Xiupeng X Wu Weining W Nie Er E Yu Tianfu T Zhou Xu X Bao Zhongyuan Z Jin Xin X Zhang Junxia J Wang Yingyi Y Liu Ning N

American journal of cancer research 20170401 4

Glioma is one of the most common, rapidly progressive and fatal brain tumors, and accumulating evidence shows that microRNAs (miRNAs) play important roles in the development of cancers, including glioma. Therapeutic applications of miRNAs in Ras-driven glioma have been proposed; however, their specific functions and mechanisms are poorly understood. Here, we report that miR-1301-3p directly targets the neuroblastoma Ras viral oncogene homolog (N-Ras) and functions as a tumor-suppressor in glioma ...[more]

PMID: 28469970

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Project description:Glioma accounts for the majority of primary malignant brain tumors in adults and is highly aggressive. Although various therapeutic approaches have been applied, outcomes of glioma treatment remain poor. Acquiring a better understanding of the pathogenic mechanisms is essential to the design of effective therapeutic strategies. Previous studies have found that miR-520d-5p was negatively correlated with glioma grade, but its role and mechanism in glioma progression remain largely unknown. In the present study, we reported that miR-520d-5p directly targeted the Pituitary Tumor Transforming Gene 1 (PTTG1) and functioned as a tumor-suppressor in glioma. The expression of miR-520d-5p in glioma cells and specimens were detected by Quantitative reverse transcription-PCR and Fluorescence in situ hybridization (FISH). The effects of miR-520d-5p on glioma progression was examined by cell-counting kit 8, colony formation, 5-ethynyl-2-deoxyuridine (EDU) and flow cytometry assays. Using bioinformatics and luciferase reporter assays, we identified PTTG1 as a novel and direct target of miR-520d-3p. A xenograft model was used to study the effect of miR-520d-5p on tumor growth and angiogenesis. We found that miR-520d-5p expression was significantly decreased in glioma cell lines and tissues. Overexpression of miR-520d-5p showed a significant inhibitory effect on cell proliferation and accompanied cell cycle G0/G1 arrest in U87-MG and LN229 glioma cells. PTTG1 was a novel and direct target of miR-520d-5p, and the protein expression of PTTG1 was markedly reduced after overexpression of miR-520d-5p in U87-MG and LN229 cells. Overexpression of PTTG1 reversed the inhibitory effect of miR-520d-5p on glioma cell proliferation. In vivo studies confirmed that miR-520d-5p overexpression retarded the growth of U87 xenograft tumors, which was accompanied by reduced expression of PTTG1. In conclusion, these results provide compelling evidence that miR-520d-5p functions as an anti-onco-miRNA, which is important in inhibiting cell proliferation in GBM, and its anti-oncogenic effects are mediated chiefly through direct suppression of PTTG1 expression. Therefore, we suggest that miR-520d-5p is a potential candidate for the prevention of glioblastoma.

Project description:Objective:Glioma has the highest incidence among the different tumor types within the nervous system, accounting for about 40% of them. Malignant glioma has a high invasion and metastasis rate, which leads to the poor prognosis of patients. By targeting specific genes, microRNAs serve as key regulators in the epithelial-mesenchymal transformation (EMT) process, which could provide new insights into the treatment of glioblastomas (GBM). The detailed molecular role that miR-623 plays in GBM still remains unclear. Materials and Methods:The level of miR-623 in GBM cells was evaluated by RT-PCR. The function of miR-623 overexpression on GBM cell proliferation, migration, and invasion was assessed by MTS, Transwell analysis, and colony formation assay. In addition, a mouse subcutaneous xenograft model was used to study in vivo effects. The binding between miR-623 and TRIM44 was verified by a dual-luciferase reporter assay and the regulatory function of miR-623 on EMT markers was evaluated using Western blot. Results:The expression of miR-623 was repressed in the GBM cancer cell lines. MiR-623 overexpression or TRIM44 knockdown attenuated the proliferation, migration, and invasion of GBM cell lines. TRIM44 could facilitate the reverse suppression of EMT and miR-623 in GBM progression. MiR-623 was found to inhibit TRIM44 expression by directly binding to its 3'UTR. In addition, systemic delivery of miR-623 mimic reduced tumor growth and inhibited TRIM44 protein expression in tumor-bearing nude mice. Furthermore, our findings indicated that miR-623 overexpression or TRIM44 down-regulation impeded the proliferation and migratory ability of LN229 and U251MG glioma cells, and miR-623 attenuates TRIM44-induced EMT by directly targeting the 3'UTR of TRIM44, which could serve as preliminary research to identify potential therapeutic targets for future treatment of GBM. Conclusion:Overall, microRNA-623 inhibits epithelial-mesenchymal transition to attenuate glioma proliferation by targeting TRIM44.

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MicroRNA-1301 inhibits proliferation of human glioma cells by directly targeting N-Ras.

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MicroRNA-1301 inhibits proliferation of human glioma cells by directly targeting N-Ras.

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