BackgroundAngiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.MethodsThe expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .ResultsWe demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.ConclusionOur data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1065-7) contains supplementary material, which is available to authorized users.

Glioblastoma (GBM) is the most aggressive and malignant primary tumor. Angiogenesis plays a critical role in the progression of GBM. Previous studies have indicated that long non-coding RNAs (lncRNAs) are abnormally expressed in various cancers and participate in the regulation of the malignant behaviors of tumors. The present study demonstrated that lncRNA antisense 1 to Micro-chromosome maintenance protein 3-associated protein (MCM3AP-AS1) was upregulated whereas miR-211 was downregulated in glioma-associated endothelial cells (GECs). Knockdown of MCM3AP-AS1 suppressed the cell viability, migration, and tube formation of GECs and played a role in inhibiting angiogenesis of GBM in vitro. Furthermore, knockdown of MCM3AP-AS1 increased the expression of miR-211. Luciferase reporter assay implicated that miR-211 targeted KLF5 3′-UTR and consequently inhibited KLF5 expression. Besides, in this study we found that MCM3AP-AS1 knockdown decreased KLF5 and AGGF1 expression by upregulating miR-211. In addition, KLF5 was associated with the promoter region of AGGF1. Knockdown of KLF5 decreased AGGF1 expression by transcriptional repression, and also inhibited the activation of PI3K/AKT and ERK1/2 signaling pathways. Overall, this study reveals that MCM3AP-AS1/miR-211/KLF5/AGGF1 axis plays a prominent role in the regulation of GBM angiogenesis and also serves as new therapeutic target for the anti-angiogenic therapy of glioma.

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BackgroundGlial activation and neuroinflammation in the spinal trigeminal nucleus (STN) play a pivotal role in the genesis and maintenance of trigeminal neuralgia (TN). Resveratrol, a natural compound from grape and red wine, has a potential anti-inflammatory effect. We hypothesized that resveratrol could significantly suppress neuroinflammation in the STN mediated by glial activation and further relieve TN. In this study, we evaluated whether resveratrol could alleviate trigeminal allodynia and explore the mechanism underlying the antinociceptive effect of resveratrol.MethodsAnimals were orally injected with resveratrol after chronic constriction injury (CCI) of the infraorbital nerve. Mechanical thresholds of the affected whisker pad were measured to assess nociceptive behaviors. The STN was harvested to quantify the changing levels of p-NR1, p-PKC, TNF-α, and IL1-β by western blotting and detect the expression of calcitonin gene-related peptide (CGRP) and c-Fos by immunofluorescence. Glial activation was observed by immunofluorescence and western blotting. Mitogen-activated protein kinase (MAPK) phosphorylation in vivo and in vitro was examined by western blotting.ResultsWe found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN. Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN. Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation.ConclusionsAMPK activation in the STN glia via resveratrol has utility in the treatment of CCI-induced neuroinflammation and further implicates AMPK as a novel target for the attenuation of trigeminal neuralgia.

Warburg effect is a hallmark of cancer cells, wherein glycolysis is preferred over oxidative phosphorylation even in aerobic conditions. Reprogramming of glycometabolism is especially crucial for malignancy in glioma. RNA-binding proteins and long noncoding RNAs are important for aerobic glycolysis during malignant transformation. Thus, we determined the expression and function of RNA-binding protein Lin28A, long noncoding RNA SNHG14, and transcription factor IRF6 in human glioma cells to elucidate the mechanism(s) underlying their role in glycolysis. Quantitative real-time polymerase chain reaction and western blotting showed that Lin28A and SNHG14 were overexpressed and IRF6 was downregulated in glioma. Depleting Lin28A from cells decreased the stability and expression of SNHG14. Furthermore, depleting SNHG14 reduced IRF6 mRNA degradation by targeting its 3′ untranslated region and inhibiting STAU1-mediated degradation, thereby increasing the expression of IRF6. PKM2 is an important enzyme in aerobic glycolysis, and GLUT1 is the primary transporter that facilitates glucose uptake. IRF6 inhibited the transcription of PKM2 and GLUT1, thereby impairing glycolysis and cell proliferation and inducing apoptosis in glioma. Notably, depleting Lin28A and SNHG14 and overexpressing IRF6 reduced the growth of xenograft tumors in vivo and prolonged the survival of nude mice. Taken together, our data revealed that the Lin28A/SNHG14/IRF6 axis is crucial for reprogramming glucose metabolism and stimulating tumorigenesis in glioma cells. Thus, targeting this axis might help in the development of a novel therapeutic strategy for glioma metabolism.

Dysregulation of long non‐coding RNAs (lncRNAs) confirm that it plays a crucial role in tumourigenesis and malignant progression of glioma. The present study demonstrated that LncRNA secretory carrier membrane protein 1 (SCAMP1) was up‐regulated and functioned as an oncogene in glioma cells. In addition, miR‐499a‐5p was down‐regulated meanwhile exerted tumour‐suppressive function in glioma cells. Subsequently, inhibition of SCAMP1 significantly restrained the cell proliferation, migration and invasion, as well as promoted apoptosis by acting as a molecular sponge of miR‐499a‐5p. Transcription factor LIM homeobox transcription factor 1, alpha (LMX1A) was overexpressed in glioma tissues and cells. Moreover, miR‐499a‐5p targeted LMX1A 3′‐UTR in a sequence‐specific manner. Hence, down‐regulation of SCAMP1 remarkably reduced the expression level of LMX1A, indicating that LMX1A participated in miR‐499a‐5p‐induced tumour‐suppressive effects on glioma cells. Furthermore, knockdown of LMX1A decreased NLR family, CARD domain containing 5 (NLRC5) mRNA and protein expression levels through directly binding to the NLRC5 promoter region. Down‐regulation of NLRC5 obviously inhibited malignant biological behaviours of glioma cells through attenuating the activity of Wnt/β‐catenin signalling pathway. In conclusion, our study clarifies that SCAMP1/miR‐499a‐5p/LMX1A/NLRC5 axis plays a critical role in modulating malignant progression of glioma cells, which provide a novel therapeutic strategy for glioma treatment.

Glioma is a brain cancer characterized by strong invasiveness with limited treatment options and poor prognosis. Recently, dysregulation of long non-coding RNAs (lncRNAs) has emerged as an important component in cellular processes and tumorigenesis. In this study, we demonstrated that TATA-box binding protein associated factor 15 (TAF15) and long intergenic non-protein coding RNA 665 (LINC00665) were both downregulated in glioma tissues and cells. TAF15 overexpression enhanced the stability of LINC00665, inhibiting malignant biological behaviors of glioma cells. Both metal regulatory transcription factor 1 (MTF1) and YY2 transcription factor (YY2) showed high expression levels in glioma tissues and cells, and their knockdown inhibited malignant progression. Mechanistically, overexpression of LINC00665 was confirmed to destabilize MTF1 and YY2 mRNA by interacting with STAU1, and knockdown of STAU1 could rescue the MTF1 and YY2 mRNA degradation caused by LINC00665 overexpression. G 2 and S-phase expressed 1 (GTSE1) was identified as an oncogene in glioma, and knockdown of MTF1 or YY2 decreased the mRNA and protein expression levels of GTSE1 through direct binding to the GTSE1 promoter region. Our study highlights a key role of the TAF15/LINC00665/ MTF1(YY2)/GTSE1 axis in modulating the malignant biological behaviors of glioma cells, suggesting novel mechanisms by which lncRNAs affect STAU1-mediated mRNA stability, which can inform new molecular therapies for glioma.

BackgroundAccumulating evidence has highlighted the potential role of RNA binding proteins (RBPs) in the biological behaviors of glioblastoma cells. Herein, the expression and function of RNA binding proteins FXR1 were investigated in human glioma cells.MethodsQuantitative real-time PCR were conducted to evaluate the expression of MIR17HG and miR-346, miRNA-425-5p in glioma tissues and cells. Western blot were used to explore the expression of FXR1, TAL1 and DEC1 in glioma tissues and cells. Stable knockdown of FXR1 and MIR17HG in glioma cells were established to explore the function of FXR1, MIR17HG in glioma cells. Further, RIP and RNA pull-down assays were used to investigate the correlation between FXR1 and MIR17HG. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate the function of FXR1 and MIR17HG in malignant biological behaviors of glioma cells. ChIP assays were employed to ascertain the correlations between TAL1 and MIR17HG.ResultsFXR1and MIR17HG were upregulated in glioma tissues and cell lines. Downregulation of FXR1 or MIR17HG resulted in inhibition of glioma cells progression. We also found that FXR1 regulates the biological behavior of glioma cells via stabilizing MIR17HG. In addition, downregulated MIR17HG increased miR-346/miR-425-5p expression and MIR17HG acted as ceRNA to sponge miR-346/miR-425-5p. TAL1 was a direct target of miR-346/miR-425-5p, and played oncogenic role in glioma cells. More importantly, TAL1 activated MIR17HG promoter and upregulated its expression, forming a feedback loop. Remarkably, FXR1 knockdown combined with inhibition of MIR17HG resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo.ConclusionsFXR1/MIR17HG/miR-346(miR-425-5p)/TAL1/DEC1 axis plays a novel role in regulating the malignant behavior of glioma cells, which may be a new potential therapeutic strategy for glioma therapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0991-0) contains supplementary material, which is available to authorized users.