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Glioma is primary brain tumour with a poor prognosis. Metabolic reprogramming is a hallmark of glioma, and is critical in the development of antiglioma agents and glioma therapy. Cuproptosis is a novel form of cell death mediated by protein lipidation and highly associated with mitochondrial metabolism. However, the clinical impact of cuproptosis-related genes (CRGs) in glioma remains largely unknown. The purpose of this study is to create a new CRGs signature that can be used to predict survival and immunotherapy in glioma patients. LASSO regression analysis was applied to establish prognostic gene signatures. Furthermore, a CRGs signature-based nomogram was developed and demonstrated good predictive potential. We also analyzed the relationship of CRGs and immune infiltration and the correlation with the pathological grade of glioma. Finally, we explored the miRNA that may regulate cuproptosis-related gene FDX1. We found that miR-606 was markedly downregulated in GBM, overexpression of miR-606 can significantly inhibit aerobic glycolysis and proliferation of GBM cells. FDX1 was upregulated in GBM, knockdown of FDX1 significantly inhibit aerobic glycolysis and proliferation of GBM cells. And luciferase assay was used to verified that miR-606 binds to and regulates FDX1 mRNA. These results provide a basis for further exploring the biological mechanisms of cuproptosis. This study may provide new potential therapeutic perspectives for patients with glioma.

Glioblastoma multiforme (GBM) is the most common tumor of the human central nervous system. Aerobic glycolysis has been strongly related to tumor development and malignant behavior. In this study, we found that MBNL1, circNTRK2, and NTRK2-243aa were markedly downregulated and inhibited glycolysis in GBM, whereas PAX5 was upregulated and promoted glycolysis. Functionally, MBNL1 promoted the expression of circNTRK2 by binding to NTRK2 pre-mRNA, as validated using RNA pull-down and nascent RNA immunoprecipitation assays. Mass spectrometry, western blotting, and immunofluorescence staining methods were used to detect the expression of NTRK2-243aa. NTRK2-243aa—encoded by circNTRK2—phosphorylated PAX5 at Y102, leading to the attenuation of the half-life of PAX5, as validated by in vitro kinase and MG132 rescue assays. Besides, PAX5 transcriptionally facilitated the expression of PKM2 and HK2 by binding to their promoter regions, as verified by luciferase reporter and chromatin immunoprecipitation assays. Finally, overexpression of MBNL1 and circNTRK2 combined with PAX5 knockdown effectively inhibited the formation of GBM xenograft tumors and significantly prolonged the survival of orthotopic nude mice. We have delineated that the MBNL1/circNTRK2/PAX5 pathway plays a crucial role in regulating GBM glycolysis and could provide potential targets and alternative strategies for the treatment of GBM.

The blood–tumor barrier (BTB) contributes to poor therapeutic efficacy by limiting drug uptake; therefore, elevating BTB permeability is essential for glioma treatment. Here, we prepared astrocyte microvascular endothelial cells (ECs) and glioma microvascular ECs (GECs) as in vitro blood–brain barrier (BBB) and BTB models. Upregulation of METTL3 and IGF2BP3 in GECs increased the stability of CPEB2 mRNA through its m6A methylation. CPEB2 bound to and increased SRSF5 mRNA stability, which promoted the ETS1 exon inclusion. P51-ETS1 promoted the expression of ZO-1, occludin, and claudin-5 transcriptionally, thus regulating BTB permeability. Subsequent in vivo knockdown of these molecules in glioblastoma xenograft mice elevated BTB permeability, promoted doxorubicin penetration, and improved glioma-specific chemotherapeutic effects. These results provide a theoretical and experimental basis for epigenetic regulation of the BTB, as well as insight into comprehensive glioma treatment.

Vasculogenic mimicry (VM) is an endothelium-independent tumor microcirculation that provides adequate blood supply for tumor growth. The presence of VM greatly hinders the treatment of glioblastoma (GBM) with anti-angiogenic drugs. Therefore, targeting VM formation may be a feasible therapeutic strategy for GBM. The research aimed to evaluate the roles of BUD13, CDK12, MBNL1 in regulating VM formation of GBM. BUD13 and CDK12 were upregulated and MBNL1 was downregulated in GBM tissues and cells. Knockdown of BUD13, CDK12, or overexpression of MBNL1 inhibited GBM VM formation. METTL3 enhanced the stability of BUD13 mRNA and upregulated its expression through m6A methylation. BUD13 enhanced the stability of CDK12 mRNA and upregulated its expression. CDK12 phosphorylated MBNL1, thereby regulating VM formation of GBM. The simultaneous knockdown of BUD13, CDK12, and overexpression of MBNL1 reduced the volume of subcutaneously transplanted tumors in nude mice and prolonged the survival period. Thus, the BUD13/CDK12/MBNL1 axis plays a crucial role in regulating VM formation of GBM and provides a potential target for GBM therapy.

Study Objectives The mechanical efficiency of upper airway (UA) muscles are pivotal in maintaining UA stability. We aimed to investigate if different tongue training approaches could differently induce signs of neuroplastic in the corticomotor pathways and upper airway stability changes. Methods 36 Sprague–Dawley rats were trained daily for eight weeks to lick an isotonic force-sensing disc at targeting forces using 30%–50% of maximal achieved lick force (MALF) for tongue task training (TTT) or targeting force set above 50%, 60%, and 70% of MALF progressively for tongue strength training (TST). Corticomotor excitability was dynamically assessed by GG response to transcortical magnetic stimulation (TMS) at different sessions. GG EMG activity, GG ultrastructure and myosin heavy chain (MHC), UA dynamics were assessed after eight weeks. Results After 4 weeks, GG TMS latencies decreased in both tongue training groups when compared with the control group (p < .05) and this excitability was more stable in TTT group. After 8 weeks, both GG TMS response and EMG activity revealed increased excitability in TTT and TST groups. The apoptotic pathological morphology changes of GG ultrastructure were observed in TST group, but not TTT. Percentage of GG MHC type I fibers in TST group was higher than the control and TTT groups (p < .05). The UA Pcrit decreased significantly in TTT group (p < .05) and tend to decrease in TST group (p = .09). Conclusion TTT could improve the UA stability and induce the neuroplastic changes more efficiently without training-induced muscle injury, while TST revealed a fatigue-resistance change in GG.

RNA-binding proteins (RBPs) are significantly dysregulated in glioma. In this study, we demonstrated the upregulation of Nuclear cap-binding subunit 3 (NCBP3) in glioma tissues and cells. Further, knockdown of NCBP3 inhibited the malignant progression of glioma. NCBP3 directly bound to small nucleolar RNA host gene 6 (SNHG6) and stabilized SNHG6 expression. In contrast, the gastrulation brain homeobox 2 (GBX2) transcription factor was downregulated in glioma tissues and cells. SNHG6 inhibited GBX2 transcription by mediating the H3K27me3 modification induced by polycomb repressive complex 2 (PRC2). Moreover, GBX2 decreased the promoter activities and downregulated the expression of the flotillin protein family 1 (FLOT1) oncogene. In conclusion, NCBP3/SNHG6 inhibits GBX2 transcription in a PRC2-dependent manner to facilitate the malignant progression of gliomas.

Blood-tumour barrier (BTB) has been known to significantly attenuate the efficacy of chemotherapy for glioma. In this report, we identified that insulin-like grown factor 2 mRNA-binding protein 2 (IGF2BP2) was over-expressed in glioma microvessel and glioma endothelial cells (GECs). Knockdown of IGF2BP2 decreased the expression of lncRNA FBXL19-AS1 and tight junction-related proteins, thereby promoting BTB permeability. FBXL19-AS1 was over-expressed and more enriched in the cytoplasm of GECs. In addition, FBXL19-AS1 could bind to 3'-UTR of ZNF765 mRNA and down-regulate ZNF765 mRNA expression through STAU1-mediated mRNA decay (SMD). The low expression of ZNF765 was discovered in GECs and verified to increase BTB permeability by inhibiting the promoter activities of tight junction-related proteins. Meanwhile, ZNF765 also inhibited the transcriptional activity of IGF2BP2, thereby forming a feedback loop in regulating the BTB permeability. Single or combined application of silenced IGF2BP2 and FBXL19-AS1 improved the delivery and antitumor efficiency of doxorubicin (DOX). In general, our study revealed the regulation mechanism of IGF2BP2/FBXL19-AS1/ZNF765 axis on BTB permeability, which may provide valuable insight into treatment strategy for glioma.

Glioma is the most common primary malignancy in the brain, and vasculogenic mimicry (VM) is one of the blood supply methods. Here we investigated the possibility that lncRNAs regulate the stability of transcription factors through the SMD pathway, which affects proliferation, migration, invasion, and the ability to form VMs in glioma. Expression of PABPC5, HCG15, and ZNF331 was detected by real-time qPCR or western blot in glioma. Cell Counting Kit-8, Transwell assays, and in vitro VM tube formation were used to investigate PABPC5, HCG15, and ZNF331 function in cell proliferation, migration, invasion, and VM, respectively. ChIP assays were used to ascertain the interaction betweenZNF331 and LAMC2 or PABPC5. PABPC5 and HCG15 were highly expressed in glioma cells. ZNF331 was lowly expressed. PABPC5 bound HCG15 to increase its stability. Knockdown HCG15 reduced the degradation of ZNF331 mRNA by the SMD pathway. ZNF331 inhibited transcription through binding to the promoter region of LAMC2 and PABPC5 and inhibited the ability to form VMs in glioma cells. The PABPC5/HCG15/ZNF331 feedback loop plays an important role in regulating VM formation in glioma and provides new targets for glioma treatment., Graphical Abstract, Glioma is the most common primary intracranial malignant tumor, and its main treatment methods are mainly surgical treatment combined with radiotherapy and chemotherapy and other comprehensive treatments after surgery, but after systematic treatment, the average median survival time of patients with glioma is only 12–18 months. Jing et al. demonstrate that PABPC5 increases the stability of HCG15. HCG15 promotes degradation of ZNF331 mRNA through the SMD pathway. ZNF331 binds to the promoter regions of LAMC2 and PABPC5 and inhibits their transcription, inhibiting formation of vasculogenic mimicry of glioma cells, which can affect the malignant biological behavior of glioma cells.

Vasculogenic mimicry (VM) is the formation of a "vessel-like" structure without endothelial cells. VM exists in vascular-dependent solid tumors and is a special blood supply source involved in the highly invasive tumor progression. VM is observed in a variety of human malignant tumors and is closely related to tumor proliferation, invasion, and recurrence. Here, we review the mechanism, related signaling pathways, and molecular regulation of VM in glioma and discuss current research problems and the potential future applications of VM in glioma treatment. This review may provide a new viewpoint for glioma therapy.

Upstream ORF (uORF) is a translational initiation element located in the 5′UTR of eukaryotic mRNAs. Studies have found that uORFs play an important regulatory role in many diseases. Based on The Cancer Genome Atlas database, the results of our experiments and previous research evidence, we investigated transcription factor AP‐4 (TFAP4) and its uORF, LIM and SH3 protein 1 (LASP1), long noncoding RNA 00520 (LINC00520), and microRNA (miR)‐520f‐3p as candidates involved in glioma malignancy, which is a poorly understood process. Both TFAP4‐66aa‐uORF and miR‐520f‐3p were downregulated, and TFAP4, LASP1, and LINC00520 were highly expressed in glioma tissues and cells. TFAP4‐66aa‐uORF or miR‐520f‐3p overexpression or TFAP4, LASP1, or LINC00520 knockdown inhibited glioma cell proliferation, migration, and invasion, but promoted apoptosis. TFAP4‐66aa‐uORF inhibited the translation of TFAP4 by binding to the TFAP4 mRNA. MicroRNA‐520f‐3p inhibited TFAP4 expression by binding to its 3′UTR. However, LINC00520 could promote the expression of TFAP4 by competitively binding to miR‐520f‐3p. In addition, TFAP4 transcriptionally activated LASP1 and LINC00520 expression by binding to their promoter regions, forming a positive feedback loop of TFAP4/LINC00520/miR‐520f‐3p. Our findings together indicated that TFAP4‐66aa‐uORF inhibited the TFAP4/LINC00520/miR‐520f‐3p feedback loop by directly inhibiting TFAP4 expression, subsequently leading to inhibition of glioma malignancy. This provides a basis for developing new therapeutic approaches for glioma treatment., This study used TFAP4‐66aa‐uORF as a starting point to reveal a new mechanism for regulating the malignant biological behavior of glioma cells, and also provides new strategies and new approaches for the treatment of gliomas.

Studies have found that RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are dysregulated and play an important regulatory role in the development of tumors. Based on The Cancer Genome Atlas (TCGA) database, our findings from experiments, and the evidence of previous studies, we screened DiGeorge syndrome critical region gene 8 (DGCR8), ZFAT antisense RNA 1 (ZFAT-AS1), and caudal type homeobox 2 (CDX2) as research candidates. In the present study, DGCR8 and CDX2 were highly expressed and ZFAT-AS1 was markedly downregulated in glioma tissues and cells. DGCR8 or CDX2 knockdown or ZFAT-AS1 overexpression suppressed glioma cell proliferation, migration, and invasion and facilitated apoptosis. DGCR8 might decrease ZFAT-AS1 expression by attenuating its stability in a manner of inducing its cleavage. Importantly, ZFAT-AS1 could inhibit CDX2 transcription by mediating the methylation of histone H3 on lysine 27 (H3K27me3) modification induced by PRC2 in the CDX2 promoter region. In addition, CDX2 transcriptionally activated DGCR8 expression by binding to its promoter regions, forming a positive feedback loop of DGCR8/ZFAT-AS1/CDX2. In conclusion, DGCR8/ZFAT-AS1 promotes CDX2 transcription in a PRC2 complex-dependent manner to facilitate the malignant biological behavior of glioma cells.

The blood-tumor barrier (BTB) limits the transport of chemotherapeutic drugs to brain tumor tissues and impacts the treatment of glioma. Long non-coding RNAs play critical roles in various biological processes of tumors; however, the function of these in BTB permeability is still unclear. In this study, we have identified that long intergenic non-protein coding RNA 174 (linc00174) was upregulated in glioma endothelial cells (GECs) from glioma tissues. Additionally, linc00174 was also upregulated in GECs from the BTB model in vitro. Knock down of linc00174 increased BTB permeability and reduced the expression of the tight junction-related proteins ZO-1, occludin, and claudin-5. Both bioinformatics data and results of luciferase reporter assays demonstrated that linc00174 regulated BTB permeability by binding to miR-138-5p and miR-150-5p. Furthermore, knock down of linc00174 inhibited FOSL2 expression via upregulating miR-138-5p and miR-150-5p. FOSL2 interacted with the promoter regions and upregulated the promoter activity of ZO-1, occludin, claudin-5, and linc00174 in GECs. In conclusion, the present study demonstrated that the linc00174/miR-138-5p (miR-150-5p)/FOSL2 feedback loop played an essential role in regulating BTB permeability. Keywords: blood-tumor barrier, linc00174, miR-138-5p, miR-150-5p, FOSL2

The efficacy of anti-PD-1 therapy is not as expected in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) was overexpressed and activated in HCC. This study aimed to investigate the potential mechanism and inhibitor of YAP1 on immune evasion, and promote anti-PD-1 therapy in HCC. Here, we showed that dihydroartemisinin (DHA), an FDA approved drug, directly suppressed YAP1 expression, leading to break immune evasion in liver tumor niche, characterized by decreased PD-L1 in liver tumor cells and increased CD8+ T cell infiltration. Mechanismly, YAP1 is not only directly related to PD-L1, but also involved in activating the JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche of Yap1LKO mice. Consistently, verteporfin, YAP1 inhibitor, decreased TGF-β in liver tumor niche and exhausted CD8+ T cells in spleen. Furthermore, DHA combined with anti-PD-1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cells in tumor tissues. Thus, we provide a new combined therapeutic strategy for anti-PD-1 with DHA, a potent YAP1 inhibitor, in HCC.

The existence of the blood–tumor barrier (BTB) severely hinders the transport of anti-tumor drugs to brain tumor tissues. Selectively opening BTB is of great significance to improve the chemotherapy effect of glioma. Pseudogenes have been recognized as important regulators in various biologic processes. In this study, we identified that ribosomal protein L32 pseudogene 3 (RPL32P3) was highly expressed in glioma-exposed endothelial cells (GECs). Knockdown of RPL32P3 decreased the expression of tight junction-related proteins (TJPs) and increased BTB permeability. Subsequent analysis of the underlying mechanism indicated that RPL32P3 recruited lysine methyltransferase 2 A (KMT2A) to the Y-box binding protein 2 (YBX2) promoter region and mediated H3K4me3 to promote YBX2 transcription. Highly expressed YBX2 bound and stabilized hepatocyte nuclear factor 4 gamma (HNF4G) mRNA. Highly expressed HNF4G directly bound to the promoters of TJPs ZO-1, occludin and claudin-5 to promote their transcriptional activities and regulated BTB permeability. The simultaneous knockdown of RPL32P3, YBX2, and HNF4G combined with doxorubicin (DOX) increased the apoptosis of glioma cells. In conclusion, the current study indicated that RPL32P3 knockdown increased BTB permeability through the YBX2/HNF4G pathway. These findings may provide new targets for the comprehensive treatment of glioma.

The blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

The dysfunction of the blood‐brain barrier (BBB) is one of the main pathological features of Alzheimer's disease (AD). Memantine (MEM), an N‐methyl‐d‐aspartate (NMDA) receptor antagonist, has been reported that been used widely for AD therapy. This study was performed to demonstrate the role of the MEM in regulating BBB permeability in AD microenvironment as well as its possible mechanisms. The present study showed that LINC00094 was dramatically increased in Abeta1‐42‐incubated microvascular endothelial cells (ECs) of BBB model in vitro. Besides, it was decreased in MEM‐incubated ECs. Silencing LINC00094 significantly decreased BBB permeability, meanwhile up‐regulating the expression of ZO‐1, occludin and claudin‐5. Furthermore, silencing LINC00094 enhance the effect of MEM on decreasing BBB permeability in AD microenvironment. The analysis of the mechanism demonstrated that reduction of LINC00094 inhibited Endophilin‐1 expression by up‐regulating miR‐224‐4p/miR‐497‐5p, promoted the expression of ZO‐1, occludin and claudin‐5, and ultimately alleviated BBB permeability in AD microenvironment. Taken together, the present study suggests that the MEM/LINC00094/miR‐224‐5p (miR‐497‐5p)/Endophilin‐1 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment. Silencing LINC00094 combined with MEM provides a novel target for the therapy of AD.

The blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

Researchers have found that RNA-binding proteins (RBPs) and circular RNAs (circRNAs) are dysregulated in tumors and play crucial roles in the development and progression of tumors. By analyzing the data of The Cancer Genome Atlas (TCGA) and our experimental findings, we screened the tumor suppressor MBNL1 (muscleblind like splicing regulator 1), and circRNA microarray was used to screen circNTRK2. Further, the transcription factor PAX5 (paired box 5) was selected as a research candidate by correlation analysis. In this study, MBNL1 and circNTRK2 were markedly downregulated, while PAX5 was highly expressed in glioblastoma multiforme (GBM). Moreover, gain and loss-of-function assays indicated that MBNL1 or circNTRK2 significantly abrogated, while PAX5 promoted, glycolysis and proliferation of GBM cells. MBNL1 may promote the cyclization of circNTRK2 by binding to NTRK2 pre-mRNA. Importantly, NTRK2-243aa encoded by circNTRK2 phosphorylated PAX5 at Y102 leading to half-life of PAX5 protein attenuating. Besides, PAX5 could transcriptionally faciltate the expression of PKM2 (pyruvate kinase M2) and HK2 (hexokinase 2) by binding to their promoter regions. Furthermore, in vivo experiments confirmed that MBNL1 and circNTRK2 could suppress tumor growth while PAX5 imped. In conclusion, our study revealed that the MBNL1/circNTRK2/PAX5 pathway regulated glycolysis and proliferation of GBM cells via encoding a novel protein NTRK2-243aa, which may provide a new strategy for targeted therapy of GBM.

Background: Traumatic brain injury (TBI) is a brain function change caused by external forces, which is one of the main causes of death and disability worldwide. The aim of this study was to identify early diagnostic markers and potential therapeutic targets for TBI.Methods: Differences between TBI and controls in GSE89866 and GSE104687 were analyzed. The two groups of differentially expressed genes (DEGs) were combined for coexpression analysis, and the modules of interest were performed using enrichment analysis. Hub genes were identified by calculating area under curve (AUC) values of module genes, PPI network analysis, and functional similarity. Finally, the difference in immune cell infiltration between TBI and control was calculated by ssGSEA.Results: A total of 4,817 DEGs were identified in GSE89866 and 1,329 DEGs in GSE104687. They were clustered into nine modules. The genes of modules 1, 4, and 7 had the most crosstalk and were identified as important modules. Enrichment analysis revealed that they were mainly associated with neurodevelopment and immune inflammation. In the PPI network constructed by genes with top 50 AUC values in module genes, we identified the top 10 genes with the greatest connectivity. Among them, down-regulated RPL27, RPS4X, RPL23A, RPS15A, and RPL7A had similar functions and were identified as hub genes. In addition, DC and Tem were significantly up-regulated and down-regulated between TBI and control, respectively.Conclusion: We found that hub genes may have a diagnostic role for TBI. Molecular dysregulation mechanisms of TBI are associated with neurological and immune inflammation. These results may provide new ideas for the diagnosis and treatment of TBI.

Background: Increasing studies have been demonstrated that circRNAs play vital regulatory roles in the biological behaviors of glioblastoma cells, and increasing circRNAs are found to have the capacity of encoding small peptides, which are involved in the regulatory process.Methods: Western blot and qRT-PCR were conducted to confirm the expression of SRSF7 and circ-PLEKHA5 respectively. RNase R digestion assay and fluorescence in situ hybridization assays were conducted to evaluate the existence and cellular location of circ-PLEKHA5. RIP assay was used to access the relationship between SRSF7 and circ-PLEKHA5. Dual-luciferase assay and FLAG tag assays were performed to test the coding capability of circ-PLEKHA5. Immunofluorescence assay was conducted to evaluate the location of circ-PLEKHA5-622aa. CCK-8, vasculogenic mimicry (VM) formation and transwell assays were used to evaluate the roles of SRSF7, circ-PLEKHA5, circ-PLEKHA5-622aa on proliferation, VM formation, migration and invasion. Nude mice xenograft studys with PAS-CD34 staining were used to clarify the functional roles of SRSF7 and circ-PLEKHA5 on VM formation in vivo.Results: SRSF7 was up-regulated in glioma, and promoted the proliferation, migration, invasion, VM formation and the expression of VM-associated proteins of glioma cells by increasing the expression of circ-PLEKHA5. Circ-PLEKHA5 was mainly localized in cytoplasm and promoted the proliferation, migration, invasion, VM formation and the expression of VM-associated proteins of glioma cells by encoding a novel protein circ-PLEKHA5-622aa. The application of SRSF7 and circ-PLEKHA5 inhibitor significantly suppressed the tumor growth and VM formation in vivo.Conclusions: This study first demonstrated the coding ability of circ-PLEKHA5, and identified the regulatory roles of SRSF7/circ-PLEKHA5/circ-PLEKHA5-622aa pathway in VM formation of glioblastoma cells. Our findings might provide a novel strategy for glioma treatment.

Objective To explore the potential of the transcription factor LMX1B and downstream gankyrin as prognostic biomarkers of glioma. Methods The expression levels of gankyrin and LMX1B were detected in 52 normal brain specimens and 339 glioma specimens. Correlations of gankyrin and LMX1B expression levels with pathological stages and clinical characteristics were statistically analyzed. Furthermore, the binding of LMX1B to the gankyrin promoter was evaluated using ALGGEN PROMO. Results Levels of LMX1B and gankyrin were significantly increased in tumor tissue, and were significantly associated with advanced glioma grade and poor survival. Compared with gankyrin- and LMX1B-negative glioma, the mean survival of patients with higher gankyrin and LMX1B expression was significantly reduced, from 83.46 to 18.87 months and from 63.79 to 18.29 months, respectively. Furthermore, LMX1B had a moderate positive correlation with gankyrin expression (Pearson’s r = 0.650), and it was also found to act as a transcription factor with NF-κB and E47 on the gankyrin promoter. Conclusions Increased expression of LMX1B and gankyrin has independent prognostic value in glioma patients. The transcription factor LMX1B may have an upstream role in the mechanism of action.

Glioma is the most common form of primary central nervous malignant tumors. Vasculogenic mimicry (VM) is a blood supply channel that is different from endothelial blood vessels in glioma. VM is related to tumor invasion and metastasis. Therefore, it plays an important role to target therapy for glioma VM. Our experimental results showed abnormal expression of UBE2I, PUM2, CEBPD, and DSG2 in glioma cells. The Co‐IP and Immunofluorescence staining were used to detect that PUM2 can be modified by SUMO2/3. The interaction between PUM2 and CEBPD mRNA was detected by the RIP assays. The interaction between transcription factor CEBPD and promoter region of DSG2 was detected by the ChIP assays and luciferase assays. The capacity for migration in glioma cells was observed by the laser holographic microscope. The capacity for invasion in glioma cells was detected by Transwell method. The VM in glioma cells was detected by three‐dimensional cell culture method. The experimental results found that the upregulation of UBE2I in glioma tissues and cells promotes the SUMOylation of PUM2, which decreases not only the stability of PUM2 protein but also decreases the inhibitory effect of PUM2 on CEBPD mRNA. The upregulation of CEBPD promotes the binding to the upstream promoter region of DSG2 gene, further upregulates the expression of DSG2, and finally promotes the development of glioma VM. In conclusion, this study found that the UBE2I/PUM2/CEBPD/DSG2 played crucial roles in regulating glioma VM. It also provides potential targets and alternative strategies for combined treatment of glioma., The expression of UBE2I in glioma cells is significantly increased, thereby promoting PUM2 SUMOylation, leading to the degradation of PUM2 protein by proteasome. UBE2I inhibits the role of PUM2 protein in the degradation of CEBPD mRNA. CEBPD overexpression promotes the transcriptional expression of DSG2, which in turn promotes the capacities for migration, invasion and VM in glioma cells.

Background: Molecular-targeted therapy plays an important role in the combined treatment of breast cancer. Long noncoding RNA (LncRNA) plays a significant role in regulating breast cancer progression. The present study is to reveal the potential roles and molecular mechanism that the secretory carrier-associated membrane protein 1-transcript variant 2 (SCAMP1-TV2) has in breast. Methods: Cell Counting Kit-8 (CCK-8), RNA Immunoprecipitation (RIP), and RNA pull-down assays were employed to determine the interactions between SCAMP1-TV2 and Pumilio RNA binding family member 2 (PUM2). The luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were used to get to know the effect of human insulinoma-associated 1 (INSM1) directly on the SAM and SH3 domain containing 1 (SASH1) promoter. Results: Silenced SCAMP1-TV2 inhibited the proliferation, migration, and invasion of breast cancer cells, and promoted cell apoptosis. Meanwhile, SCAMP1-TV2 downregulation decreased its binding to PUM2 and increased the binding of PUM2 to INSM1 messenger RNA (mRNA), thus promoting the degradation of INSM1 mRNA. Silencing INSM1 decreased its inhibitory effect on SASH1 transcription and inhibited the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. The xenograft tumor growth in a nude mice was significantly inhibited by the silencing of SCAMP1-TV2 in combination with the overexpression of PUM2. Conclusions: SCAMP1-TV2/PUM2/INSM1 pathway plays an important role in regulating the biological behavior of breast cancer cells.

The blood-tumor barrier limits the delivery of therapeutic drugs to brain tumor tissues. Selectively opening the blood-tumor barrier is considered crucial for effective chemotherapy of glioma. RNA-binding proteins have emerged as crucial regulators in various biologic processes. This study found that RNA-binding Fox-1 homolog 1 (RBFOX1) was downregulated in glioma vascular endothelial cells derived from glioma tissues, and in glioma endothelial cells obtained by co-culturing endothelial cells with glioma cells. Overexpression of RBFOX1 impaired the integrity of the blood-tumor barrier and increased its permeability. Additionally, RBFOX1 overexpression decreased the expression of tight junction proteins ZO-1, occludin, and claudin-5. Subsequent analysis of the mechanism indicated that the overexpression of RBFOX1 increased musculoaponeurotic fibrosarcoma protein basic leucine zipper [bZIP] transcription factor F (MAFF) expression by downregulating LINC00673, which stabilized MAFF messenger RNA (mRNA) through Staufen1-mediated mRNA decay. Moreover, MAFF could bind to the promoter region and inhibit the promoter activities of ZO-1, occludin, and claudin-5, which reduced its expression. The combination of RBFOX1 upregulation and LINC00673 downregulation promoted doxorubicin delivery across the blood-tumor barrier, resulting in apoptosis of glioma cells. In conclusion, this study indicated that overexpression of RBFOX1 increased blood-tumor barrier permeability through the LINC00673/MAFF pathway, which might provide a new useful target for future enhancement of blood-tumor barrier permeability., Graphical Abstract, In this article, the authors systematically elucidate the molecular network between RNA-binding proteins and lncRNAs and its functional role in regulating the permeability of the blood-tumor barrier at the molecular level. Additionally, this article provides a new theoretical basis and strategies for the clinical treatment of glioma.

Vasculogenic mimicry (VM) is the formation of a “vessel-like” structure without endothelial cells. VM exists in vascular-dependent solid tumors and is a special blood supply source involved in the highly invasive tumor progression. VM is observed in a variety of human malignant tumors and is closely related to tumor proliferation, invasion, and recurrence. Here, we review the mechanism, related signaling pathways, and molecular regulation of VM in glioma and discuss current research problems and the potential future applications of VM in glioma treatment. This review may provide a new viewpoint for glioma therapy.

Blood-brain tumor barrier (BTB) severely restricts the efficient delivery of chemotherapeutic drugs into brain tumor tissue, which is a critical obstacle for glioma treatment. Recently, long noncoding RNAs (lncRNAs) have shown as regulation factors of numerous biological processes. In this study, we identified that Lnc00462717 was upregulated in glioma endothelial cells (GECs), and that knockdown of Lnc00462717 significantly increased the BTB permeability. Both bioinformatics and RNA immunoprecipitation (RIP) results revealed that Lnc00462717 interacts with polypyrimidine tract binding protein (PTBP1). Moreover, overexpression of PTBP1 significantly reversed the increase in BTB permeability caused by siLnc00462717. Furthermore, the binding sites between miR-186 and PTBP1 as well as between miR-186 and 3'UTR of Occludin mRNA were confirmed by RIP and luciferase assays, respectively. And the interaction of Lnc00462717 and PTBP1 significantly facilitated the binding of PTBP1 to 3'UTR of Occludin mRNA and then blocked the miR-186-5p-induced downregulation of Occludin. In addition, we identified that knockdown of Lnc00462717 or overexpression of miR-186-5p increased the accumulation of doxorubicin (Dox) in brain glioma via the ultrafast liquid chromatography-mass spectrometry system (UFLC-MS/MS system) and decreased the intracranial glioma volume in BALB/c nude mice. Taken together, these results show a novel molecular pathway in BTB that may provide a potential innovative strategy for glioma therapy.

Increasing evidence has suggested that gliomas can supply blood through vasculogenic mimicry. In this study, the expression and function of ZNRD1‐AS1‐144aa‐uORF (144aa‐uORF) and some non‐coding RNAs in gliomas were assessed. Real‐time quantitative PCR or Western blot was used to discover the expression of 144aa‐uORF, ZNRD1‐AS1, miR‐499a‐5p, ELF1 and EMI1 in gliomas. In addition, RIP and RNA pull‐down assays were applied to explore the interrelationship between 144aa‐uORF and ZNRD1‐AS1. The role of the 144aa‐uORF\ZNRD1‐AS1\miR‐499a‐5p\ELF1\EMI1 axis in vasculogenic mimicry formation of gliomas was analysed. This study illustrates the reduced expression of the 144aa‐uORF in glioma tissues and cells. Up‐regulation of 144aa‐uORF inhibits proliferation, migration, invasion and vasculogenic mimicry formation within glioma cells. The up‐regulated 144aa‐uORF can increase the degradation of ZNRD1‐AS1 through the nonsense‐mediated RNA decay (NMD) pathway. Knockdown of ZNRD1‐AS1 inhibits vasculogenic mimicry in glioma cells by modulating miR‐499a‐5p. At the same time, miR‐499a‐5p is down‐regulated and has a tumour‐suppressive effect in gliomas. In addition, ZNRD1‐AS1 serves as a competitive endogenous RNA (ceRNA) and regulates the expression of ELF1 by binding to miR‐499a‐5p. Notably, ELF1 binds to the promoter region of EMI1 and up‐regulates EMI1 expression, while simultaneously promoting vasculogenic mimicry in glioma cells. This study suggests that the 144aa‐uORF\ZNRD1‐AS1\miR‐499a‐5p\ELF1\EMI1 axis takes key part in regulating the formation of vasculogenic mimicry in gliomas and may provide a potential target for glioma treatment.

Blood-brain tumor barrier (BTB) impedes the transportation of antitumor therapeutic drugs into brain tumors. Its mechanism is still unknown, but learning how to improve the BTB permeability is critical for drug intervention. Recently, microRNAs (miRNAs) have appeared as regulation factors of numerous biologic processes and therapeutic targets of diverse diseases. In this study, we have identified that miR-132-3p is an essential miRNA by increasing the transcellular transport through the BTB. We found that miR-132-3p expression was significantly up-regulated in glioma endothelial cells (GECs). Furthermore we showed that miR132-3p

Glioma is recognized as a highly angiogenic malignant brain tumor. Vasculogenic mimicry (VM) greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. However, the molecular mechanisms of VM formation in glioma remain unclear. Here, we demonstrated that LINC00339 was upregulated in glioma tissue as well as in glioma cell lines. The expression of LINC00339 in glioma tissues was positively correlated with glioma VM formation. Knockdown of LINC00339 inhibited glioma cell proliferation, migration, invasion, and tube formation, meanwhile downregulating the expression of VM-related molecular MMP-2 and MMP-14. Furthermore, knockdown of LINC00339 significantly increased the expression of miR-539-5p. Both bioinformatics and luciferase reporter assay revealed that LINC00339 regulated the above effects via binding to miR-539-5p. Besides, overexpression of miR-539-5p resulted in decreased expression of TWIST1, a transcription factor known to play an oncogenic role in glioma and identified as a direct target of miR-539-5p. TWIST1 upregulated the promoter activities of MMP-2 and MMP-14. The in vivo study showed that nude mice carrying tumors with knockdown of LINC00339 and overexpression of miR-539-5p exhibited the smallest tumor volume through inhibiting VM formation. In conclusion, LINC00339 may be used as a novel therapeutic target for VM formation in glioma.

In middle and old age, Alzheimer's disease (AD) is a progressive neurodegenerative disorder of brain. As an increasingly aging population, AD represents a huge burden for the patients' family and the country. However, current therapeutical strategies have shown limited effectiveness. Allicin, which is the main composition of garlic, was reported to prevent the learning and memory impairment of AD mouse model. As the mechanism is not clear, in this study, we used the APP (amyloid precursor protein)/PS1 (presenilin 1) double transgenic mice, which express human mutant APP and PS1, to determine the protective effect of allicin on neurons. AD involves a broad range of clinical, cellular, and biochemical manifestations. This has led to many views of AD, e.g. the amyloid, presenilin, oxidative stress, and mitochondrial dysfunction. We confirmed that allicin improves the cognitive function of APP/PS1 double transgenic mice by reducing the expression levels of Aβ, oxidative stress, and improving mitochondrial dysfunction. Application of behavioral, morphological and molecular biology, and other means were conducted to investigate the effect of allicin, which provide an experimental basis for the reliable application of allicin in the treatment of neurodegenerative diseases.

Background Coronary slow flow (CSF) refers to coronary arteries with no obvious stenosis but have slow coronary flow without effective treatment. The main cause of CSF is endothelial dysfunction. The long non-coding RNA (lncRNA) MALAT1 is involved in regulating endothelial dysfunction, but its role in CSF endothelial dysfunction is still unclear. Methods We included 41 CSF patients and 37 controls in the study, who all underwent coronary angiography, echocardiography, and brachial artery flow-mediated dilatation (FMD) examination. Human umbilical vein endothelial cells (HUVECs) stimulated by oxygen–glucose deprivation were used as CSF-induced HUVECs. Plasma endothelin-1 (ET-1) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of MALAT1, miR-181b-5p, myocyte enhancer factor 2A (MEF2A), and ET-1 were measured by qRT-PCR or western blotting. Cell proliferation was determined by 5-ethynyl-2′-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays. Apoptosis was examined by flow cytometry. The relationship between miR-181b-5p and MALAT1 or MEF2A was verified by dual-luciferase reporter assay. MEF2A binding directly to the ET-1 promoter region was verified via chromatin immunoprecipitation (ChIP) assay. Results MALAT1 and ET-1 were increased, and miR-181b-5p was decreased in the peripheral blood of the CSF patients, and could be used as predictors of CSF. In the CSF-induced HUVECs, MALAT1 was highly expressed, and MALAT1 knockdown improved endothelial function. In contrast, miR-181b-5p was downregulated in the CSF-induced HUVECs, and miR-181b-5p overexpression improved endothelial function. While MEF2A was highly enriched in CSF-induced HUVECs, MEF2A knockdown reduced ET-1 and increased the endothelial function of CSF-induced HUVECs as a transcriptional regulator of ET-1. MALAT1 modulated MEF2A expression positively by sponging miR-181b-5p. Conclusions Endothelial function is reduced in CSF. MALAT1 participates in regulating CSF endothelial dysfunction through the miR-181b-5p–MEF2A–ET-1 axis, and could provide a new target for CSF treatment.

Glioma stem cells (GSCs) make up highly tumorigenic subpopulations within gliomas, and aberrant expression of GSC genes is a major underlying cause of glioma pathogenesis and treatment failure. The present study characterized the expression and function of long non-coding RNA growth arrest specific 5 (GAS5) in GSCs in order to elucidate the molecular mechanisms by which GAS5 contributes to glioma pathogenesis. We demonstrate that GAS5 suppresses GSC malignancy by binding to miR-196a-5p. miR-196a-5p, an onco-miRNA, stimulates GSC proliferation, migration, and invasion, in addition to reducing levels of apoptosis. miR-196a-5p specifically downregulates the expression of forkhead box protein O1 (FOXO1) by targeting its 3' untranslated region (3'-UTR). FOXO1 upregulates expression of phosphotyrosine interaction domain containing 1 (PID1), thereby inhibiting GSC tumorigenicity and growth. FOXO1 also upregulates migration and invasion inhibitory protein (MIIP), resulting in attenuation of migration and invasion activities. Interestingly, we also show that FOXO1 promotes GAS5 transcription, thus forminga positive feedback loop. These data provide insights into potential new pathways for GSC molecular therapy and suggest that GAS5 may be an efficacious target for glioma treatments.

The blood-tumor barrier (BTB) constitutes an efficient organization of tight junctions that limits the delivery of chemotherapeutic drugs to brain tumor tissues and impacts the treatment of glioma. Long non-coding RNAs (lncRNAs) are non-protein coding RNAs regulating gene expression, some lncRNAs play a crucial role in BTB permeability. However, the function of lncRNAs in BTB permeability is still largely unclear. Here, we have identified lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), was remarkably up-regulated in glioma endothelial cells (GECs) obtained from an in vitro BTB model. Knockdown of NEAT1 impaired the integrity and increased the permeability of the BTB, accompanied by downregulation of expression of the tight junction proteins ZO-1, occludin and claudin-5 in GECs. Both bioinformatics data and results of luciferase reporter assays demonstrated that NEAT1 influenced BTB permeability by binding to miR-181d-5p. Knockdown of NEAT1 also down-regulated the expression of sex determining region Y-box protein 5 (SOX5), which was defined as a direct and functional downstream target of miR-181d-5p. SOX5 interacts with the promoter region of ZO-1, occludin and claudin-5 in GECs. In conclusion, knockdown of NEAT1 increased BTB permeability by binding to miR-181d-5p and then reducing tight junction protein expression by targeting SOX5. These results suggest an important role for NEAT1 in regulating BTB permeability and provide an additional strategy for treating glioma.

Despite the fact that temozolomide (TMZ) has been widely accepted as the key chemotherapeutic agent to prolong the survival of patients with glioblastoma, failure and recurrence cases can still be observed in clinics. Glioma stem-like cells (GSCs) are thought to be responsible for the drug resistance. In this study, we investigate whether endothelial monocyte-activating polypeptide-II (EMAP-II), a pro-inflammatory cytokine, can enhance TMZ cytotoxicity on U87MG and GSCs or not. As described in prior research, GSCs have been isolated from U87MG and maintained in the serum-free DMEM/F12 medium containing EGF, b-FGF, and B27. TMZ and/or EMAP-II administration were performed for 72 h, respectively. The results showed that TMZ combined with EMAP-II inhibit the proliferation of U87MG and GSCs by a larger measure than TMZ single treatment by decreasing the IC50. EMAP-II also enhanced TMZ-induced autophagy-mediated cell death and G2/M arrest. Moreover, we found that EMAP-II functioned a targeted suppression on mTOR, which may involve in the anti-neoplasm mechanism. The results suggest that EMAP-II could be considered as a combined chemotherapeutic agent against glioblastoma by sensitizing U87MG and GSCs to TMZ.

Dihydroartemisinin(DHA) is the active metabolic derivative of artemisinin. DHA has potential therapeutic effects on glioma but the detailed mechanism is unclear. In this study, we investigated the role and the underlying mechanisms of DHA in its inhibition of glioma cells. U87 cells are wild-type p53 glioblastoma cells and U251 cells contain mutant p53. DHA inhibited the proliferation, migration and invasion of glioma cells in a dose-dependent manner. DHA promoted reactive oxygen species production and activated p53 in two glioma cell lines, U87 and U251. In U87 cells, DHA significantly up-regulated the expression of p-β-catenin (S45) and inhibited EGFR, β-catenin, p-β-catenin (Y333) and matrix metalloprotease7/9 activity. In U251 cells, DHA significantly up-regulated p-β-catenin (S45), p-β-catenin (Y333) and EGFR, but the expression of β-cateninwas unchanged. We also found that DHA and sh-β-catenin prevented the proliferation of U87 and U251 cells in vivo. In conclusion, DHA inhibited the migration and invasion of human glioma cells with different types of p53 via different pathways.

// Zhuo Xi 1, 2 , Ping Wang 3 , Yixue Xue 3 , Chao Shang 3 , Xiaobai Liu 1, 2 , Jun Ma 3 , Zhiqing Li 3 , Zhen Li 1, 2 , Min Bao 1, 2 , Yunhui Liu 1, 2 1 Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of China 2 Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang 110004, People’s Republic of China 3 Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People’s Republic of China Correspondence to: Yunhui Liu, email: neurosurgery_sj@163.com Keywords: miR-29a, QKI-6, WTAP, glioma, glioblastoma stem cells Received: May 05, 2016 Accepted: January 23, 2017 Published: February 15, 2017 ABSTRACT Glioblastoma is the most common type of malignant primary brain tumor and has high recurrence and lethality rates. Glioblastoma stem cells (GSCs), a subpopulation of glioblastoma cells, may promote rapid tumor recurrence and therapy resistance. Because altered microRNA (miR) expression in GSCs may lead to glioblastoma progression, we assessed the effects of miR-29a expression on the oncogenic behavior of GSCs. MiR-29a expression was lower in GSCs than non-GSCs, and overexpression of miR-29a in GSCs inhibited cell proliferation, migration and invasion, but promoted apoptosis. MiR-29a directly inhibited the expression of Quaking gene isoform 6 ( QKI-6 ) by binding to its 3’-UTR, and thus inhibited GSC malignant behavior. In addition, Wilms’ tumor 1-associating protein ( WTAP ) was identified as a downstream target of QKI-6. Overexpression of miR-29a in GSCs inhibited expression of WTAP and suppressed both phosphoinositide 3-kinase/AKT and extracellular signal-related kinase pathways by downregulating QKI-6, thereby inhibiting cell proliferation, migration, and invasion but promoting apoptosis. We have characterized a novel miR-29a/QKI-6/WTAP axis in GSCs, which may provide theoretical support for the treatment of glioblastoma with miR-29a agomirs.

Diffuse intrinsic pontine glioma (DIPG) remains the leading cause of death among pediatric brain tumor patients. Its pontine location and aggressive nature make developing effective treatment an ongoing challenge in pediatric oncology. Although studies have found that one of the hallmark features of glioma is immunosuppression, the immune status of DIPG patient is not clearly understood. We tested the lymphocyte profile in four radiologically diagnosed DIPG patients. All the four patients did not receive any steroids, radiotherapy, and chemotherapy before the collection of blood. We found decreased natural killer (NK) cell level and increased B cell level in all four cases. These findings suggested that decreased NK cells and increased B cells may aid the tumorigenesis and growth seen in DIPG patient. Increased NK and decreased B cells may be the future direction for the treatment of DIPG patient.

Glioblastoma is the most common and malignant form of primary central nervous tumor in adults. Long noncoding RNAs (lncRNAs) have been reported to play a pivotal role in modulating gene expression and regulating human tumor’s malignant behaviors. In this study, we confirmed that lncRNA brain-derived neurotrophic factor antisense (BDNF-AS) was downregulated in glioblastoma tissues and cells, interacted and stabilized by polyadenylate-binding protein cytoplasmic 1 (PABPC1). Overexpression of BDNF-AS inhibited the proliferation, migration, and invasion, as well as induced the apoptosis of glioblastoma cells. In the in vivo study, PABPC1 overexpression combined with BDNF-AS overexpression produced the smallest tumor and the longest survival. Moreover, BDNF-AS could elicit retina and anterior neural fold homeobox 2 (RAX2) mRNA decay through STAU1-mediated decay (SMD), and thereby regulated the malignant behaviors glioblastoma cells. Knockdown of RAX2 produced tumor-suppressive function in glioblastoma cells and increased the expression of discs large homolog 5 (DLG5), leading to the activation of the Hippo pathway. In general, this study elucidated that the PABPC1-BDNF-AS-RAX2-DLG5 mechanism may contribute to the anticancer potential of glioma cells and may provide potential therapeutic targets for human glioma.

Following the publication of this article, the authors realized there was an error in Figure 6H in which two versions of the figure appear.This does not impact the conclusions of the article.