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Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the formation of a tumor blood supply system independently of endothelial cells, contributes to the malignant progression of glioma. Therefore, VM is considered a potential target for glioma therapy. Accumulated evidence indicates that alterations in SUMOylation, a reversible post-translational modification, are involved in tumorigenesis and progression. In the present study, we found that UBA2 and RALY were upregulated in glioma tissues and cell lines. Downregulation of UBA2 and RALY inhibited the migration, invasion, and VM of glioma cells. RALY can be SUMOylated by conjugation with SUMO1, which is facilitated by the overexpression of UBA2. The SUMOylation of RALY increases its stability, which in turn increases its expression as well as its promoting effect on FOXD1 mRNA. The overexpression of FOXD1 promotes DKK1 transcription by activating its promoter, thereby promoting glioma cell migration, invasion, and VM. Remarkably, the combined knockdown of UBA2, RALY, and FOXD1 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. UBA2/RALY/FOXD1/DKK1 axis may play crucial roles in regulating VM in glioma, which may contribute to the development of potential strategies for the treatment of gliomas. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abnormal energy metabolism, including enhanced aerobic glycolysis and lipid synthesis, is a well‐established feature of glioblastoma (GBM) cells. Thus, targeting the cellular glycolipid metabolism can be a feasible therapeutic strategy for GBM. This study aimed to evaluate the roles of MSI2, SNORD12B, and ZBTB4 in regulating the glycolipid metabolism and proliferation of GBM cells. MSI2 and SNORD12B expression was significantly upregulated and ZBTB4 expression was significantly low in GBM tissues and cells. Knockdown of MSI2 or SNORD12B or overexpression of ZBTB4 inhibited GBM cell glycolipid metabolism and proliferation. MSI2 may improve SNORD12B expression by increasing its stability. Importantly, SNORD12B increased utilization of the ZBTB4 mRNA transcript distal polyadenylation signal in alternative polyadenylation processing by competitively combining with FIP1L1, which decreased ZBTB4 expression because of the increased proportion of the 3′ untranslated region long transcript. ZBTB4 transcriptionally suppressed the expression of HK2 and ACLY by binding directly to the promoter regions. Additionally, ZBTB4 bound the MSI promoter region to transcriptionally suppress MSI2 expression, thereby forming an MSI2/SNORD12B/FIP1L1/ZBTB4 feedback loop to regulate the glycolipid metabolism and proliferation of GBM cells. In conclusion, MSI2 increased the stability of SNORD12B, which regulated ZBTB4 alternative polyadenylation processing by competitively binding to FIP1L1. Thus, the MSI2/SNORD12B/FIP1L1/ZBTB4 positive feedback loop plays a crucial role in regulating the glycolipid metabolism of GBM cells and provides a potential drug target for glioma treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 3ʹ-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aims: Vasculogenic mimicry (VM) has been reported to be a novel glioma neovascularization process. Anti-VM therapy provides new insight into glioma clinical management. In this study, we revealed the role of the long non-coding RNA HOXA cluster antisense RNA 2 (HOXA-AS2) in malignant glioma behaviors and VM formation. Methods: Quantitative real-time PCR was performed to determine the expression levels of HOXA-AS2 in glioma samples and glioblastoma cell lines. CD34-periodic acid-Schiff dual-staining was performed to assess VM in glioma samples. CCK-8, transwell, and Matrigel tube formation assays were performed to measure the effects of HOXA-AS2 knockdown on cell viability, migration, invasion, and VM tube formation, respectively. RNA immunoprecipitation, dual-luciferase reporter and Western blot assays were performed to explore the molecular mechanisms underlying the functions of HOXS-AS2 in glioblastoma cells. A nude mouse xenograft model was used to investigate the role of HOXA-AS2 in xenograft glioma growth and VM density. Student’s t-tests, one-way ANOVAs followed by Bonferroni posthoc tests, and chi-square tests were used for the statistical analyses. Results: HOXA-AS2 was upregulated in glioma samples and cell lines and was positively correlated with VM. HOXA-AS2 knockdown attenuated cell viability, migration, invasion, and VM formation in glioma cells and inhibited the expression of vascular endothelial-cadherin (VE-cadherin), as well as the expression and activity of matrix metalloproteinase matrix metalloproteinase (MMP)-2 and MMP-9. miR-373 was downregulated in glioma samples and cell lines and suppressed malignancy in glioblastoma cells. HOXA-AS2 bound to miR-373 and negatively regulated its expression. Epidermal growth factor receptor (EGFR), a target of miR-373, increased the expression levels of VE-cadherin, as well as the expression and activity levels of MMP-2 and MMP-9, via activating phosphatidylinositol 3-kinase/serine/threonine kinase pathways. HOXA-AS2 knockdown combined with miR-373 overexpression yielded optimal tumor suppressive effects and the lowest VM density in vivo. Conclusion: HOXA-AS2 knockdown inhibited malignant glioma behaviors and VM formation via the miR-373/EGFR axis. [ABSTRACT FROM AUTHOR]

Background: Glioma is the most common and lethal type of malignant brain tumor. Accumulating evidence has highlighted that RNA binding protein APOBEC1 complementation factor (A1CF) is involved in various cellular processes by modulating RNA expression, and acts as an oncogene in breast cancer. However, the function of A1CF in glioma remained unclear. Methods: Quantitative RT-PCR and western blot analysis were employed to detect the expression levels of A1CF, lncRNA family with sequence similarity 224 member A (FAM224A), miR-590-3p, zinc finger protein 143 (ZNF143) and ArfGAP with SH3 domain, ankyrin repeat and PH domain 3 (ASAP3) in glioma tissues and cell lines. The Cell Counting Kit-8 assay, migration and invasion assays, and flow cytometry analysis were conducted to evaluate the function of A1CF, FAM224A, miR-590-3p, ZNF143 and ASAP3 in the malignant biological behaviors of glioma cells. Moreover, luciferase reporter, RIP and ChIP assays were used to investigate the interactions among A1CF, FAM224A, miR-590-3p, ZNF143, ASAP3 and MYB. Finally, the xenograft tumor growth assay further ascertained the biological roles of A1CF, FAM224A and miR-590-3p in glioma cells. Results: A1CF was upregulated and functioned as an oncogene via stabilizing and increasing FAM224A expression; moreover, high A1CF and FAM224A expression levels indicated a poorer prognosis for glioma patients. Conversely, miR-590-3p was downregulated and exerted a tumor-suppressive function in glioma cells. Inhibition of A1CF significantly restrained cell proliferation, migration and invasion, and promoted apoptosis by upregulating miR-590-3p in a FAM224A-dependent manner. FAM224A was a molecular sponge of miR-590-3p and they were in an RNA-induced silencing complex. ZNF143 was upregulated in glioma tissues and cell lines. MiR-590-3p could negatively modulate the expression of ZNF143 via binding to the ZNF143 3′ UTR. Moreover, ZNF143 participated in miR-590-3p-induced tumor-suppressive activity on glioma cells. ASAP3 and MYB were transcriptionally activated by ZNF143, and importantly, ZNF143 could directly target the promoter of FAM224A and stimulate its expression, collectively forming a positive feedback loop. Conclusions: The present study clarifies that the A1CF-FAM224A-miR-590-3p-ZNF143 positive feedback loop conducts critical regulatory effects on the malignant progression of glioma cells, which provides a novel molecular target for glioma therapy. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs has been reported in tumorigenesis and play important roles in regulating malignant behavior of cancers, including glioma. Methods: According to the TCGA database, we identified SNHG1, miRNA-154-5p and miR-376b-3p whose expression were significantly changed in the glioma samples. Furthermore, we investigated SNHG1, miRNA-154-5p and miR-376b-3p expression in clinical samples and glioma cell lines using qRT-PCR analysis and the correlation between them using RNA immunoprecipitation and dual-luciferase reporter. The underlying mechanisms of SNHG1 in glioma were also investigated using immunohistochemistry staining, Western blotting, chromatin immunoprecipitation, and RNA pulldown. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate malignant biological behaviors. Results: We have elucidated the potential molecular mechanism of long non-coding RNA SNHG1 regulating the malignant behavior of glioma cells by binding to microRNA-154-5p or miR-376b-3p. Moreover, our deep-going results showed that FOXP2 existed as a direct downstream target of both microRNA-154-5p and miR-376b-3p; FOXP2 increased promoter activities and enhanced the expression of the oncogenic gene KDM5B; and KDM5B also acts as a RNA-binding protein to maintain the stability of SNHG1. Conclusion: Collectively, this study demonstrates that the SNHG1- microRNA-154-5p/miR-376b-3p- FOXP2- KDM5B feedback loop plays a pivotal role in regulating the malignant behavior of glioma cells. [ABSTRACT FROM AUTHOR]

Background: Accumulating 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. Methods: Quantitative 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. Results: FXR1and 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. Conclusions: FXR1/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. [ABSTRACT FROM AUTHOR]

Background: The blood-brain barrier (BBB) strongly restricts the entry of anti-glioma drugs into tumor tissues and thus decreases chemotherapy efficacy. Malignant gliomas are highly invasive tumours that use the perivascular space for invasion and co-opt existing vessels as satellite tumor form. Because regulation of the effect of noncoding RNA on BBB function is attracting growing attention, we investigated the effects of noncoding RNA on the permeability of glioma conditioned normal BBB and the mechanism involved using PIWI-associated RNA piR-DQ590027 as a starting point. Methods: The mRNA levels of MIR17HG, miR-153, miR-377, ZO-1, occludin, and claudin-5 were determined using real-time PCR. Transient cell transfection was performed using Lipofectamine 3000 reagent. TEER and HRP flux were applied to measure the permeability of glioma conditioned normal BBB. Western blotting and immunofluorescence assays were used to measure ZO-1, occludin, and claudin-5 levels. Reporter vector construction and a luciferase reporter assay were performed to detect the binding sites of MIR17HG and piR-DQ590027, MIR17HG and miR-153 (miR-377), and FOXR2 and miR-153 (miR-377). RNA immunoprecipitation was used to test the interaction between miR-153 (miR-377) and its target proteins. Chromatin immunoprecipitation was performed to detect the interaction between the transcription factor FOXR2 and ZO-1, occludin, and claudin-5. Results: piR-DQ590027 was expressed at low levels in glioma-conditioned ECs (GECs) of the in vitro glioma conditioned normal BBB model. Overexpression of piR-DQ590027 down-regulated the expressions of ZO-1, occludin, and claudin-5 and increased the permeability of glioma conditioned normal BBB. MIR17HG had high expression in GECs but miR-153 and miR-377 had low expression. piR-DQ590027 bound to and negatively regulated MIR17HG. FOXR2 was a downstream target of miR-153 and miR-377; MIR17HG bound separately to miR-153 and miR-377 and negatively regulated their ability to mediate FOXR2 expression. FOXR2 associated with the promoter regions of ZO-1, occludin, and claudin-5 in GECs to promote their transcription. Conclusion: The piR-DQ590027/MIR17HG/miR-153 (miR-377)/FOXR2 pathway plays an important role in regulating glioma conditioned normal BBB permeability and provides a new target for the comprehensive treatment of glioma. [ABSTRACT FROM AUTHOR]

The long non-coding RNA (lncRNA) PVT1 is reported to be involved in tumorigenesis and the progression of many malignancies. However, the function of PVT1 in gliomas remains unclarified. The present study demonstrated the expression level of PVT1 using qRT-PCR. The role of PVT1 in the regulation of biological behaviors of glioma cells was investigated using CCK-8 assay, Transwell assay and flow cytometry. The possible molecular mechanisms were also elucidated. In our results, PVT1 was up-regulated in glioma specimens and cell lines. Knockdown of PVT1 impaired the malignant behaviors of glioma cells via the suppression of proliferation, migration and invasion, as well as through promotion of apoptosis. Furthermore, PVT1 was identified to affect the glioma cells via binding to miR-190a-5p and miR-488-3p, which were down-regulated and played tumor suppressor roles in glioma cells. Up-regulated miR-190a-5p or miR-488-3p partially rescued the suppressive effect induced by PVT1 knockdown. Myocyte enhancer factor 2C (MEF2C) was a direct downstream target of miR-190a-5p and miR-488-3p, which was proved to be an oncogene and involved in the PVT1 knockdown induced regulation of biological behaviors of glioma cells. Over-expression of MEF2C up-regulated JAGGED1 by increasing the promoter activity of JAGGED1. PVT1 knockdown combined with miR-190a-5p and miR-488-3p over-expression contributed to the smallest tumor volume and the longest survivals in nude mice. In conclusion, PVT1-miR-190a-5p/miR-488-3p-MEF2C-JAGGED1 axis is involved in proliferation and progression of glioma. Thus, PVT1 may become a novel target in glioma therapy. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) play crucial roles in the development and progression of glioma. Previous studies indicated that lncRNA H19 regulated tumor carcinogenesis, angiogenesis and metastasis. This study aimed to investigate its functional role in glioma-induced endothelial cell proliferation, migration and tube formation as well as its possible molecular mechanisms. H19 was up-regulated in microvessels from glioma tissues and glioma-associated endothelial cells (GEC) cultured in glioma conditioned medium. Knockdown of H19 suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro and meanwhile up-regulated the expression of miR-29a. Bioinformatics analysis and luciferase reporter assay defined that H19 mediated the above effects via directly binding to miR-29a. In addition, miR-29a targeted 3'-UTR region of vasohibin 2 (VASH2) and decreased its expression. VASH2 has been identified as an angiogenic factor. Knockdown of H19 also decreased the VASH2 expression by up-regulating miR-29a. In conclusion, the results indicated that knockdown of H19 suppressed glioma induced angiogenesis by inhibiting microRNA-29a, which may modulate the onset of glioma by regulating biological behaviors of glioma vascular endothelial cells. [ABSTRACT FROM AUTHOR]

Angiogenesis plays a major role in tumor initiation, progression, and metastasis. This is why finding antiangiogenic targets is essential in the treatment of gliomas. In this study, NSUN2 and LINC00324 were significantly upregulated in conditionally cultured glioblastoma endothelial cells (GECs). Knockdown of NSUN2 or LINC00324 inhibits GECs angiogenesis. NSUN2 increased the stability of LINC00324 by m5C modification and upregulated LINC00324 expression. LINC00324 competes with the 3'UTR of CBX3 mRNA to bind to AUH protein, reducing the degradation of CBX3 mRNA. In addition, CBX3 directly binds to the promoter region of VEGFR2, enhances VEGFR2 transcription, and promotes GECs angiogenesis. These findings demonstrated NSUN2/LINC00324/CBX3 axis plays a crucial role in regulating glioma angiogenesis, which provides new strategies for glioma therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]