BACKGROUND:Environmental pollution was a global problem that caused great damage to human health. Perfluorodecanoic acid (PFDA) and perfluorooctane sulfonic acid (PFOS), as members of perfluoroalkyl and polyfluoroalkyl substances (PFASs), were considered as "permanent environmental pollutants," and have been reported to be risk factors in cancer. Research has reported that the exposure to PFASs increased the risk of developing glioma, and PFDA and PFOS promoted glioblastoma (GBM) cells proliferation. However, research linking PFASs exposure to GBM prognosis is lacking. METHODS:This study utilized network toxicology and bioinformatics analysis to elucidate the potential mechanism of PFDA and PFOS on GBM. Functional experiments were conducted to verify the biological function of PFDA/PFOS target genes on GBM. RESULTS:Seven target genes of PFDA/PFOS were identified as being specifically and abnormally expressed in GBM, with AUC values reaching 0.95 for CTSB, 0.95 for CHI3L1, 0.84 for VEGFA, 0.95 for MMP2, 0.96 for FAM83D, 0.98 for MMP9, and 0.97 for HOXD10 in TCGA cohort. PFDA/PFOS exposure related GBM prognosis model based on XGBoost algorithm, with the highest C-index reaching 0.84, uncovering that PFDA/PFOS may affect the prognosis via FN1, CHI3L1 and HOXD10. Molecular docking results verified the interactions between PFDA/PFOS and the identified genes. The VinaScore was -7.4 kcal/mol between FN1 and PFOS, -8.1 kcal/mol between CHI3L1 and PFOS, and -6.2 kcal/mol between HOXD10 and PFDA. In vitro experiments proved the roles that the prognostic genes contributed to the maligant behaviors of GBM. CONCLUSIONS:This study combined bioinformatics and network toxicology analysis strategies to identified hub genes potentially mediating the effects of PFDA/PFOS, providing evidences that PFDA/PFOS exposure have a potential association with GBM prognosis. Our study emphasized the need for further epidemiological and clinical studies.

Glioblastoma is a highly aggressive brain tumor characterized by substantial intratumoral heterogeneity and poor clinical outcomes. Understanding the transcriptional programs and microenvironmental cues that drive aggressive tumor cell states is essential for developing targeted therapies. We integrated bulk and single-cell RNA-seq data from TCGA, CGGA, and published spatial datasets. Using BayesPrism deconvolution, we identified a glioblastoma subpopulation (G1) whose abundance consistently correlated with poor prognosis. Pseudotime analysis with Monocle2 positioned G1 at the terminal state of malignant differentiation. To uncover regulatory mechanisms, we applied NetAct and SCENIC, which highlighted KLF10 as a key transcription factor. Spatial transcriptomic deconvolution and NicheNet analysis suggest that microenvironment-derived TNF likely drives G1 transition via FAT1/TNFRSF1A and ceruloplasmin (CP) induction. Functional experiments including CCK-8, EdU, Transwell, and wound healing assays validated the TNF/CP/KLF10 axis as a driver of glioblastoma cell proliferation and migration. Among the eight glioma cell subtypes identified, the G1 subtype was consistently associated with poor prognosis and showed higher proliferation and migration scores. G1 cells showed enhanced ER stress signaling. Integrated analysis identified TNF-α as a key ligand secreted by cDCs, macrophages, and microglia within G1-enriched spatial niches. FAT1 and TNFRSF1A were identified as G1-specific TNF receptors. Transcription factor KLF10 was identified as a master regulator of G1 identity. Functional assays demonstrated that TNF-α promotes glioblastoma cell proliferation and migration through a CP/KLF10 axis, wherein TNF-α-induced CP upregulation modulates KLF10 expression, and these biological effects were reversed by CP suppression. Our study defines a malignant glioblastoma cell state (G1) regulated by intrinsic transcriptional programs and extrinsic immune-derived TNF–CP signaling. Targeting the G1 program or interrupting the TNF-α/CP/KLF10 axis may offer new therapeutic strategies for glioblastoma.

Background: Low-grade glioma (LGG, WHO2-3 grade), a kind of common primary tumor of the central nervous system, exhibits high 5-year survival rates but frequently recurs and progresses to higher-grade tumors, leading to poor prognosis. Effective prognostic biomarkers and therapeutic targets are urgently needed. Tumor necrosis factor alpha-induced proteins (TNFAIPs), key regulators within the inflammatory microenvironment, have been proven to play an important role in regulating tumor invasion and metastasis via immunoinflammatory suppression. Nevertheless, their functional mechanism and clinical significance in LGG remained unclear. Lacking studies focused on the direct effects of TNFAIPs themselves on regulating the malignant biological behaviors of LGG. Materials and methods: In this study, we employed bioinformatics analysis, machine learning algorithms, and in vitro cell experiments to investigate the potential effects of TNFAIP6 on LGG. Results: It found that TNFAIP6 can be a reliable prognostic marker for LGG, which directly regulates the malignant behaviors of LGG, including proliferation, invasion, and migration, thereby promoting LGG recurrence and progression. These processes were proven to be closely associated with the activation of the JAK3-STAT6 signaling pathway. Conclusion: Our findings demonstrated that TNFAIP6 can directly contribute to the malignant behaviors of LGG, providing a theoretical basis for developing targeted therapeutic strategies against TNFAIP6 and the JAK3-STAT6 signaling axis in LGG.

BackgroundGlioma was the most common malignant tumor of the central nervous system in adults. Low-grade gliomas (LGGs) have a potential of grade progression and histological transformation, and the relevant mechanisms of this malignant evolution were still unclear.MethodsIn this study, we used 61 primary-recurrent paired glioma samples from 28 patients for proteomics analysis based upon DIA-NN approach.ResultsOur results indicated that the Ras/p38-MAPK pathways were hub signaling pathways driving grade progression and histological transformation in LGG. The activation of non-MGMT dependent unspecific DNA damage repair system mediated by Replication Factor C (RFC) can be an important reason for the treatment resistance. Moreover, metabolic reprogramming was widely involved in the regulation of LGG grade progression and histological transformation. The enhanced synthesis of unsaturated fatty acids and the significantly activated peroxisomal fatty acid beta-oxidation pathways were metabolic characteristics of LGG after histological transformation. Last, we constructed a reliable LGG progression prediction model consisted of 2 proteins, which can be monitor biomarkers for LGG progression, with potential clinical translation value.ConclusionsIn summary, glioma grade progression and histological transformation were complex biological processes, which involved the abnormal up-regulation of Ras/p38-MAPK signalings, enhanced non-MGMT dependent unspecific DNA damage repair system regulated by RFC complex and metabolic reprogramming based on HK1-PFKP-ENO2 mediated glycolysis and peroxisomal FA beta oxidation. This study filled the gap in relevant research on the grade progression and histological transformation of LGG, providing novel and unique insights into the biological mechanisms of glioma progression.

Background We conducted this meta-analysis to investigate the potential association between maternal smoking, alcohol and caffeinated beverages consumption during pregnancy and the risk of childhood brain tumors (CBTs).Methods A thorough search was carried out on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Internet to identify pertinent articles. Fixed or random effects model was applied to meta-analyze the data.Results The results suggested a borderline statistically significant increased risk of CBTs associated with maternal smoking during pregnancy (OR 1.04, 95% CI 0.99-1.09). We found that passive smoking (OR 1.12, 95% CI 1.03-1.20), rather than active smoking (OR 1.00, 95% CI 0.93-1.07), led to an increased risk of CBTs. The results suggested a higher risk in 0-1 year old children (OR 1.21, 95% CI 0.94-1.56), followed by 0-4 years old children (OR 1.12, 95% CI 0.97-1.28) and 5-9 years old children (OR 1.11, 95% CI 0.95-1.29). This meta-analysis found no significant association between maternal alcohol consumption during pregnancy and CBTs risk (OR 1.00, 95% CI 0.80-1.24). An increased risk of CBTs was found to be associated with maternal consumption of caffeinated beverages (OR 1.16, 95% CI 1.07-1.26) during pregnancy, especially coffee (OR 1.18, 95% CI 1.00-1.38).Conclusions Maternal passive smoking, consumption of caffeinated beverages during pregnancy should be considered as risk factors for CBTs, especially glioma. More prospective cohort studies are warranted to provide a higher level of evidence.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis. A better understanding of mechanisms concerned in glioma invasion might be critical for treatment optimization. Given that epithelial-mesenchymal transition in tumor cells is closely associated with glioma progression and recurrence, identifying pivotal mediators in GBM EMT process is urgently needed. As a member of Fatty acid binding protein (FABP) family, FABP4 serves as chaperones for free fatty acids and participates in cellular process including fatty acid uptake, transport, and metabolism. In this study, our data revealed that FABP4 expression was elevated in human GBM samples and correlated with a mesenchymal glioma subtype. Gain of function and loss of function experiments indicated that FABP4 potently rendered glioma cells increased filopodia formation and cell invasiveness. Differential expression genes analysis and GSEA in TCGA dataset revealed an EMT-related molecular signature in FABP4-mediated signaling pathways. Cell interaction analysis suggested CD36 as a potential target regulated by FABP4. Furthermore, in vitro mechanistic experiments demonstrated that FABP4-induced CD36 expression promoted EMT via non-canonical TGFβ pathways. An intracranial glioma model was constructed to assess the effect of FABP4 on tumor progression in vivo. Together, our findings demonstrated a critical role for FABP4 in the regulation invasion and EMT in GBM, and suggest that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for treatment of GBM.

Objectives: The prognosis of patients with recurrent low-grade glioma (rLGG) varies greatly. Some patients can survive >10 years after recurrence, whereas other patients have <1 year of survival. Methods: To identify the related risk factors affecting the prognosis of patients with rLGG, we performed a series of bioinformatics analyses on RNA sequencing data of rLGG based on the Chinese Glioma Genome Altas database. Results: We constructed a 12-gene prognostic signature, dividing all the patients with rLGG into high- and low-risk subgroups. The result showed an excellent predictive effect in both the training cohort and the validation cohort using LASSO-Cox regression. Moreover, multivariate Cox analysis identified 4 independent prognostic factors of rLGG; among them, ZCWPW1 is identified as a high-value protective factor. Conclusions: In all, this prognostic model displayed robust predictive capability for the overall survival of patients with rLGG, providing a new monitoring method for rLGG. The 4 independent prognostic factors, especially ZCWPW1, can be potential targets for rLGG, bringing new possibilities for the treatment of patients with rLGG.

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive extranodal lymphoma with poor prognosis. Currently there is no standard therapeutic strategy for PCNSL, and high-dose methotrexate-based regimens remain the first option (Siegal et al. Acta Haematologica 2019). Recently, studies have shown that Bruton's tyrosine kinase (BTK) plays a crucial part in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in PCNSL (Shen et al. Front Oncol. 2022). BTK inhibitor has been proven effective in treating chronic lymphocytic leukemia and other B-cell lymphomas (Yoshitaka et al. Neuro-Oncology 2021). Orelabrutinib is a novel and highly selective BTK inhibitor with high cerebrospinal fluid (CSF) concentration, which has demonstrated efficacy and safety in PCNSL (Wu et al. Invest New Drugs. 2022). Thus, we conducted a retrospective study to evaluate the efficacy and safety of the orelabrutinib-containing regimens as first-line therapy for patients (pts) with PCNSL. Methods: This isa retrospective analysis of pts with PCNSL who received TORM regimens (temozolomide 150 mg/m 2 day 2-5; orelabrutinib 150 mg qd day 2-21; rituximab 375 mg/m 2 day 1; methotrexate 3.5 g/m 2 day 2; 3 weeks per cycle) as first-line induction therapy between June 2021 and April 2023. It was proposed to receive autologous stem cells transplantation (ASCT) as consolidation therapy or orelabrutinib monotherapy as maintenance after TORM therapy when deemed necessary. The primary endpoint was overall response rate (ORR) according to the International PCNSL Collaborative Group (IPCG) criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Twelve pts (8 males) with PCNSL were included, with a median age of 63.5 years (range, 40-77). All pts had a histologically confirmed diffuse large B-cell lymphoma and a history of deep intracranial lesions. 8 pts (66.7%) had non-germinal center B-cell-like subtypes. 5 pts (41.7%) had an Eastern Cooperative Oncology Group performance status of ≥2, and 10 pts (83.3%) had International Extranodal Lymphoma Study Group scores ≥2. 4 pts (33.3%) underwent ASCT after induction therapy and 4 pts (33.3%) received orelabrutinib maintenance monotherapy. As of the cut-off date (July 1, 2023), the median follow-up was 11.7 (range, 1.9-23.0) months, and median treatment cycle was 6 cycles (range, 2-9). All 12 pts were evaluated for the treatment response. An interim evaluation after 3/4 cycles was available for 12 pts, showing complete remission (CR) rate of 83.3% (10/12), partial response (PR) rate of 16.7% (2/12), giving an ORR of 100.0% (12/12, Table 1). At data cutoff, of all 12 evaluable pts, the best ORR was 100.0% (12/12), with all pts achieved CR ( Table 1). The median time to response was 1.7 (range, 0.7-2.4) months. Of 12 responders, 9 had an ongoing response, 2 developed progressive disease, and 1 died of covid-19 infection ( Figure 1). Median PFS was 22.6 months, with a 95% CI of 10.4-not reached (NR). Based one OS event, median OS was 22.6 months (95% CI, NR-NR). The most common AEs were anemia. Reported AEs were generally manageable and resolved soon after supportive treatment. AEs associated with off-target activities such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusions: TORM regimens demonstrated encouraging efficacy and well-tolerated safety profile among pts with PCNSL in this retrospective study. This orelabrutinib-containing regimens may provide a potential treatment strategy for pts with PCNSL.

Mesenchymal stem cells (MSCs) have emerged as putative therapeutic tools due to their intrinsic tumor tropism, and anti-tumor and immunoregulatory properties. The limited passage and self-differentiation abilities of MSCs in vitro hinder preclinical studies on them. In this study, we focused on the safety of immortalized mesenchymal stem cells (im-MSCs) and, for the first time, studied the feasibility of im-MSCs as candidates for the treatment of glioma. The im-MSCs were constructed by lentiviral transfection of genes. The proliferative capacity of im-MSCs and the proliferative phenotype of MSCs and MSCs co-cultured with glioma cells (U87) were measured using CCK-8 or EdU assays. After long-term culture, karyotyping of im-MSCs was conducted. The tumorigenicity of engineered MSCs was evaluated using soft agar cloning assays. Next, the engineered cells were injected into the brain of female BALB/c nude mice. Finally, the cell membranes of im-MSCs were labeled with DiO or DiR to detect their ability to be taken up by glioma cells and target in situ gliomas using the IVIS system. Engineered cells retained the immunophenotype of MSC; im-MSCs maintained the ability to differentiate into mesenchymal lineages in vitro; and im-MSCs showed stronger proliferative capacity than unengineered MSCs but without colony formation in soft agar, no tumorigenicity in the brain, and normal chromosomes. MSCs or im-MSCs co-cultured with U87 cells showed enhanced proliferation ability, but did not show malignant characteristics in vitro. Immortalized cells continued to express homing molecules. The cell membranes of im-MSCs were taken up by glioma cells and targeted in situ gliomas in vivo, suggesting that im-MSCs and their plasma membranes can be used as natural drug carriers for targeting gliomas, and providing a safe, adequate, quality-controlled, and continuous source for the treatment of gliomas based on whole-cell or cell membrane carriers.

Glioblastoma multiforme (GBM) is the most aggressive and highly vascularized brain tumor with poor prognosis. Endothelial cell-dependent angiogenesis and tumor cell-dependent Vasculogenic mimicry (VM) synergistically contribute to glioma vascularization and progression. However, the mechanism underlying GBM vascularization remains unclear. In this study, GBM stem cells (GSCs) were divided into high and low β8 integrin (ITGB8) subpopulations. Co-culture assays followed by Cell Counting Kit-8 (CCK-8), migration, Matrigel tube formation, and sprouting assays were conducted to assess the proliferative, migratory and angiogenic capacity of GBM cells and human brain microvascular endothelial cells (hBMECs). An intracranial glioma model was constructed to assess the effect of ITGB8 on tumor vascularization in vivo. Our results indicated that ITGB8 expression was elevated in GSCs and positively associated with stem cell markers in glioma tissues, and could be induced by hypoxia and p38 activation. ITGB8 in GSCs inhibited the angiogenesis of hBMECs in vitro, while it promoted the ability of network formation and expression of VM-related proteins. The orthotopic GBM model showed that ITGB8 contributed to decreased angiogenesis, meanwhile enhanced invasiveness and VM formation. Mechanistic studies indicated that ITGB8-TGFβ1 axis modulates VM and epithelial-mesenchymal transition (EMT) process via Smad2/3-RhoA signaling. Together, our findings demonstrated a differential role for ITGB8 in the regulation of angiogenesis and VM formation in GBM, and suggest that pharmacological inhibition of ITGB8 may represent a promising therapeutic strategy for treatment of GBM.

Gliomas are the most common primary brain tumors with dismal prognoses. Temozolomide (TMZ), the frontline therapeutic agent for gliomas, has shown limited clinical benefit primarily due to the acquired chemoresistance. Although growing evidence has suggested that the multi-drug resistance phenotype and abnormal vascular microenvironment are responsible for the intrinsic and extrinsic TMZ resistance, the molecular mechanism of TMZ resistance remains to be elucidated. In this study, we found Paired-related homeobox 1 (Prrx1) was an independent prognostic factor for the efficacy of chemotherapy-based postoperative treatment. Silencing Prrx1 markedly enhanced the TMZ-induced cytotoxicity both in vitro and in vivo. We also demonstrated that Prrx1 increased the expression of ABCC1, a member of ATP-Binding Cassette (ABC) transporter protein family, through binding to the promoter region of ABCC1 gene and initiating its transcription. Silencing ABCC1 mitigated the TMZ resistance induced by Prrx1. Furthermore, Prrx1 facilitates the formation of vasculogenic mimicry (VM), a critical extrinsic mechanism for glioma TMZ resistance. Collectively, our findings supported the critical role of Prrx1 in TMZ resistance via intrinsic and extrinsic mechanism. Targeting Prrx1 might represent a feasible strategy to overcome therapeutic resistance in glioma.

Glioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.

Background Exosomes are membrane-bound extracellular vesicles of 40–150 nm in size, that are produced by many cell types, and play an important role in the maintenance of cellular homeostasis. Exosome secretion allows for the selective removal of harmful substances from cells. However, it remains unclear whether this process also takes place in glioma cells. Methods Herein, the role of the tumour-suppressor miR-375 was explored in human glioma cells. Immunoblotting and qRT-PCR experiments demonstrated a functional link between miR-375 and its target, connective tissue growth factor ( CTGF ), which led to the identification of the underlying molecular pathways. The exosomes secreted by glioma cells were extracted by ultracentrifugation and examined by transmission electron microscopy. Exosomal expression of miR-375 was then analysed by qRT-PCR; while the exosome secretion inhibitor, GW4869, was used to examine the biological significance of miR-375 release. Moreover, the dynamics of miR-375 release by glioma cells was investigated using fluorescently labelled exosomes. Finally, exosomal miR-375 release was examined in an orthotopic xenograft model in nude mice. Results MiR-375 expression was downregulated in gliomas. MiR-375 suppressed glioma proliferation, migration, and invasion by inhibiting the CTGF - epidermal growth factor receptor (EGFR) signalling pathway. MiR-375-containing exosomes were also identified in human peripheral blood samples from glioma patients, and their level correlated with disease progression status. Exosomal miR-375 secretion impacted the CTGF -EGFR pathway activity. Once secreted, exosomal miR-375 was not taken back up by glioma cells. Conclusions Exosomal miR-375 secretion allowed for sustained activation of the CTGF -EGFR oncogenic pathway, promoting the proliferation and invasion of glioma cells. These findings enhance our understanding of exosome biology and may inspire development of new glioma therapies.

Glioma is a devastating cancer with a rich vascular network. No anti-angiogenic treatment is available for prolonging the overall survival of glioma patients. Recent studies have demonstrated that the endothelial differentiation of glioma stem cells (GSCs) into glioma-derived endothelial cells (GDECs) may be a novel target for anti-angiogenic therapy in glioma; however, the underlying mechanisms of this process remain unknown. Here, we report that wingless-related integration site (WNT) family member 5A (WNT5A) plays significant roles in GSC endothelial differentiation and GDECs angiogenesis. WNT5A is preferentially secreted by GDECs, and inhibition of WNT5A suppresses angiogenesis and tumorigenesis in GDECs. Silencing of WNT5A in GDECs also disrupts the impact of GDECs on stimulating GSC endothelial differentiation. Frizzled-4 is a receptor that mediates the effect of WNT5A on GSC endothelial differentiation and angiogenesis of GDECs via GSK3β/β-catenin/epithelial-mesenchymal transition signalling. The shWNT5A@cRGD-DDD liposomes, targeting WNT5A, exert anti-angiogenic effects in vivo. In this study, we identified that WNT5A has a dual functional role in modulating the endothelial differentiation of GSCs and angiogenesis of GDECs, indicating that WNT5A is a potential target for anti-angiogenesis-based therapeutics in glioma.

目的 探讨改良经皮气管旋切术对重症脑出血昏迷患者手术指标、早期意识水平及生活质量的影响.方法 选取2016年1月～2020年2月广东省肇庆市怀集县人民医院神经外科收治的140例重症脑出血昏迷患者作为研究对象,以随机数字表法将其分为对照组与研究组,每组各70例.对照组行常规气管切开术,研究组行改良经皮气管旋切术.采用脑电双频指数(BIS)、格拉斯哥昏迷评分量表(GCS)评估两组患者的早期意识水平,采用生活质量量表(SF-36)评估两组患者的生活质量.随访3个月,比较两组患者的手术相关指标、早期意识水平以及术前、术后3个月的生活质量变化.结果 研究组患者的切口大小小于对照组,手术时间短于对照组,术中出血量、丙泊酚使用量少于对照组,差异有统计学意义(P＜0.05).研究组患者术后的BISmean、GCSmean与对照组比较,差异无统计学意义(P＞0.05);研究组患者术后的BISmax低于对照组,BISmin高于对照组,差异有统计学意义(P＜0.05).两组患者术前的生理职能、心理功能、认知功能、情绪功能、角色功能、总生活质量评分比较,差异无统计学意义(P＞0.05);术后3个月,两组患者的生理职能、心理功能、认知功能、情绪功能、角色功能、总生活质量评分高于本组术前,且研究组患者术后3个月的生理职能、心理功能、认知功能、情绪功能、角色功能、总生活质量评分高于对照组,差异有统计学意义(P＜0.05).结论 相对于常规气管切开术,改良经皮气管旋切术的手术操作时间较短,且切口小、术中出血量少、麻醉药物使用量较少,可更有效地改善重症脑出血昏迷患者的早期意识水平,提高患者生活质量.

Abstract Background: Exosomes are membrane-bound extracellular vesicles of 40–150 nm produced by many cell types, and playing an important role in the maintenance of cellular homeostasis. Exosome secretion allows for the selective removal of harmful substances from cells. Whether this process also takes place in glioma cells is unknown. Methods: The role of the tumour suppressor miR-375 was explored in human glioma cell lines. Immunoblotting and qRT-PCR experiments demonstrated a functional link between miR-375 and its target, connective tissue growth factor (CTGF), and led to identify the involved molecular pathways. The exosomes secreted by glioma cells were extracted by ultracentrifugation and examined by transmission electron microscopy. The exosomal expression of miR-375 was analyzed by qRT-PCR. The exosome secretion inhibitor, GW4869, was used to study the biological significance of miR-375 release. Moreover, the dynamics of miR-375 release by glioma cells was investigated by using fluorescently labelled exosomes. Finally, exosomal miR-375 release was studied in an orthotopic xenograft model in nude mice. Results: MiR-375 expression was downregulated in gliomas. MiR-375 suppressed glioma proliferation, migration, and invasion by inhibiting the CTGF-epidermal growth factor receptor (EGFR) signalling pathway. MiR-375-containing exosomes were also found in human peripheral blood samples from glioma patients, and their level was correlated with the status of disease progression. Exosomal miR-375 secretion had an impact on the activity of the CTGF-EGFR pathway. Once secreted, exosomal miR-375 was not reuptaken by glioma cells. Conclusions: Exosomal miR-375 secretion allowed for sustained activation of the CTGF-EGFR oncogenic pathway, promoting the proliferation and invasion of glioma cells. These findings enhance our understanding of exosome biology, and may inspire the development of new therapies for glioma.

脑膜瘤是常见的颅内肿瘤,大多数脑膜瘤为良性,生长缓慢,预后良好.然而即使全切除后,脑膜瘤仍有较高的复发率.随着影像学技术的发展,人们发现脑膜瘤的某些术前影像学特征即可在一定程度上预测其术后复发率.是否有重要结构受累、肿瘤的形状、瘤周水肿、脑膜尾征、磁共振成像特点等均是影响脑膜瘤术后复发的预测因素.本文将与脑膜瘤术后复发相关的术前影像学特征进行综述.

BACKGROUND:Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumor. We aim to explore the role of circRNA in glioma and elucidate how circRNA acts.METHODS:Real-time PCR was used to examine the expression of circPTN in glioma tissues and normal brain tissues (NBT). Assays of dual- luciferase reporter system, biotin label RNA pull-down and FISH were used to determine that circPTN could sponge miR-145-5p and miR-330-5p. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs). Cell counting Kit-8 (CCK8), EdU assay and flow cytometry were used to investigate proliferation and cell cycle. Intracranial xenograft was established to determine how circPTN impacts in vivo. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs).RESULTS:We demonstrated circPTN was significantly higher expression in glioma tissues and glioma cell lines, compared with NBT and HEB (human astrocyte). In gain- and loss-of-function experiments, circPTN significantly promoted glioma growth in vitro and in vivo. Furthermore, we performed dual-luciferase reporter assays and RNA pull-down assays to verify that circPTN acts through sponging miR-145-5p and miR-330-5p. Increasing expression of circPTN rescued the inhibition of proliferation and downregulation of SOX9/ITGA5 in glioma cells by miR-145-5p/miR-330-5p. In addition, we found that circPTN promoted self-renewal and increased the expression of stemness markers (Nestin, CD133, SOX9, and SOX2) via sponging miR-145-5p. Moreover, this regulation was disappeared when circPTN binding sites in miR-145-5p were mutated.CONCLUSIONS:Our results suggest that circPTN is an oncogenic factor that acts by sponging miR-145-5p/miR-330-5p in glioma.

Vasculogenic mimicry (VM) refers to the fluid-conducting channels formed by aggressive tumor cells rather than endothelial cells (EC) with elevated expression of genes associated with vascularization. VM has been considered as one of the reasons that glioblastoma becomes resistant to anti-VEGF therapy. However, the molecular basis underlying VM formation remains unclear. Here we report that the insulin-like growth factor–binding protein 2 (IGFBP2) acts as a potent factor to enhance VM formation in glioma. Evidence showed that elevated IGFBP2 expression was positively related with VM formation in patients with glioma. Enforced expression of IGFBP2 increased network formation of glioma cells in vitro by activating CD144 and MMP2 (Matrix Metalloproteinase 2). U251 cells with stable knockdown of IGFBP2 led to decreased VM formation and tumor progression in orthotopic mouse model. Mechanistically, IGFBP2 interacts with integrin α5 and β1 subunits and augments CD144 expression in a FAK/ERK pathway-dependent manner. Luciferase reporter and ChIP assay suggested that IGFBP2 activated the transcription factor SP1, which could bind to CD144 promoter. Thus, IGFBP2 acts as a stimulator of VM formation in glioma cells via enhancing CD144 and MMP2 expression.

The prognosis for human glioma, a malignant tumor of the central nervous system, is poor due to its rapid growth, genetic heterogeneity, and inadequate understanding of its underlying molecular mechanisms. Circular RNAs composed of exonic sequences, represent an understudied form of noncoding RNAs (ncRNAs) that was discovered more than a decade ago, function as microRNA sponges. We aimed to assess the relationship between circ-U2AF1 (CircRNA ID: hsa_circ_0061868) and hsa-mir-7-5p and examine their effects on proliferation, apoptosis, and the metastatic phenotype of glioma cells regulated by neuro-oncological ventral antigen 2 (NOVA2). We found that the expression levels of circ-U2AF1 and NOVA2 were upregulated, while hsa-miR-7-5p was downregulated in human glioma tissues and glioma cell lines. Our data and bioinformatic analysis indicated the association of these molecules with glioma grade, a positive correlation between circ-U2AF1 and NOVA2 expression levels and a negative correlation of hsa-miR-7-5p with both circ-U2AF1 and NOVA2, respectively. In addition, silencing of circ-U2AF1 expression resulted in increased hsa-miR-7-5p expression and decreased NOVA2 expression both in vitro and in vivo. Luciferase assay confirmed hsa-miR-7-5p as a direct target of circ-U2AF1 and NOVA2 as a direct target of hsa-miR-7-5p. Functionally, silencing of circ-U2AF1 inhibits glioma development by repressing NOVA2 via upregulating hsa-miR-7-5p both in vitro and in vivo. Thus, we assumed that circ-U2AF1 promotes glioma malignancy via derepressing NOVA2 by sponging hsa-miR-7-5p. Taken together, we suggest that circ-U2AF1 can be a prognostic biomarker and the circ-U2AF1/hsa-miR-7-5p/NOVA2 regulatory pathway may be a novel therapeutic target for treating gliomas.