Glioma Development Research Articles

NIMG-31. PROPOSED ORIGINS AND PATHWAYS OF DIFFUSE GLIOMAS REVEALED BY LESION COVARIANCE NETWORKS

Abstract Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone and develop along previously healthy brain networks. Here, we evaluated these hypotheses by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers, and large-scale connectivity networks. Using lesion data from a total of 410 patients with high- and low-grade glioma, we identified – and replicated in an independent sample – three lesion covariance networks (LCNs), which reflect clusters of frequent glioma localization. These three LCNs overlapped with the anterior, posterior, and inferior horns of the lateral ventricles respectively, extending into the frontal, parietal, and temporal cortices. The first LCN, which overlapped with the anterior horn, was associated with low-grade, IDH-mutated/1p19q-codeleted tumors, as well as a neural transcriptomic signature and improved overall survival. Each LCN significantly coincided with multiple structural and functional connectivity networks, with LCN1 bearing an especially strong relationship with brain connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each LCN. These results build upon prior reports of glioma growth along white matter pathways, as well as evidence for the coordination of glioma stem cell proliferation by neuronal activity. Cumulatively, our findings support a model wherein periventricular brain connectivity guides glioma development from the subventricular zone into distributed brain regions.

Deletion of miR-15a inhibited glioma development via targeting Smad7 and inhibiting EMT pathway.

In the present study, we found the expression of miR-15a-5p (miR-15a) was increased in glioma tissues, and we further explore the underlying mechanism of miR-15a in glioma progression. Microarray analysis used to identify the differentially expressed microRNAs (miRNAs) in glioma tissues. The expression of miR-15a in glioma tissues and cell lines was tested by qRT-PCR. Luciferase assay was used to determine the binding between miR-15a and Smad7. Wound healing and transwell assay were used to examine the role of miR-15a/Smad7 in SHG139 cells. Western blot was used to detect the protein level of Smad7 and epithelial-mesenchymal transition (EMT) markers. A tumor formation model in nude mice was established to measure the role of miR-15a in vivo. MiR-15a was significantly increased in glioma tissues and cells, which indicated a poor prognosis of glioma patients. MiR-15a mimics induced miR-15a level in SHG139 cells, and promoted the malignancy of SHG139 cells, while miR-15a inhibitor showed the opposite effects. Luciferase assay indicated that Smad7 was the direct target of miR-15a, and Smad7 was down-regulated in glioma tissues. Functional experiments revealed that miR-15a inhibitor inhibited the EMT pathway and the migration and invasion of glioma cells, but the silencing of Smad7 reversed the effects of miR-15a inhibitor in EMT pathway and glioma progression. Finally, we performed animal experiments to verify the role of miR-15a in vivo. Present study showed that deletion of miR-15a inhibited the activation of EMT signaling via targeting Smad7, thus suppressed the tumorigenesis and tumor growth of glioma.

The Expression and Prognostic Value of ILK and YAP1 in Glioma

Integrin-linked kinase (ILK) is a widely expressed serine/threonine-protein kinase that has been implicated in cancer development, progression, and metastasis. Yes-associated protein (YAP), as the most important effector of Hippo signaling pathway, which is considered to be a tumor suppressor pathway, acts as an oncogene in a variety of human cancers. The present study aimed to explore the expression of ILK and YAP1, the relationship between them, and the effect of ILK, YAP1 on prognosis in gliomas. Immunohistochemistry was used to examine the expression of ILK and YAP1. The χ2 test analyzes the relationship between ILK, YAP1, and pathologic parameters. The Spearman correlation analyzes the relationship between ILK and YAP1. Survival analysis was used to investigate the effect of ILK and YAP1 on prognosis. High expression of ILK was associated with the age above 50 (P=0.003), higher World Health Organization (WHO) grade (P<0.001), recurrence (P<0.001), and Ki-67 expression≥10% (P<0.001). High expression of YAP1 was associated with higher WHO grade (P<0.001), recurrence (P=0.043), and Ki-67 expression ≥10% (P=0.037). In lower grade gliomas, the high expression rate of ILK in isocitrate dehydrogenase 1 wild-type was higher than that in isocitrate dehydrogenase 1 mutant (P=0.048). The high expression rate of YAP1 in 1p19q non-codeletion was higher than that in 1p19q codeletion (P=0.022). There was a positive correlation between ILK and YAP1 (r=0.344). The patients with high expression of ILK and YAP1 had worse OS and PFS. As an upstream factor of the Hippo signaling pathway, ILK may affect the development and prognosis of gliomas by regulating YAP1.

The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.

While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development.

Ventricle wall resection contributes to supramaximal resection and prognosis in SVZ-involved frontal gliomas: A single center retrospective study

BackgroundFrontal glioma frequently invaded the subventricular zone (SVZ), which existed glioma stem cells and might be involved in the development of primary and recurrent gliomas. We attempted to identify whether ventricle wall resection contributed to the maximal extent of resection (EOR) and increased the patient’s survival during frontal glioma resection. MethodsA total of 151 adult patients with primary SVZ-involved frontal gliomas were obtained between January 2012 and December 2018. We analyzed clinical data, EOR, complications and survival profiles between the ventricle wall group and the ventricle intact/opening group. ResultsApplying ventricle wall removal had similar effect on the improvement of neurological function compared to applying ventricle intact/opening and did not increase the incidence of new neurological deficits, hydrocephalus, and ependymal dissemination in SVZ-involved frontal gliomas. A positive correlation was identified between EOR and the ventricle wall handling (r = 0.487, P < 0.001), which indicated that ventricle wall resection could contribute to achieve supramaximal resection. Applying supramaximal resection and ventricle wall resection could significantly prolong overall survival and progression free survival. Ventricle wall resection could be regarded as an independent prognostic indicator for both overall survival and progression free survival in patients with SVZ-involved frontal gliomas. ConclusionsVentricle wall resection in SVZ-involved frontal gliomas could contribute to achieve supramaximal resection and could significantly prolong overall survival and progression free survival.

LncRNA CDKN2B-AS1 contributes to glioma development by regulating the miR-199a-5p/DDR1 axis.

Although cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) is upregulated in glioma, its function and potential mechanism in glioma remain unclear. CDKN2B-AS1 level in glioma tissues and cell lines LN229, U251, and U87 was measured by qRT-PCR. Loss-of-function assays using short hairpin RNA for CDKN2B-AS1 (sh-CDKN2B-AS1) were performed to evaluate the effect of CDKN2B-AS1 on cell invasion, migration, proliferation, and apoptosis. The relationship among CDKN2B-AS1, miR-199a-5p, and DDR1 was determined by bioinformatics analysis and luciferase reporter assay. Rescue experiments were conducted to explore the function of CDKN2B-AS1 and miR-199a-5p in glioma. An in vivo animal model of lentivirally transduced U87 glioma xenografts in mice was established to confirm the role of CDKN2B-AS1. CDKN2B-AS1 is significantly upregulated in glioma tissues and cell lines. CDKN2B-AS1 knockdown significantly inhibits cell proliferation, invasion, and migration, while promoting apoptosis of glioma cell lines U251 and U87. Further, a miR-199a-5p inhibitor attenuates the inhibitory effects of sh-CDKN2B-AS1 on these cell phenotypes. CDKN2B-AS1 positively regulates DDR1 expression by directly sponging miR-199a-5p. Moreover, CDKN2B-AS1 knockdown efficiently inhibits U87 tumor xenograft growth in mice. Our study reveals that CDKN2B-AS1 promotes glioma development by regulating the miR-199a-5p/DDR1 axis, suggesting that this lncRNA might be a potential therapeutic target.

IFI30 as a prognostic biomarker and correlation with immune infiltrates in glioma.

BackgroundIncreased evidence indicates that the tumour microenvironment (TME) plays an essential role in the development, treatment and prognosis of glioma. High expression of interferon-gamma-inducible protein 30 (IFI30) is associated with the malignant phenotype, but the effect of IFI30 on the tumour immune microenvironment and its potential role in the carcinogenesis of glioma remain unknown.MethodsThe RNA sequencing (RNA-seq) data of 33 types of human cancer were obtained from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC). R software was used to perform analyses, such as the expression of IFI30 in pan-cancer, evaluation of IFI30 as a prognostic biomarker in glioma, the relationship between IFI30 expression and clinical characteristics, and immune checkpoint. TIMER was used to analyse the correlation of IFI30 expression level with immune cell infiltration, and also to conduct survival analysis for immune cells and IFI30 in low grade glioma (LGG). DAVID was used for Gene Ontology (GO) functional annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway analysis of the genes similar to IFI30 in glioma. The differentially expressed genes (DEGs) between the high- and low-IFI30 expression groups were determined by DESeq2. Gene set enrichment analysis (GSEA) was then conducted to identify IFI30-related functional significance based on the hallmark gene set.ResultsDysregulated expression of IFI30 was associated with human cancers. High IFI30 expression was associated with poor overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI). Univariate and multivariate analyses identified IFI30 as an independent predictor for glioma. Meanwhile, IFI30 overexpression significantly correlated with high-grade tumours, poor OS, and immune infiltration. In addition, IFI30-associated genes significantly enriched the hallmark tumour progression-related clusters and cancer pathways.ConclusionsIFI30 is a prognostic biomarker correlated with immune infiltrates and acts as an oncogene in glioma.

LncRNA LINC01094 contributes to glioma progression by modulating miR-224-5p/CHSY1 axis.

Glioma serves as the most common malignancy influencing modern people and is associated with severe morbidity and high mortality. Long non-coding RNAs (lncRNAs) as crucial regulators participate in multiple cancer progression. However, the role of lncRNA LINC01094 in the development of glioma remains unclear. Here, we aimed to explore the effect of lncRNA LINC01094 on the glioma progression and the underlying mechanism. Significantly, we revealed that the expression levels of LINC01094 were elevated in the glioma patient tissues compared to adjacent normal tissues. The LINC01094 expression was enhanced in the glioma cell lines. The depletion of LINC01094 inhibited cell viability and colony formation in the glioma cells. Meanwhile, the migration and invasion of glioma cells were impaired by the depletion of LINC01094. Mechanically, we identified that LINC01094 was able to sponge the miR-224-5p in the glioma cells and miR-224-5p inhibitor could reverse the effect of LINC01094 on glioma progression. In addition, miR-224-5p targeted CHSY1 and LINC01094 up-regulated CHSY1 by targeting miR-224-5p in the glioma cells. LINC01094 promoted glioma progression by the positive regulation of CHSY1. Moreover, tumorigenicity analysis showed that LINC01094 enhanced tumor growth of glioma in vivo. Thus, we conclude that lncRNA LINC01094 promotes glioma progression by modulating miR-224-5p/CHSY1 axis. Our finding provides new insights into the mechanism by which lncRNA LINC01094 contributes to the development of glioma, improving the understanding of lncRNA LINC01094 and glioma. LncRNA LINC01094, miR-224-5p, and CHSY1 may serve as potential targets for glioma.

MicroRNA-25 promotes cell proliferation, migration and invasion in glioma by directly targeting cell adhesion molecule 2.

Numerous microRNAs (miRNAs/miRs) have been demonstrated to serve oncogenic or suppressive roles in glioma. Exploration of the underlying molecular mechanism of miRNAs in the development and progression of glioma is beneficial for the identification of novel therapeutic targets. In the present study, the function of miR-25 in glioma progression, as well as its underlying mechanism, were investigated. It was determined that miR-25 was significantly upregulated in glioma tissues and cell lines compared with normal brain tissues and cells, respectively. Furthermore, high expression levels of miR-25 were associated with an advanced clinical stage. The knockdown of miR-25 expression significantly reduced glioma cell proliferation, migration and invasion. Cell adhesion molecule 2 (CADM2) was identified as a direct target of miR-25 in glioma cells. Moreover, CADM2 expression level was significantly downregulated and inversely correlated with miR-25 expression level in glioma tissues, indicating that the expression of CADM2 was negatively regulated by miR-25. The inhibition of CADM2 expression counteracted the effects on glioma cell proliferation, migration and invasion caused by miR-25 downregulation. Furthermore, CADM2 knockdown considerably promoted the proliferation and migration of glioma cells. In summary, the present study demonstrated that miR-25 was significantly upregulated in glioma and that it promoted glioma cell proliferation, migration and invasion, at least partially, by directly targeting CADM2. These findings expanded the understanding of the molecular mechanism that underlies glioma progression.

History of atopy confers improved outcomes in IDH mutant and wildtype lower grade gliomas.

A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. 374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5months, p = 00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85months, p = 0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p = 0.002, HR 0.257, 95% 0.109-0.604), (p = < 0.001, HR 0.217, 95% 0.107-0.444), and (p = 0.004, HR 2.72, 95% 1.373-5.397), respectively. In terms of treatment outcomes, patients with atopy did not differ in treatment response compared to their counterpart. Pathway analysis demonstrated an upstream activation of the BDNF pathway (p = 0.00027). A history of atopy confers a survival benefit in patients with diffuse low-grade glioma. Activation of the BDNF pathway may drive the observed differences.

Glioma cell-derived FGF20 suppresses macrophage function by activating β-catenin

Macrophages, which are the main regulators of the tumor-associated microenvironment, play a crucial role in the progression of various tumors. The anti-inflammatory role of β-catenin in macrophages has been extensively studied in recent years. However, the association between macrophages and β-catenin with regards to the development of glioma has not yet been investigated, at least to the best of our knowledge. The present study found that fibroblast growth factor 20 (FGF20), as a paracrine cytokine, was secreted by glioma cells and acted on macrophages. FGF20 treated macrophages exhibited a decreased pro-inflammatory phenotype upon LPS and IFN-γ stimulation, characterized by the decreased the level of M1 macrophage markers and the reduced production of pro-inflammatory cytokines. Mechanistic analysis revealed that FGF20 interacted with FGF receptor 1 isoform of macrophages, and subsequently increased the stability of β-catenin via phosphorylating GSK3β, which suppressed macrophage polarization to the M1-phenotype. Finally, it was found that FGF20 of glioma cells expression was upregulated by the glucocorticoids (GCs) treatment, and decreased FGF20 expression of glioma cells markedly blocked the effects of GCs on the polarization of macrophages. On the whole, the present study demonstrates that FGF20, secreted from glioma cells, participates the GCs regulated macrophage function and exerts anti-inflammatory effects during the treatment of glioma by GCs. Moreover, a molecular link was identified between glioma cells and macrophages, demonstrating that FGF20 modulates the GCs-induced dysfunction of macrophages during glioma development.

CRNDE/ETS1/GPR17 Facilitates the Proliferation, Migration, and Invasion of Glioma.

Background Numerous lncRNAs were found as regulatory factors for occurrence and progression of various tumors, but there is still less research on the role of lncRNAs in malignant progression of glioma. Methods Bioinformatics analysis analyzed differential genes (DEGs) in the TCGA database. MTT, flow cytometry, and Transwell assays were performed to test the proliferation, apoptosis, migration, and invasion of cells. qRT-PCR and western blot were conducted to detect RNA and protein expressions of each gene, respectively. CHIP assay verified the binding relationship between genes. FISH assayed subcellar location of CRNDE, and xenograft in nude mice was performed for in vivo verification. Results CRNDE was upregulated in glioma cells, and overexpression of CRNDE facilitated malignant progression of glioma cells. CRNDE regulated occurrence and development of glioma through the CRNDE-ETS1-GPR17 axis. ETS1 was proved to target promoter region of GPR17. Overexpression of CRNDE promoted the binding between ETS1 and the promoter region of GPR17, thus, promoting the transcription of GPR17, while silencing of GPR17 inhibited promotion of CRNDE on proliferation, migration, and invasion of glioma cells. Conclusions These results demonstrated that CRNDE regulated GPR17 expression by binding ETS1, a transcription factor, thereby affecting glioma development. The results also indicated that CRNDE could serve as a possible therapeutic target and prognostic biomarker for glioma.

Downregulation of STOX1 is a novel prognostic biomarker for glioma patients.

Storkhead box 1 (STOX1) is a winged helix transcription factor structurally and functionally related to the forkhead family of transcription factors. Recent studies have highlighted its role in the central nervous system and revealed hints in the development of glioma. However, the expression profiles of STOX1, its association with clinicopathological characteristics, and potential functions in glioma remain unknown. In this study, we analyzed three publicly available datasets including CGGA, TCGA, and Rembrandt and revealed a grade-dependent reduction in STOX1 expression in glioma (P < 0.001). Chi-square test demonstrated that low STOX1 expression was significantly associated with older age at initial diagnosis (P < 0.001), less IDH1 mutation (P < 0.001), and advanced WHO grade (P < 0.001). Moreover, multivariate Cox regression analysis showed that STOX1 expression may serve as a novel independent prognostic biomarker in glioma patients. Bioinformatic functional analysis (GSEA) predicted that STOX1 was related to many key cancer pathways including P53 signaling pathway (P < 0.01), DNA replication (P < 0.05), homologous recombination (P < 0.05), and Wnt signaling pathway (P < 0.05). Taken together, these findings suggested that STOX1 may be used as a novel predictive molecular biomarker for glioma grading and overall patient survival. Further investigations on the functional roles and therapeutic value of STOX1 in glioma are warranted.

Spatial Glioma Distribution and Development of Post-Radiation Injury: The Left Temporal Region

Post-radiation injury, such as early pseudoprogression or late-onset radionecrosis, is a relatively common finding after high-dose radiotherapy and occurs in 20%-30% of glioma patients treated with cranial radiotherapy. This side effect often leads to a treatment dilemma, as it can be difficult to distinguish from tumor progression on MRI. Associated risk factors are radiation dose and chemotherapeutic treatment. However, not much is known about the role of tumor location in development of these lesions. Therefore, we aimed to explore the spatial distribution, in location as well as volume, of glioma in relation to development of post-radiation injury.In a retrospective database of 144 adult cases of histologically confirmed WHO grade II-IV supratentorial gliomas, we identified 73 patients who received first surgery in 2012 till 2014 with postoperative MRI within 3 days, and subsequent radiotherapy with a follow-up of at least 6 months. Tumors were manually delineated on pre-operative T1 contrast-enhanced (T1-CE) MRI and location and volume were registered. Among the 73 patients, 15 had tumors which were not delineable on T1-CE, due to lack of clear contrast enhancement, and were thus excluded. Post-radiation injury lesions were defined as new enhancements on CE-T1 MRI which stabilized or decreased after at least 3 months follow-up. These lesions were investigated with regard to pre-operative tumor location and size. Tumor location was investigated after transformation to MNI space and determined with the neuroanatomical atlas by Neuromorphometrics Inc. and subsequently classified by frontal, insular, parietal, temporal and occipital involvement of either hemisphere.Incidence of tumors with and without post-radiation injury lesions did not differ between hemispheres. When considering tumor location, however, involvement of the left temporal region was significantly associated with development of post-radiation injury (P = 0.012). Pre-operative volumetric tumor size was not associated with development of post-radiation injury.Tumor location may predispose for post-radiation injury, either by local processes or factors involving prior surgical treatment. Our study showed a significantly increased occurrence of post-radiation injury in the left temporal region. Thorough examination of the spatial distribution of tumors and subsequent complications might be useful in further exploring etiology and eventually guiding treatment decisions.

FAM87A as a Competing Endogenous RNA of miR-424-5p Suppresses Glioma Progression by Regulating PPM1H.

Far less has been unveiled about the functions of lncRNAs on cancers yet. Here, we reported that lncRNA FAM87A, as a ceRNA of miR-424-5p, played a vital role in glioma development. qRT-PCR result indicated that FAM87A was abnormally downregulated in glioma tissue and cells. Survival analysis suggested that the FAM87A expression was negatively correlated with the survival rate. Effects of FAM87A on human glioma cell lines were also analyzed by MTT, Edu, and transwell assays. FAM87A hastened proliferation and migration of glioma cells. MiR-424-5p, predicted target of FAM87A, was fostered in glioma, which was examined by qRT-PCR. A negative correlation was indicated between FAM87A and miR-424-5p. Results of bioinformatics, dual luciferase, and RIP assays unveiled that FAM87A and miR-424-5p act upon each other. In addition, miR-424-5p targeted 3′-UTR of PPM1H. Also, effects of miR-424-5p/FAM87A on glioma cells were identified via the cell function experiments. FAM87A suppressed PPM1H by binding to miR-424-5p competitively, thereby restraining cell proliferation, migration, and invasion. Collectively, these findings illuminated a new mechanism for glioma progression. Therefore, FAM87A may act as a feasible target for glioma treatment.

MicroRNA-30e-3p inhibits glioma development and promotes drug sensitivity to temozolomide treatment via targeting canopy FGF signaling regulator 2

ABSTRACT Glioma is one of the most aggressive malignancies in the central nervous system and the prognosis of glioma patients remains poor. In this study, we investigated the function of microRNA-30e-3p (miR-30e-3p) in glioma development and its regulatory role in drug-resistance to temozolomide (TMZ). We found that miR-30e-3p was downregulated in glioma tissues and cell lines. Ectopic expression of miR-30e-3p inhibited the growth of glioma cells and arrested cell cycle at G0/G1 phase. Canopy FGF signaling regulator 2 (CNPY2) was predicted as a direct target of miR-30e-3p by bioinformatics analysis. Luciferase reporter assay confirmed the interaction between miR-30e-3p and CNPY2. We also demonstrated that miR-30e-3p suppressed glioma xenograft tumor development in vivo and the inhibition was abolished by CNPY2 overexpression. In addition, we showed that overexpression of miR-30e-3p enhanced the sensitivity of glioma cell to TMZ treatment. Glioma cells with miR-30e-3p overexpression had decreased cell proliferation and enhanced cell apoptosis upon TMZ treatment. Moreover, we revealed that miR-30e-3p modulated TMZ sensitivity of glioma cells via negatively regulating CNPY2. Taken together, our findings demonstrate that miR-30e-3p plays a critical role in glioma development and drug sensitivity to TMZ treatment via negatively regulating CNPY2 expression. The study suggests that miR-30e-3p/CNPY2 could be developed as a novel target to improve the glioma therapy. Abbreviations: miR-30e-3p, microRNA-30e-3p; TMZ, temozolomide; CNPY2, canopy FGF signaling regulator 2; 3ʹ-UTR, 3ʹ untranslated region; NC, negative control.

PBX2-Mediated circTLK1 Activates JAK/STAT Signaling to Promote Gliomagenesis via miR-452-5p/SSR1 Axis.

Glioma is considered one of the most lethal brain tumors, as the aggressive blood vessel formation leads to high morbidity and mortality rates. However, the mechanisms underlying the initiation and progression of glioma remain unclear. Here, we aimed to reveal the role of circTLK1 in glioma development. Our results revealed that circTLK1 is highly expressed in glioma tumor tissues and glioma cell lines. We then conducted a series of experiments that showed that circTLK1 was involved in the progression of gliomas. Mechanistically, investigation of the factors downstream of circTLK1 revealed that circTLK1 activated JAK/STAT signaling in glioma cells. Furthermore, AGO2-RIP, RNA-pull down, and luciferase reporter gene assays led to the identification of the novel circTLK1/miR-452-5p/SSR1 axis. Moreover, we investigated the upstream regulator of circTLK1 and found that circTLK1 expression in glioma cells could be regulated by the transcriptional factor PBX2. Taken together, our findings show that circTLK1 mediated by PBX2 activates JAK/STAT signaling to promote glioma progression through the miR-452-5p/SSR1 pathway. These results provide new insights into glioma diagnosis and therapy.

Construction of a novel microRNA-based signature for predicting the prognosis of glioma

Background and purpose: Glioma is a frequent primary brain tumor. MicroRNAs (miRNA) have been shown to potentially play a crucial part in tumor development. Based on miRNAs and clinical factors, a model was constructed to predict the glioma prognosis. Methods: The miRNA expression profiles of glioma come from The Cancer Genome Atlas (TCGA, training group) and Chinese Glioma Genome Atlas (CGGA, validation group). Regression analyses of Cox and Lasso were applied to identity miRNAs associated with glioma prognosis in the TCGA database. The miRNAs were combined with clinical factors to construct individualized prognostic prediction models, whose performance was validated in the CGGA database. The role of miRNA in glioma development was investigated by in vitro experiments. Results: We identified five key miRNAs associated with glioma prognosis and constructed a prediction model. The area under ROC curve for predicting 3-year survival of glioma patients in the TCGA and CGGA groups was 0.844 and 0.770, respectively. The nomogram constructed using the miRNA risk scores and clinical factors showed high accuracy of prediction in the TCGA group (C-index of 0.820) and the CGGA group (C-index of 0.722). The miR-196b-5p altered the migration, proliferation, invasion, and apoptosis of glioma cells by regulating target genes, according to in vitro experiments. Conclusions: A miRNA-based individualized prognostic prediction model was constructed for glioma and miR-196b-5p was identified as a potential biomarker of glioma development.

A Novel Six Autophagy-Related Genes Signature Associated With Outcomes and Immune Microenvironment in Lower-Grade Glioma.

Since autophagy and the immune microenvironment are deeply involved in the tumor development and progression of Lower-grade gliomas (LGG), our study aimed to construct an autophagy-related risk model for prognosis prediction and investigate the relationship between the immune microenvironment and risk signature in LGG. Therefore, we identified six autophagy-related genes (BAG1, PTK6, EEF2, PEA15, ITGA6, and MAP1LC3C) to build in the training cohort (n = 305 patients) and verify the prognostic model in the validation cohort (n = 128) and the whole cohort (n = 433), based on the data from The Cancer Genome Atlas (TCGA). The six-gene risk signature could divide LGG patients into high- and low-risk groups with distinct overall survival in multiple cohorts (all p < 0.001). The prognostic effect was assessed by area under the time-dependent ROC (t-ROC) analysis in the training, validation, and whole cohorts, in which the AUC value at the survival time of 5 years was 0.837, 0.755, and 0.803, respectively. Cox regression analysis demonstrated that the risk model was an independent risk predictor of OS (HR > 1, p < 0.05). A nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its robust predictive capacity. KM analysis revealed a significant difference in the subgroup analyses’ survival. Functional enrichment analysis revealed that these autophagy-related signatures were mainly involved in the phagosome and immune-related pathways. Besides, we also found significant differences in immune cell infiltration and immunotherapy targets between risk groups. In conclusion, we built a powerful predictive signature and explored immune components (including immune cells and emerging immunotherapy targets) in LGG.

Establishment and validation of five autophagy-related signatures for predicting survival and immune microenvironment in glioma.

Gliomas, especially Glioblastoma multiforme, are the most frequent type of primary tumors in central nervous system. Increasing researches have revealed the relationship between autophagy and tumor, while the molecular mechanism of autophagy in glioma is still rarely reported. Our research aims to conform the autophagy-related genes (ARGs) implicated in the development and progression of glioma and improve our understanding of autophagy in glioma. 20 candidate ARGs were screened through the protein-protein interaction network. We also downloaded the publicly accessible glioma data for 665 individuals from TCGA and 970 individuals from CGGA with RNA sequences and clinicopathological information. Subsequently, univariate and multivariate Cox regression analysis identified 5 key ARGs among the 20 candidate genes as key prognostic genes for survival, GSEA and immune response analysis. ATG5, BCL2L1, CASP3, CASP8, GAPDH were identified as key ARGs in our research. Further studies showed that the high-risk population was linked to a dismal prognosis and suggested an immune-inhibitory microenvironment. GSEA results demonstrated that high risk population was closely related to DNA repair, hypoxia pathways, implicated in immunosuppression and carcinogenesis. Through CMap, we finally identified 14 candidate drugs for the ARG high risk population. This study established and verified an ARG risk model, which can serve as an independent predictor for prognosis, reflect on the strength of the immune response and predict the potential drugs in glioma. Our findings offer new understandings of ARG molecular mechanism and promising therapeutic targets for glioma treatment.