Glioma Growth Research Articles

Overcoming multiple barriers to deliver photo-gene system for glioma-targeted combined therapy

Overcoming multiple barriers to deliver macromolecular drugs is an urgent challenge for glioma treatment. Herein, a strategy of protein corona-regulation synergizing with photoactivation based on T10 peptide-modified and indocyanine green (ICG)-loaded dendrigraft poly-L-lysines was proposed to augment prime editing therapy of glioma. First, the modified T10 peptide could escape the interference barrier of protein crown in blood via its specific binding with endogenous transferrin, thus crossing the blood-brain barrier (BBB) and achieving the targeting recognition of glioma cells. Next, the loaded ICG could weaken the tumor stromal barrier, decrease the cell membrane barrier and escape the lysosomal degradation/autophagy barrier via its photothermal and photodynamic effects. Subsequently, a therapeutic gene that could downregulate p-ERK1/2 for tumor growth inhibition and immunoregulation could be effectively delivered into the glioma cells. The glioma-targeted photo-gene combined immunotherapy effectively inhibit the glioma growth, especially co-dosing with the PD-1 antibody.

Procollagen C-protease enhancer protein promotes glioma growth by activating ERK signaling.

Procollagen C-proteinase enhancer (PCOLCE) promotes tumor progression in multiple cancers. However, the specific role of PCOLCE in gliomas remains enigmatic. In this study, we focused on analyzing PCOLCE expression and its correlation with clinicopathological parameters in glioma specimens; moreover, we explored the effects of PCOLCE in glioma proliferation in vitro and in vivo. A tissue microarray containing 159 human glioma specimens was pressed to explore the correlation between PCOLCE expression and the survival of glioma patients. Cell Counting Kit-8 (CCK8), colony formation, and immunoblot assays were used to detect the role of PCOLCE on cell proliferation in glioma. Furthermore, the in vivo role of PCOLCE was investigated using a subcutaneous glioma xenograft model. The expression of PCOLCE was higher in grade III and IV gliomas than in grade I and II gliomas. High PCOLCE expression was related to a remarkably worse prognosis in glioma patients. Additionally, PCOLCE downregulation impeded glioma cell proliferation. Furthermore, PCOLCE knockdown markedly abrogated p-ERK expression in glioma cells, whereas, it negligibly influenced p38 and JNK signaling. These results indicate that PCOLCE is a feasible prognostic biomarker for glioma, and PCOLCE-induced activation of ERK signaling may be a pro-growth mechanism in glioma cells.

Pan-cancer analysis and experimental validation of FPR3 as a prognostic and immune infiltration-related biomarker for glioma.

Formyl peptide receptor 3 (FPR3) is known to have implications in the progression of various cancer types. Despite this, its biological significance within pan-cancer datasets has yet to be investigated. In this investigation, we scrutinized FPR3's expression profiles, genetic alterations, prognostic significance, immune-related characteristics, methylation status, tumor mutation burden (TMB), and microsatellite instability (MSI) across different types of cancer. We utilized TISCH's single-cell data to identify immune cells closely associated with FPR3. The predictive significance of FPR3 was evaluated independently in gliomas using data from TCGA and CGGA datasets, leading to the development of a prognostic nomogram. Immunohistochemistry and Western blot analysis confirmed FPR3 expression in gliomas. Lastly, the CCK-8 and wound-healing assays were employed to assess the impact of FPR3 on the proliferation and metastasis of GBM cell lines. In numerous cancer types, heightened FPR3 expression correlated with adverse outcomes, immune cell infiltration, immune checkpoints, TMB, and MSI. In glioma, FPR3 emerged as a notable risk factor, with the prognostic model effectively forecasting patient results. The potential biological relevance of FPR3 was confirmed in glioma, and it was shown to have significant involvement in the processes of glioma growth, immune infiltration, and metastasis. Our results imply a potential association of FPR3 with tumor immunity, indicating its viability as a prognostic indicator in glioma.

Emerging Role of the Slit/Roundabout (Robo) Signaling Pathway in Glioma Pathogenesis and Potential Therapeutic Options

Gliomas represent the most common primary Central Nervous System (CNS) tumors, characterized by increased heterogeneity, dysregulated intracellular signaling, extremely invasive properties, and a dismal prognosis. They are generally resistant to existing therapies and only a few molecular targeting options are currently available. In search of signal transduction pathways with a potential impact in glioma growth and immunotherapy, the Slit guidance ligands (Slits) and their Roundabout (Robo) family of receptors have been revealed as key regulators of tumor cells and their microenvironment. Recent evidence indicates the implication of the Slit/Robo signaling pathway in inflammation, cell migration, angiogenesis, and immune cell infiltration of gliomas, suppressing or promoting the expression of pivotal proteins, such as cell adhesion molecules, matrix metalloproteinases, interleukins, angiogenic growth factors, and immune checkpoints. Herein, we discuss recent data on the significant implication of the Slit/Robo signaling pathway in glioma pathology along with the respective targeting options, including immunotherapy, monoclonal antibody therapy, and protein expression modifiers.

Novel therapies for pediatric low grade glioma.

Current biological findings provide new insights into the genetics driving growth of low-grade gliomas in pediatric patients. This has provided new targets for novel therapies. The purpose of this paper is to review novel therapies for pediatric low-grade gliomas that have been published in the past 24 months. Low-grade gliomas are often driven by mitogen activated protein kinase (MAPK) alterations either with BRAF V600E point mutations or BRAF fusions. Current advances have also highlighted novel fusions of fibroblast growth factor receptor (FGFR), myeloblastosis family of transcription factors (MYB), meningioma 1 tumor suppressor (MN1), neurotrophic receptor kinase family of receptors (NTRK), Kristen RAS (Rat Sarcoma Virus) oncogene homolog in mammals (KRAS), Receptor tyrosine kinase ROS proto oncogene 1 (ROS1), protein kinase C alpha (PRKCA), and platelet derive growth factor receptor (PDGFR) amplification. Novel therapies have been employed and are showing encouraging results in pediatric low-grade gliomas. Current trials are underway with newer generation pan RAF inhibitors and mitogen activated protein kinase - kinase (MEK) inhibitors. Other early phase clinical trials have provided safety data in pediatric patients targeting FGFR fusion, NTRK fusion, PDGFR amplification and ROS1 mutations. Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.

Cholinergic Neuronal Activity Promotes Diffuse Midline Glioma Growth through Muscarinic Signaling.

Neuronal activity promotes the proliferation of healthy oligodendrocyte precursor cells (OPC) and their malignant counterparts, gliomas. Many gliomas arise from and closely resemble oligodendroglial lineage precursors, including diffuse midline glioma (DMG), a cancer affecting midline structures such as the thalamus, brainstem and spinal cord. In DMG, glutamatergic and GABAergic neuronal activity promotes progression through both paracrine signaling and through bona-fide neuron-to-glioma synapses. However, the putative roles of other neuronal subpopulations - especially neuromodulatory neurons located in the brainstem that project to long-range target sites in midline anatomical locations where DMGs arise - remain largely unexplored. Here, we demonstrate that the activity of cholinergic midbrain neurons modulates both healthy OPC and malignant DMG proliferation in a circuit-specific manner at sites of long-range cholinergic projections. Optogenetic stimulation of the cholinergic pedunculopontine nucleus (PPN) promotes glioma growth in pons, while stimulation of the laterodorsal tegmentum nucleus (LDT) facilitates proliferation in thalamus, consistent with the predominant projection patterns of each cholinergic midbrain nucleus. Reciprocal signaling was evident, as increased activity of cholinergic neurons in the PPN and LDT was observed in pontine DMG-bearing mice. In co-culture, hiPSC-derived cholinergic neurons form neuron-to-glioma networks with DMG cells and robustly promote proliferation. Single-cell RNA sequencing analyses revealed prominent expression of the muscarinic receptor genes CHRM1 and CHRM3 in primary patient DMG samples, particularly enriched in the OPC-like tumor subpopulation. Acetylcholine, the neurotransmitter cholinergic neurons release, exerts a direct effect on DMG tumor cells, promoting increased proliferation and invasion through muscarinic receptors. Pharmacological blockade of M1 and M3 acetylcholine receptors abolished the activity-regulated increase in DMG proliferation in cholinergic neuron-glioma co-culture and in vivo. Taken together, these findings demonstrate that midbrain cholinergic neuron long-range projections to midline structures promote activity-dependent DMG growth through M1 and M3 cholinergic receptors, mirroring a parallel proliferative effect on healthy OPCs.

Rosmarinic acid attenuates glioblastoma cells and spheroids’ growth and EMT/stem-like state by PTEN/PI3K/AKT downregulation and ERK-induced apoptosis

BackgroundGlioblastoma (GB) is a highly malignant type of brain cancer with a poor prognosis. Therapeutic strategies for GB are still limited. Rosmarinic acid (RA), a polyphenolic compound, is a promising experimental anticancer agent, but its specific protein targets for GB remain unclear. PurposeThis study aimed to elucidate the anticancer effects of RA in 2D- and 3D-GB cells and the underlying mechanisms. Methods3D-tumor spheroids (mimics in vivo tumors) were obtained by the hanging-drop/agarose method. RA's anti-glioma activity on U-87MG (p53-wt/PTEN-mt) and LN229 (p53-mt/PTEN-wt) cells was evaluated through cell viability, colony-formation, migration/invasion/angiogenesis assays, fluorescence imaging, and spheroid growth analysis. The underlying mechanism of the anticancer effects of RA was investigated by Western blot and immunofluorescence analysis. The MEK inhibitor U0126 was used to block ERK phosphorylation. ResultsRA treatments exerted anti-proliferative and pro-apoptotic effects on human GB cells. RA dose-dependently reduced angiogenesis and intracellular ROS levels, suppressed glioma growth, and migration/invasion in 2D-culture and cancer stem cell (CSC)-like 3D-spheroid culture (SPC). Repeated therapy in SPC was more effective by leading to disrupted structure than a single treatment. Treatments in SPC also suppressed epithelial-mesenchymal transition (EMT) and CSC-like properties. Strikingly, RA downregulated the SIRT1/FOXO1/NF-κB axis independently of p53 or PTEN function in both gliomas. Immunofluorescence labeling revealed decreased SIRT1 and NF-κB-p65 and increased FOXO1 and GAPDH proteins in nuclear location (associated with apoptosis). Surprisingly, RA increased p-ERK1/2 levels, but priming with U0126 abolished RA-mediated p-ERK upregulation; thus, autophagy and apoptosis induction in GB cells were prevented, and the growth of GB spheroids accelerated. Specifically, RA also inhibited the PTEN/PI3K/AKT pathway in U-87MG cells. Due to genetic differences in cells, U-87MG cells were more sensitive to RA treatments than LN229 cells. Meanwhile, our positive control drug trial results with FDA-approved temozolomide (TMZ) used in GB treatment showed that our test compound rosmarinic acid exhibited higher therapeutic effects than TMZ at lower doses. ConclusionSuppression of EMT, downregulation of SIRT1/FOXO1/NF-κB axis, inhibition of PTEN/PI3K/AKT signaling pathway, and ERK-induced apoptosis and autophagy were determined to be involved in stopping glioma progression. Our findings for the first time, revealed that RA may have potential therapeutic use by having multiple targets in human brain cancer with further clinical studies.

Glial Malignancies.

Gliomas comprise a diverse spectrum of related tumor subtypes with varying biological and molecular features and clinical outcomes. Advances in detailed genetic and epigenetic characterizations along with an appreciation that subtypes associated with developmental origins, including brain location and patient age, have shifted glioma classification from the historical reliance on histopathological features to updated categories incorporating molecular signatures and spatiotemporal incidence. Within a subtype, individual gliomas show cellular heterogeneity, generally containing subpopulations resembling different types of normal glial and progenitor cells. In addition to tumor-autonomous mechanisms of aberrant growth regulation driven by genetic mutations and signaling between tumor cells, interactions with the tumor microenvironment, including neurons, astrocytes, oligodendrocyte precursor cells, and the immune microenvironment play important roles in driving glioma growth and influencing response to treatment. The emerging understanding of the complex contributions of normal brain to glioma growth represents new opportunities for therapeutic advances.

Unlocking the potential of LHPP: Inhibiting glioma growth and cell cycle via the MDM2/p53 pathway

The recurrence of glioma after treatment has remained an intractable problem for many years. Recently, numerous studies have explored the pivotal role of the mouse double minute 2 (MDM2)/p53 pathway in cancer treatment. Lysine phosphate phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a newly discovered tumor suppressor, has been confirmed in numerous studies on tumors, but its role in glioma remains poorly understood. Expression matrices in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were analyzed using gene set enrichment analysis (GSEA), revealing significant alterations in the p53 pathway among glioma patients with high LHPP expression. The overexpression of LHPP in glioma cells resulted in a reduction in cell proliferation, migration, and invasive ability, as well as an increase in apoptosis and alterations to the cell cycle. The present study has identified a novel inhibitory mechanism of LHPP against glioma, both in vivo and in vitro. The results demonstrate that LHPP exerts anti-glioma effects via the MDM2/p53 pathway. These findings may offer a new perspective for the treatment of glioma in the clinic.

Oleanonic acid inhibits glioma growth by inactivating STAT3 via upregulating SIRT6 in nude mice

Oleanonic acid inhibits glioma growth by inactivating STAT3 via upregulating SIRT6 in nude mice

The tumorigenic effect of the high expression of ABRACL in glioma and its potential as a therapeutic target

Gliomas are the most common malignant intracranial tumors, with no effective treatments. Better understanding and identification of novel targets are urgently warranted. Actin-binding Rho activating C-terminal like (ABRACL) has been reported as an oncogene in several cancer types. However, the potential roles of ABRACL in the tumorigenesis of malignant glioma remain unknown. We discovered that ABRACL is highly expressed in different sub-types of gliomas in both CGGA and TCGA databases, which was further validated in glioblastoma cell lines and normal human astrocyte lines. RT-qPCR, Western blotting and immunohistochemistry demonstrated that ABRACL expression in glioma tissues was upregulated along with the increasing WHO grades. Further survival analysis of glioma patients also revealed that the overall survival of patients in the ABRACL high expression level group were significantly shorter than those in the low expression level group. Knockdown of ABRACL inhibited the proliferation, cell migration, invasion and cytodynamics behaviors in glioma cell lines via activating STAT3 signaling, which also induced apoptosis and cell cycle arrest. Conversely, overexpressing ABRACL promoted cell renewing and migration, enabled more flexible cell deformation, supporting ABRACL being a bona fide oncogene. Intracranial orthotopic xenograft experiment further confirmed that ABRACL downregulation significantly suppressed glioma growth. These results have demonstrated that the tumorigenic effect of ABRACL is partly mediated by STAT3, whose expression also correlates with clinical prognosis. ABRACL facilitates glioma malignancy phenotype through regulating the cytoskeleton by activating STAT3 pathway, suggesting that it may represent a potential therapeutic target for glioblastoma.

TLR agonists promote formation of Tertiary Lymphoid Structure and improve anti-glioma immunity.

Glioma, characterized by limited lymphocytic infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study aims to explore therapeutic strategies for inducing tertiary lymphoid structure (TLS) formation within the glioma microenvironment (GME) to transition it from an immune-resistant to an activated state. TLS formation in GME was successfully induced by intracranial administration of Toll-like receptor (TLR) agonists (OK-432, TLR2/4/9 agonist) and glioma antigens (i.c. αTLR-mix). We employed staining analysis, antibody neutralization, single-cell RNA sequencing (scRNA-Seq), and BCR/TCR sequencing to investigate the underlying mechanisms of TLS formation and its role in anti-glioma immunity. Additionally, a preliminary translational clinical study was conducted. TLS formation correlated with increased lymphocyte infiltration in GME and led to improved prognosis in glioma-bearing mice. In the study of TLS induction mechanisms, certain macrophages/microglia and Th17 displayed markers of "LTo" and "LTi" cells, respectively, interaction through LTα/β-LTβR promoted TLS induction. Post-TLS formation, CD4+ and CD8+ T cells but not CD19+ B cells contributed to anti-glioma immunity. Comparative analysis of B/T cells between brain and lymph node showed that brain B/T cells unveiled switch from naïve to mature, some B cells highlighted an enrichment of CSR-associated genes, V gene usage and clonotype bias were observed. In related clinical studies, i.c. αTLR-mix treatment exhibited tolerability, and chemokines/cytokines assay provided preliminary evidence supporting TLS formation in GME. TLS induction in GME enhanced anti-glioma immunity, improved the immune microenvironment, and controlled glioma growth, suggesting potential therapeutic avenues for treating glioma in the future.

Juglone suppresses vasculogenic mimicry in glioma through inhibition of HuR-mediated VEGF-A expression

Vasculogenic mimicry (VM) serves as a vascular-like channel that provides important substances for tumor growth and is a primary factor in glioblastoma (GBM) drug resistance. Human Antigen R (HuR)—an mRNA-binding protein—is highly expressed in GBM, closely related to tumor progression, and deemed a potential drug target. Although some small-molecule compounds have been identified to disrupt HuR binding to target mRNA, they remain in the preclinical research stage, suggesting the need for further validation and development of HuR inhibitors. In our study, we aim to screen for potential HuR inhibitors and investigate their efficacy and molecular mechanisms in GBM. We employed the fluorescence polarization method to identify HuR inhibitors from a natural compound library, confirming the efficacy of juglone in effectively inhibiting the binding of HuR to AREVegf-a. Further validation of the binding of juglone to HuR at the protein level was conducted through electrophoretic mobility shift analysis, surface plasmon resonance, and molecular docking. Furthermore, juglone demonstrated inhibitory effects on glioma growth and VM formation in vitro and in vivo. Moreover, it was observed that juglone reversed epithelial-mesenchymal transition by inhibiting the VEGF-A/VEGFR2/AKT/SNAIL signaling pathway. Finally, we established the capability of juglone to target HuR in U251 cells through HuR knockdown, mRNA stability, and cell thermal shift assays. Therefore, this study identifies juglone as a novel HuR inhibitor, potentially offering promise as a lead compound for anti-VM therapy in GBM by targeting HuR.Abbreviations: AKT, protein kinase B; ARE, adenine-and uridine-rich elements; CETSA, cellular thermal shift assay; DMEM, Dulbecco’s modified Eagle’s medium; ELISA, enzyme linked immune sorbent assay; EMSA, electrophoretic mobility shift assay; EMT, epithelial mesenchymal transition; FP, fluorescence polarization; GBM, glioblastoma; HTS, high-throughput screening; HuR, human antigen R; IF, Immunofluorescence; PAS, periodic acid-Schiff; PI3K, phosphoinositide-3 kinase; qRT-PCR, quantitative real-time PCR; RRMs, RNA recognition motifs; SPR, surface plasmon resonance. TMZ, temozolomide; VM, vasculogenic mimicry; VEGF-A, Vascular endothelial growth factor-A; VEGFR2, Vascular endothelial growth factor receptor-2.

Neurosteroids in Glioma: A Novel Therapeutic Concept.

Glioma, a diverse group of brain and spinal cord tumors arising from glial cells, is characterized by varying degrees of malignancy, with some types exhibiting highly aggressive behavior, rapid proliferation, and invasive growth patterns, posing significant therapeutic challenges. This review delves into the complex interactions between glioma cells, neurotransmitters, and neurosteroids, emphasizing their potential as therapeutic targets. Key neurotransmitters, like glutamate and gamma-aminobutyric acid (GABA), play crucial roles in glioma growth, invasion, and treatment response. This review examines the involvement of neurosteroids in glioma biology and explores innovative therapeutic strategies targeting these systems. It encompasses the biosynthesis and mechanisms of neurosteroids, interactions between gliomas and neurotransmitters, the spatial distribution of neurosteroid synthesis in gliomas, the role of ion channels, hormonal influences, enzyme modulation, and the neuroimmune system in glioma progression. Additionally, it highlights the potential of neurosteroids to modulate these pathways for therapeutic benefit.

Cordycepin inhibits glioma growth by downregulating PD-L1 expression via the NOD-like receptor/NFKB1/STAT1 axis

Glioma is a serious primary malignant tumor of the human central nervous system with a poor prognosis and a high recurrence rate; however, inhibition of immune checkpoints can greatly improve the survival rate of patients. The purpose of this study was to investigate the regulation of PD-L1 by cordycepin and the mechanism of its anti-tumor action. The results of previous studies indicate that cordycepin has good anti-proliferative and anti-migratory activities and can induce apoptosis in U251 and T98G cells in vitro. Here, transcriptome sequencing showed that cordycepin may exert anti-tumor effects through the NOD-like receptor signaling pathway. Further intervention with BMS-1, a small molecule inhibitor of PD-L1, was used to explore whether inhibition of PD-L1 affected the regulation of the NOD-like receptor signaling pathway by cordycepin. Mechanistically, on the one hand, cordycepin regulated the expression of NFKB1 and STAT1 through the NOD-like receptor signaling pathway, thereby inhibiting the expression of PD-L1. In addition, inhibition of PD-L1 enhanced the regulation by cordycepin of the NOD-like receptor signaling pathway. On the other hand, cordycepin directly upregulated expression of STAT1 and downregulated that of PD-L1. In vivo studies further showed that cordycepin could downregulate expression of PD-L1 and NFKB1 and upregulate that of STAT1 in glioma xenograft tumor tissues, consistent with the results of in vitro studies. The results suggest that cordycepin may down-regulate the expression of PD-L1 through NOD-like receptor signaling pathway and NFKB signaling pathway, thereby inhibiting the immune escape of glioma, and can be developed as a PD-L1 inhibitor. Our results therefore provide a theoretical foundation for the use of cordycepin in treatment of glioma and enrich our understanding of its pharmacological mechanism.

Sodium alginate hydrogel encapsulating microglia cell lysate subjected to serum starvation for mitigating glioma cells.

Glioma is the most common malignant tumor in the brain, accounting for over 80% of all primary intracranial tumors. The current clinical treatment has shown certain limitations. Although M1 type microglia can secrete various pro-inflammatory cytokines and are expected to be used for glioma treatment, direct use of microglia may lead to overactivation and trigger immune storms. Therefore, we first found that serum starvation can stimulate the transformation of microglia into M1 type. Subsequently, we found through comparative experiments that the inhibitory effect of microglial cell lysis medium on glioma cells was stronger than that of microglial cell culture medium. Finally, we successfully prepared sodium alginate hydrogel loaded with microglia lysis solution to achieve sustained inhibitory effect on the growth of glioma and avoid its proliferation.

Patient-Centered Management of Brain Tumor-Related Epilepsy.

Brain tumor-related epilepsy is a heterogenous syndrome involving variability in incidence, timing, pathophysiology, and clinical risk factors for seizures across different brain tumor pathologies. Seizure risk and disability are dynamic over the course of disease and influenced by tumor-directed treatments, necessitating individualized patient-centered management strategies to optimize quality of life. Recent translational findings in diffuse gliomas indicate a dynamic bidirectional relationship between glioma growth and hyperexcitability. Certain non-invasive measures of hyperexcitability are correlated with survival outcomes, however it remains uncertain how to define and measure clinically relevant hyperexcitability serially over time. The extent of resection, timing of pre-operative and/or post-operative seizures, and the likelihood of tumor progression are critical factors impacting the risk of seizure recurrence. Newer anti-seizure medications are generally well-tolerated with similar efficacy in this population, and several rapid-onset seizure rescue agents are in development and available. Seizures in patients with brain tumors are strongly influenced by the underlying tumor biology and treatment. An improved understanding of the interactions between tumor cells and the spectrum of hyperexcitability will facilitate targeted therapies. Multidisciplinary management of seizures should occur with consideration of tumor-directed therapy and prognosis, and anti-seizure medication decision-making tailored to the individual priorities and quality of life of the patient.

Increased oxygen stimulation promotes chemoresistance and phenotype shifting through PLCB1 in gliomas

Gliomas, the most common CNS (central nerve system) tumors, face poor survival due to severe chemoresistance exacerbated by hypoxia. However, studies on whether altered hypoxic conditions benefit for chemo-sensitivity and how gliomas react to increased oxygen stimulation are limited. In this study, we demonstrated that increased oxygen stimulation promotes glioma growth and chemoresistance. Mechanically, increased oxygen stimulation upregulates miR-1290 levels. miR-1290, in turn, downregulates PLCB1, while PLCB1 facilitates the proteasomal degradation of β-catenin and active-β-catenin by increasing the proportion of ubiquitinated β-catenin in a destruction complex-independent mechanism. This process inhibits PLCB1 expression, leads to the accumulation of active-β-catenin, boosting Wnt signaling through an independent mechanism and ultimately promoting chemoresistance in glioma cells. Pharmacological inhibition of Wnt by WNT974 could partially inhibit glioma volume growth and prolong the shortened survival caused by increased oxygen stimulation in a glioma-bearing mouse model. Moreover, PLCB1, a key molecule regulated by increased oxygen stimulation, shows promising predictive power in survival analysis and has great potential to be a biomarker for grading and prognosis in glioma patients. These results provide preliminary insights into clinical scenarios associated with altered hypoxic conditions in gliomas, and introduce a novel perspective on the role of the hypoxic microenvironment in glioma progression. Furthermore, the outcomes reveal the potential risks of utilizing hyperbaric oxygen treatment (HBOT) in glioma patients, particularly when considering HBOT as a standalone option to ameliorate neuro-dysfunctions or when combining HBOT with a single chemotherapy agent without radiotherapy.

Retraction: MiR-205 suppresses epithelial-mesenchymal transition and inhibits tumor growth of human glioma through downregulation of HOXD9.

Retraction: MiR-205 suppresses epithelial-mesenchymal transition and inhibits tumor growth of human glioma through downregulation of HOXD9.

CHI3L1 as a Prognostic Biomarker and Therapeutic Target in Glioma.

The role of Chitinase-3-like protein 1 (CHI3L1) in tumor progression has been gradually clarified in different kinds of solid tumors. Hence, we aim to elucidate its prognostic value for glioma. In this study, we analyzed RNA sequencing data combined with corresponding clinical information obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed genes (DEGs) were acquired based on CHI3L1 expression profiles and were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Cox regression, least absolute shrinkage and selection operator (LASSO) regression methods, along with a nomogram, were employed to establish a predictive model. Compared with the corresponding non-tumor tissues, CHI3L1 expression was significantly upregulated in various types of solid tumors, correlating with poor clinical outcomes including glioma. GO analysis identified oxidative stress-related genes (ORGs) that were differentially expressed and modulated by CHI3L1, with 11 genes subsequently identified as potential predictors, using Univariate-Cox regression and LASSO regression. In addition, an index of oxidative stress-related genes (ORGI) was established, demonstrating its prognostic value in conjunction with CHI3L1 expression. The aberrant expression of CHI3L1 was proved in glioma patients through immunohistochemistry (IHC). Meanwhile, the knockdown of CHI3L1 inhibited glioma growth in vitro, and real-time Quantitative PCR (qPCR) confirmed decreased ORG expression upon CHI3L1 knockdown, suggesting the potential prognostic value of CHI3L1 as a therapeutic target for glioma.