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Annals of Medicine Dec 2023Low-grade glioma (LGG), which is the second most frequent adult brain malignancy, severely threatens patients' health and has a high recurrence rate. Histone H3/H4...
AIM
Low-grade glioma (LGG), which is the second most frequent adult brain malignancy, severely threatens patients' health and has a high recurrence rate. Histone H3/H4 chaperone anti-silencing function 1 B () has a tight association with the initiation and development of tumours. The expression and regulation mechanism of in LGG were discussed.
METHODS
expression in LGG patients as well as the association of with overall survival and disease-free survival of LGG patients were predicted by GEPIA database. The independent prognostic value of ASF1B in LGG patients was investigated by TCGA database. RT-qPCR, together with western blot was applied for the assessment of ASF1B in LGG cell lines. After expression was inhibited, CCK8 and colony formation assays judged cell proliferation. Flow cytometry analysis and TUNEL assay appraised cell cycle as well as apoptosis. Cell migratory and invasive capacities were measured by wound healing as well as Transwell assays. Western blot tested the expression of proliferation-, cycle-, apoptosis-, and metastasis-associated proteins. STRING and GeneMANIA database predicted the relationship between and tousled-like kinase 1 (. ChIP assay testified the affinity of with Subsequently, was overexpressed and expression interfered, and the functional assays were executed.
RESULTS
was discovered to be increased in LGG tissues and cells and indicates an unfavourable prognosis for LGG patients. was not an independent prognostic factor for LGG. deficiency obstructed the proliferation, cell cycle as well as metastasis of LGG cells, and induced cell death, which might be realized through the interaction with .
CONCLUSION
The interaction between and promoted the malignant progression of LGG.Key messagesTLK1 interacts with ASF1B.Interference with ASF1B inhibits the proliferative, invasive and migratory capabilities and induces the cycle arrest, along with the apoptosis of LGG cells.The interaction between ASF1B and TLK1 promotes the malignant progression of LGG.
Topics: Adult; Humans; Cell Cycle Proteins; Histones; Cell Proliferation; Glioma; Brain Neoplasms; Protein Serine-Threonine Kinases
PubMed: 36947060
DOI: 10.1080/07853890.2023.2169751 -
BMC Cancer Oct 2023Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The transfer RNA-derived fragments (tRFs) are a new group of small noncoding RNAs, which are...
BACKGROUND
Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The transfer RNA-derived fragments (tRFs) are a new group of small noncoding RNAs, which are dysregulated in many cancers. Until now, the expression and function of tRFs in glioma remain unknown.
METHODS
The expression profiles of tRF subtypes were analyzed using the Cancer Genome Atlas (TCGA)-low-grade gliomas (LGG)/GBM dataset. The target genes of tRFs were subjected to Gene Ontology, Kyoto Encyclopedia and Gene set enrichment analysis of Genes and Genomes pathway enrichment analysis. The protein-protein interaction enrichment analysis was performed by STRING. QRT-PCR was performed to detect the expressions of tRFs in human glioma cell lines U87, U373, U251, and human astrocyte cell line SVG p12. Western blot assay was used to detect to the expression of S100A11. The interaction between tRF-19-R118LOJX and S100A11 mRNA 3'UTR was detected by dual-luciferase reporter assay. The effects of tRF-19-R118LOJX, tRF-19-6SM83OJX and S100A11 on the glioma cell proliferation, migration and in vitro vasculogenic mimicry formation ability were examined by CCK-8 proliferation assay, EdU assay, HoloMonitor cell migration assay and tube formation assay, respectively.
RESULTS
tRF-19-R118LOJX and tRF-19-6SM83OJX are the most differentially expressed tRFs between LGG and GBM groups. The functional enrichment analysis showed that the target genes of tRF-19-R118LOJX and tRF-19-6SM83OJX are enriched in regulating blood vessel development. The upregulated target genes are linked to adverse survival outcomes in glioma patients. tRF-19-R118LOJX and tRF-19-6SM83OJX were identified to suppress glioma cell proliferation, migration, and in vitro vasculogenic mimicry formation. The mechanism of tRF-19-R118LOJX might be related to its function as an RNA silencer by targeting the S100A11 mRNA 3'UTR.
CONCLUSION
tRFs would become novel diagnostic biomarkers and therapeutic targets of glioma, and the mechanism might be related to its post-transcriptionally regulation of gene expression by targeting mRNA 3'UTR.
Topics: Humans; 3' Untranslated Regions; RNA, Transfer; Cell Line; Cell Differentiation; Glioma
PubMed: 37864150
DOI: 10.1186/s12885-023-11532-8 -
Scientific Reports Aug 2023Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor. Conventional treatments have not achieved breakthroughs in improving survival. Therefore, novel...
Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor. Conventional treatments have not achieved breakthroughs in improving survival. Therefore, novel molecular targets and biomarkers need to be identified. As signal transduction docks on the cell membrane, tetraspanins (TSPANs) are associated with various tumors; however, research on their role in GBM remains extremely scarce. Gene expression and clinicopathological characteristic data were obtained from GEPIA, CGGA, HPA, cBioPortal, and GSCA databases to analyze the mRNA and protein expression levels, prognostic value, clinical relevance, mutation status, and targeted drug sensitivity of TSPANs in GBM. Gene set enrichment analysis (GSEA), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for biological process enrichment. Data from TCGA and TCIA were used to construct the tumor immune microenvironment landscape of TSPANs. Different R software algorithms were used to analyze the immune score, immune cell infiltration, and immune checkpoint correlation. Univariate and multivariate analyses were performed for TSPAN4, which had the most significant predictive prognostic value, and a nomogram model was constructed to predict individual outcomes. The expression and function of TSPAN4 were verified in vitro. TSPAN3/4/6/11/12/18/23/24/25/26/27/28/29/30/31expressions were significantly upregulated in GBM, and TSPAN3/4/6/11/18/24/25/26/29/30 were strongly correlated with prognosis. The expression of multiple TSPANs significantly correlated with 1p/19q co-deletion status, IDH mutation status, recurrence, age, and tumor grade. GSEA and GO analyses revealed the potential contribution of TSPANs in cell adhesion and migration. Immune correlation analysis revealed that TSPANs are related to the formation of the GBM tumor microenvironment (TME) and may influence immunotherapy outcomes. TSPAN4 is an independent prognostic factor and TSPAN4 knockdown has been demonstrated to strongly inhibit glioma cell proliferation, invasion, and migration in vitro. We comprehensively elaborated the prognostic value and potential role of differentially expressed TSPANs in GBM, including molecules that scientists have previously overlooked. This study provides a novel and comprehensive perspective on the pathological mechanisms of GBM and the future direction of individualized tumor immunotherapy, which may be a critical link between GBM malignant progression and TME remodeling.
Topics: Humans; Glioblastoma; Tumor Microenvironment; Prognosis; Glioma; Nomograms
PubMed: 37587203
DOI: 10.1038/s41598-023-40425-w -
Aging Sep 2023Glioblastoma (GBM) is a highly malignant brain cancer with a poor prognosis despite standard treatments. This investigation aimed to explore the feasibility of PTPN6 to...
Glioblastoma (GBM) is a highly malignant brain cancer with a poor prognosis despite standard treatments. This investigation aimed to explore the feasibility of PTPN6 to combat GBM with immunotherapy. Our study employed a comprehensive analysis of publicly available datasets and functional experiments to assess PTPN6 gene expression, prognostic value, and related immune characteristics in glioma. We evaluated the influence of PTPN6 expression on CD8+ T cell exhaustion, immune suppression, and tumor growth in human GBM samples and mouse models. Our findings demonstrated that PTPN6 overexpression played an oncogenic role in GBM and was associated with advanced tumor grades and unfavorable clinical outcomes. In human GBM samples, PTPN6 upregulation showed a strong association with immunosuppressive formation and CD8+ T cell dysfunction, whereas, in mice, it hindered CD8+ T cell infiltration. Moreover, PTPN6 facilitated cell cycle progression, inhibited apoptosis, and promoted glioma cell proliferation, tumor growth, and colony formation in mice. The outcomes of our study indicate that PTPN6 is a promising immunotherapeutic target for the treatment of GBM. Inhibition of PTPN6 could enhance CD8+ T cell infiltration and improve antitumor immune response, thus leading to better clinical outcomes for GBM patients.
Topics: Humans; Animals; Mice; Glioblastoma; Glioma; Brain Neoplasms; Prognosis; Cell Proliferation; Cell Line, Tumor; Protein Tyrosine Phosphatase, Non-Receptor Type 6
PubMed: 37737713
DOI: 10.18632/aging.205052 -
Journal of Hematology & Oncology May 2024Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby... (Review)
Review
Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45 cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
Topics: Humans; Tumor Microenvironment; Brain Neoplasms; Myeloid-Derived Suppressor Cells; Glioma; Glioblastoma; Animals; Immunotherapy; T-Lymphocytes, Regulatory
PubMed: 38720342
DOI: 10.1186/s13045-024-01544-7 -
MGMT Promoter Methylation Predicts Overall Survival after Chemotherapy for 1p/19q-Codeleted Gliomas.Clinical Cancer Research : An Official... Nov 2023While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3...
PURPOSE
While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggest that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated.
EXPERIMENTAL DESIGN
We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010 to 2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, comorbidity, grade, extent of resection, chemotherapy, and radiotherapy.
RESULTS
We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared with mMGMT [70% {95% confidence interval (CI), 64%-77%} vs. 81% (95% CI, 78%-85%); P < 0.001; adjusted HR (aHR), 2.35 (95% CI, 1.77-3.14)]. uMGMT was associated with worse survival in patients who received chemotherapy [63% (95% CI, 55-73%) vs. 80% (95% CI, 76%-84%); P < 0.001; aHR, 2.61 (95% CI, 1.89-3.60)] but not in patients who did not receive chemotherapy [P = 0.38; HR, 1.31 (95% CI, 0.71-2.42)]. Similar results were observed regardless of World Health Organization grade and after single- or multiagent chemotherapy.
CONCLUSIONS
Our study demonstrates an association between mMGMT and OS in 1p/19q-codeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.
Topics: Humans; Brain Neoplasms; Methylation; Glioma; Prognosis; Glioblastoma; DNA Methylation; Isocitrate Dehydrogenase; DNA Repair Enzymes; DNA Modification Methylases; Tumor Suppressor Proteins
PubMed: 37611077
DOI: 10.1158/1078-0432.CCR-23-1295 -
Neoplasia (New York, N.Y.) Sep 2023Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and...
Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.
Topics: Humans; Child; Diffuse Intrinsic Pontine Glioma; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Glioma
PubMed: 37603953
DOI: 10.1016/j.neo.2023.100921 -
Tomography (Ann Arbor, Mich.) May 2024Despite their relatively low incidence globally, central nervous system (CNS) tumors remain amongst the most lethal cancers, with only a few other malignancies... (Review)
Review
Despite their relatively low incidence globally, central nervous system (CNS) tumors remain amongst the most lethal cancers, with only a few other malignancies surpassing them in 5-year mortality rates. Treatment decisions for brain tumors heavily rely on histopathological analysis, particularly intraoperatively, to guide surgical interventions and optimize patient outcomes. Frozen sectioning has emerged as a vital intraoperative technique, allowing for highly accurate, rapid analysis of tissue samples, although it poses challenges regarding interpretive errors and tissue distortion. Raman histology, based on Raman spectroscopy, has shown great promise in providing label-free, molecular information for accurate intraoperative diagnosis, aiding in tumor resection and the identification of neurodegenerative disease. Techniques including Stimulated Raman Scattering (SRS), Coherent Anti-Stokes Raman Scattering (CARS), Surface-Enhanced Raman Scattering (SERS), and Tip-Enhanced Raman Scattering (TERS) have profoundly enhanced the speed and resolution of Raman imaging. Similarly, Confocal Laser Endomicroscopy (CLE) allows for real-time imaging and the rapid intraoperative histologic evaluation of specimens. While CLE is primarily utilized in gastrointestinal procedures, its application in neurosurgery is promising, particularly in the context of gliomas and meningiomas. This review focuses on discussing the immense progress in intraoperative histology within neurosurgery and provides insight into the impact of these advancements on enhancing patient outcomes.
Topics: Humans; Spectrum Analysis, Raman; Neurosurgical Procedures; Brain Neoplasms; Glioma; Microscopy, Confocal
PubMed: 38787014
DOI: 10.3390/tomography10050054 -
Frontiers in Immunology 2024Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal....
INTRODUCTION
Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/β-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)-including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes.
METHODS
Using multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated cytostatic effects and a switch from proliferation to differentiation after treatment with ICG-001.
RESULTS
In these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/β-catenin target gene a hallmark of Wnt/CBP/β-catenin inhibition. We found that in a syngeneic mouse model of glioma (K-luc), ICG-001 treatment enhanced tumor infiltration by CD3 and CD8 cells with increased expression of the vascular endothelial marker CD31 (PECAM-1). We also observed differential gene expression and induced immune cell infiltration in tumors pretreated with ICG-001 and then treated with CAR T cells as compared with single treatment groups or when ICG-001 treatment was administered after CAR T cell therapy.
DISCUSSION
We conclude that specific Wnt/CBP/β-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients.
Topics: Humans; Animals; Mice; beta Catenin; Wnt Signaling Pathway; Neoplasm Recurrence, Local; Immunotherapy; Glioma; Tumor Microenvironment
PubMed: 38449858
DOI: 10.3389/fimmu.2024.1342625 -
BMC Medical Genomics Jul 2023Gliomas are tumours arising mostly from astrocytic or oligodendrocytic precursor cells. These tumours are classified according to the updated WHO classification from...
BACKGROUND
Gliomas are tumours arising mostly from astrocytic or oligodendrocytic precursor cells. These tumours are classified according to the updated WHO classification from 2021 in 4 grades depending on molecular and histopathological criteria. Despite novel multimodal therapeutic approaches, the vast majority of gliomas (WHO grade III and IV) are not curable. The circadian clock is an important regulator of numerous cellular processes and its dysregulation had been found during the progression of many cancers, including gliomas.
RESULTS
In this study, we explore expression patterns of clock-controlled genes in low-grade glioma (LGG) and glioblastoma multiforme (GBM) and show that a set of 45 clock-controlled genes can be used to distinguish GBM from normal tissue. Subsequent analysis identified 17 clock-controlled genes with a significant association with survival. The results point to a loss of correlation strength within elements of the circadian clock network in GBM compared to LGG. We further explored the progression patterns of mutations in LGG and GBM, and showed that tumour suppressor APC is lost late both in LGG and GBM. Moreover, HIF1A, involved in cellular response to hypoxia, exhibits subclonal losses in LGG, and TERT, involved in the formation of telomerase, is lost late in the GBM progression. By examining multi-sample LGG data, we find that the clock-controlled driver genes APC, HIF1A, TERT and TP53 experience frequent subclonal gains and losses.
CONCLUSIONS
Our results show a higher level of disrgulation at the gene expression level in GBM compared to LGG, and indicate an association between the differentially expressed clock-regulated genes and patient survival in both LGG and GBM. By reconstructing the patterns of progression in LGG and GBM, our data reveals the relatively late gains and losses of clock-regulated glioma drivers. Our analysis emphasizes the role of clock-regulated genes in glioma development and progression. Yet, further research is needed to asses their value in the development of new treatments.
Topics: Humans; Brain Neoplasms; Circadian Clocks; Glioma; Glioblastoma; Mutation
PubMed: 37400829
DOI: 10.1186/s12920-023-01585-w