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Neuro-oncology Jun 2018A rational treatment strategy for glioma, the most common primary central nervous system tumor, should focus on early invasive growth and resistance to current... (Review)
Review
A rational treatment strategy for glioma, the most common primary central nervous system tumor, should focus on early invasive growth and resistance to current therapeutics. Connexin 43 (Cx43), a gap junction protein, plays important roles not only in the development of the central nervous system and but also in the progression of glioma. The different structural domains of Cx43, including extracellular loops, transmembrane domains, and an intracellular carboxyl terminal, have distinct functions in the invasion and proliferation of gliomas. Targeting these domains of Cx43, which is expressed in distinct patterns in the heterogeneous glioma cell population, can inhibit tumor cell invasion and new tumor formation. Thus, this review summarizes the structural characteristics of Cx43, the effects of regulating different Cx43 domains on the biological characteristics of glioma cells, intervention strategies targeting different domains of Cx43, and future research directions.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Connexins; Glioma; Humans; Molecular Targeted Therapy; Prognosis; Protein Domains
PubMed: 29106645
DOI: 10.1093/neuonc/nox207 -
Brain and Behavior Dec 2022We attempted to investigate influence of microRNA-433-3p on malignant progression of glioma and identify its molecular mechanism, thus laying groundwork for glioma...
OBJECTIVE
We attempted to investigate influence of microRNA-433-3p on malignant progression of glioma and identify its molecular mechanism, thus laying groundwork for glioma management.
METHODS
Expression data along with clinical data of glioma were accessed from the TCGA database for differential and survival analyses to look for the target differentially expressed genes. Quantitative reverse transcriptase PCR (qRT-PCR) and western blot were utilized to assess NR5A2 mRNA and protein expression in different glioma cell lines, respectively. MTT, Transwell assay, and flow cytometry were carried out to assay the impact of NR5A2 on behaviors of glioma cells in vitro. Bioinformatics analysis was used to identify the upstream microRNA of NR5A2 in glioma, while dual-luciferase and western blot assays were used to detect binding of microRNA and NR5A2. Chemosensitivity of glioma cells was evaluated by cisplatin cytotoxicity test.
RESULTS
NR5A2 was upregulated in both glioma tissues and cell lines. Dual-luciferase assay result showed binding site of microRNA-433-3p on NR5A2 mRNA 3'UTR, and microRNA-433-3p reduced NR5A2 expression. Cell assays revealed that silencing NR5A2 could hamper proliferation, invasion, and migration and enhance chemosensitivity to cisplatin while promoting glioma cell apoptosis and blocking glioma cells in G0/G1 phase. Rescue experiments also indicated that microRNA-433-3p suppressed glioma malignant progression via inhibiting NR5A2.
CONCLUSION
MicroRNA-433-3p which is significantly poorly expressed in glioma targets NR5A2 to suppress glioma malignant progression and enhance chemosensitivity to cisplatin.
Topics: Humans; Cisplatin; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Glioma; MicroRNAs; Apoptosis; RNA, Messenger; Cell Proliferation; Receptors, Cytoplasmic and Nuclear
PubMed: 36303447
DOI: 10.1002/brb3.2632 -
Cells Dec 2022The fatal clinical course of human glioblastoma (GBM) despite aggressive adjuvant therapies is due to high rates of recurrent tumor growth driven by tumor cells with...
The fatal clinical course of human glioblastoma (GBM) despite aggressive adjuvant therapies is due to high rates of recurrent tumor growth driven by tumor cells with stem-cell characteristics (glioma stem cells, GSCs). The aldehyde dehydrogenase 1 (ALDH1) family of enzymes has been shown to be a biomarker for GSCs, and ALDH1 seems to be involved in the biological processes causing therapy resistance. Ferroptosis is a recently discovered cell death mechanism, that depends on iron overload and lipid peroxidation, and it could, therefore, be a potential therapeutic target in various cancer types. Since both ALDH1 and ferroptosis interact with lipid peroxidation (LPO), we aimed to investigate a possible connection between ALDH1 and ferroptosis. Here, we show that RSL3-induced LPO and ferroptotic cell death revealed RSL3-sensitive and -resistant malignant glioma cell lines. Most interestingly, RSL3 sensitivity correlates with ALDH1a3 expression; only high ALDH1a3-expressing cells seem to be sensitive to ferroptosis induction. In accordance, inhibition of ALDH1a3 enzymatic activity by chemical inhibition or genetic knockout protects tumor cells from RSL3-induced ferroptotic cell death. Both RSL-3-dependent binding of ALDH1a3 to LC3B and autophagic downregulation of ferritin could be completely blocked by ALDH inhibition. Therefore, ALDH1a3 seems to be involved in ferroptosis through the essential release of iron by ferritinophagy. Our results also indicate that ferroptosis induction might be a particularly interesting clinical approach for targeting the highly aggressive cell population of GSC.
Topics: Humans; Aldehyde Dehydrogenase 1 Family; Autophagy; Ferroptosis; Glioblastoma; Glioma; Neoplasm Recurrence, Local
PubMed: 36552781
DOI: 10.3390/cells11244015 -
Frontiers in Endocrinology 2023Gliomas are the most common intracranial nervous system tumours that are highly malignant and aggressive, and mitochondria are an important marker of metabolic...
BACKGROUND
Gliomas are the most common intracranial nervous system tumours that are highly malignant and aggressive, and mitochondria are an important marker of metabolic reprogramming of tumour cells, the prognosis of which cannot be accurately predicted by current histopathology. Therefore, Identify a mitochondrial gene with immune-related features that could be used to predict the prognosis of glioma patients.
METHODS
Gliomas data were downloaded from the TCGA database and mitochondrial-associated genes were obtained from the MITOCARTA 3.0 dataset. The CGGA, kamoun and gravendeel databases were used as external datasets. LASSO(Least absolute shrinkage and selection operator) regression was applied to identify prognostic features, and area and nomograms under the ROC(Receiver Operating Characteristic) curve were used to assess the robustness of the model. Single sample genomic enrichment analysis (ssGSEA) was employed to explore the relationship between model genes and immune infiltration, and drug sensitivity was used to identify targeting drugs. Cellular studies were then performed to demonstrate drug killing against tumours.
RESULTS
COX assembly mitochondrial protein homolog (), Cytochrome c oxidase protein 20 homolog () and Cytochrome b-c1 complex subunit 7 () were identified as prognostic key genes in glioma, with , progressively increasing and progressively decreasing with decreasing risk scores. ROC curve analysis of the TCGA training set model yielded AUC (Area Under The Curve) values >0.8 for 1-, 2- and 3-year survival, and the model was associated with both CD8+ T cells and immune checkpoints. Finally, using cellMiner database and molecular docking, it was confirmed that binds covalently to Amonafide lysine at position 78 and threonine at position 82, while cellular assays showed that Amonafide inhibits glioma migration and invasion.
CONCLUSION
Our three mitochondrial genomic composition-related features accurately predict Survival in glioma patients, and we also provide glioma chemotherapeutic agents that may be mitochondria-related targets.
Topics: Humans; Prognosis; Molecular Docking Simulation; Precision Medicine; DNA, Mitochondrial; Glioma; Mitochondria
PubMed: 37091853
DOI: 10.3389/fendo.2023.1172182 -
International Journal of Molecular... Jun 2020Clinically, high cyclooxygenase-2 expression in malignant glioma correlates well with poor prognosis and the use of aspirin is associated with a reduced risk of glioma....
Clinically, high cyclooxygenase-2 expression in malignant glioma correlates well with poor prognosis and the use of aspirin is associated with a reduced risk of glioma. To extend the current understanding of the apoptotic potential of aspirin in most cell types, this study provides evidence showing that aspirin induced glioma cell apoptosis and inhibited tumor growth, in vitro and in vivo. We found that the human H4 glioma cell-killing effects of aspirin involved mitochondria-mediated apoptosis accompanied by endoplasmic reticulum (ER) stress, Noxa upregulation, Mcl-1 downregulation, Bax mitochondrial distribution and oligomerization, and caspase 3/caspase 8/caspase 9 activation. Genetic silencing of Noxa or Bax attenuated aspirin-induced viability loss and apoptosis, while silencing Mcl-1 augmented the effects of aspirin. Data from genetic and pharmacological studies revealed that the axis of ER stress comprised an apoptotic cascade leading to Noxa upregulation and apoptosis. The apoptotic programs and mediators triggered by aspirin in H4 cells were duplicated in human U87 glioma cell line as well as in tumor-bearing BALB/c nude mice. The involvement of ER stress in indomethacin-induced Mcl-1 downregulation was reported in our previous study on glioma cells. Therefore, the aforementioned phenomena indicate that ER stress may be a valuable target for intervention in glioma apoptosis.
Topics: Animals; Aspirin; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Proto-Oncogene Proteins c-bcl-2; Up-Regulation; Xenograft Model Antitumor Assays
PubMed: 32545774
DOI: 10.3390/ijms21124219 -
Journal of Neuro-oncology Sep 2014Malignant glioma (MG) is a devastating neurological disease with a uniformly poor prognosis and a clinical course characterized by progressive functional and cognitive... (Review)
Review
Malignant glioma (MG) is a devastating neurological disease with a uniformly poor prognosis and a clinical course characterized by progressive functional and cognitive impairment. A small body of literature addresses patients' and caregivers' prognostic awareness (PA), or understanding of prognosis in patients with cancer. Studies that examine PA and desire for prognostic information among patients with MG are limited. We sought to review the existing literature on PA and communication of prognostic information to patients with MG. Fourteen studies examining PA or experience and preferences regarding communication of prognostic information were included. The definition and measurement of PA across studies varied, and the prevalence of accurate PA ranged from 25 to 100 % of participants. There is likely a subset of patients who do not desire accurate prognostic information, although the patient and disease characteristics that predict this preference are currently unknown. This review suggests that patients with MG desire prognostic information communicated in a manner that preserves hope. Systematic investigation to define communication needs for prognostic information in the unique clinical setting of MG is needed.
Topics: Attitude to Health; Awareness; Brain Neoplasms; Communication; Glioma; Humans; Physician-Patient Relations; Prognosis
PubMed: 24874468
DOI: 10.1007/s11060-014-1487-1 -
Journal of Neuro-oncology May 2022Managing Cancer and Living Meaningfully (CALM) is an evidence-based, brief, semi-structured psychotherapy designed to help patients with advanced cancer cope with the...
BACKGROUND
Managing Cancer and Living Meaningfully (CALM) is an evidence-based, brief, semi-structured psychotherapy designed to help patients with advanced cancer cope with the practical and profound challenges of their illness. However, no study to date has investigated its feasibility, acceptability, and preliminary effectiveness in adults with malignant glioma, despite the well-documented incidence of psychological distress in this vulnerable and underserved population.
METHODS
Fourteen patients with glioma and elevated symptoms of depression and/or death anxiety enrolled in the trial: 83% glioblastoma, 75% female, M = 56 years (SD = 15.1; range = 27-81). Feasibility was assessed based on established metrics. Acceptability was measured by post-session surveys and post-intervention interviews. Preliminary intervention effects were explored using paired t-tests, comparing psychological distress at baseline and post-intervention.
RESULTS
Of the 14 enrolled patients, 12 were evaluable. Nine completed the study (75% retention rate). Three patients withdrew due to substantial disease progression which affected their ability to participate. Participants reported high perceived benefit, and all recommended the program to others. Baseline to post-intervention assessments indicated reductions in death anxiety, generalized anxiety, and depression, and increases in spirituality. Quality of life and fear of cancer recurrence remained stable throughout the study period.
CONCLUSIONS
CALM appears feasible for use with adults with malignant glioma. Enrollment and retention rates were high and comparable to psychotherapy trials for patients with advanced cancer. High perceived benefit and reductions in symptoms of death anxiety, generalized anxiety, and depression were reported by participants. These findings are extremely encouraging and support further study of CALM in neuro-oncology.
TRIAL REGISTRATION NUMBER
NCT04646213 registered on 11/27/2020.
Topics: Adult; Anxiety; Depression; Feasibility Studies; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Psychotherapy, Brief; Quality of Life
PubMed: 35437687
DOI: 10.1007/s11060-022-03988-8 -
Journal of Cellular and Molecular... Apr 2022With the emergence of the molecular era and retreat of the histology epoch in malignant glioma, it is becoming increasingly necessary to research...
With the emergence of the molecular era and retreat of the histology epoch in malignant glioma, it is becoming increasingly necessary to research diagnostic/prognostic/therapeutic biomarkers and their related regulatory mechanisms. While accumulating studies have investigated coding gene-associated biomarkers in malignant glioma, research on comprehensive coding and noncoding RNA-associated biomarkers is lacking. Furthermore, few studies have illustrated the cross-talk signalling pathways among these biomarkers and mechanisms in detail. Here, we identified DEGs and ceRNA networks in malignant glioma and then constructed Cox/Lasso regression models to further identify the most valuable genes through stepwise refinement. Top-down comprehensive integrated analysis, including functional enrichment, SNV, immune infiltration, transcription factor binding site, and molecular docking analyses, further revealed the regulatory maps among these genes. The results revealed a novel and accurate model (AUC of 0.91 and C-index of 0.84 in the whole malignant gliomas, AUC of 0.90 and C-index of 0.86 in LGG, and AUC of 0.75 and C-index of 0.69 in GBM) that includes twelve ncRNAs, 1 miRNA and 6 coding genes. Stepwise logical reasoning based on top-down comprehensive integrated analysis and references revealed cross-talk signalling pathways among these genes that were correlated with the circadian rhythm, tumour immune microenvironment and cellular senescence pathways. In conclusion, our work reveals a novel model where the newly identified biomarkers may contribute to a precise diagnosis/prognosis and subclassification of malignant glioma, and the identified cross-talk signalling pathways would help to illustrate the noncoding RNA-associated epigenetic regulatory mechanisms of glioma tumorigenesis and aid in targeted therapy.
Topics: Biomarkers, Tumor; Brain Neoplasms; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Glioma; Humans; MicroRNAs; Molecular Docking Simulation; RNA, Long Noncoding; Tumor Microenvironment
PubMed: 35194922
DOI: 10.1111/jcmm.17244 -
BMC Cancer Feb 2023Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific...
BACKGROUND
Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific glioma biomarkers that would aid tumour subtyping and minimally invasive early diagnosis. Aberrant glycosylation is an important post-translational modification in cancer and is implicated in glioma progression. Raman spectroscopy (RS), a vibrational spectroscopic label-free technique, has already shown promise in cancer diagnostics.
METHODS
RS was combined with machine learning to discriminate glioma grades. Raman spectral signatures of glycosylation patterns were used in serum samples and fixed tissue biopsy samples, as well as in single cells and spheroids.
RESULTS
Glioma grades in fixed tissue patient samples and serum were discriminated with high accuracy. Discrimination between higher malignant glioma grades (III and IV) was achieved with high accuracy in tissue, serum, and cellular models using single cells and spheroids. Biomolecular changes were assigned to alterations in glycosylation corroborated by analysing glycan standards and other changes such as carotenoid antioxidant content.
CONCLUSION
RS combined with machine learning could pave the way for more objective and less invasive grading of glioma patients, serving as a useful tool to facilitate glioma diagnosis and delineate biomolecular glioma progression changes.
Topics: Humans; Spectrum Analysis, Raman; Glycosylation; Glioma; Brain Neoplasms; Glioblastoma; Neoplasm Grading
PubMed: 36809974
DOI: 10.1186/s12885-023-10588-w -
Oncotarget May 2017Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL...
Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL and c-myc inhibition accomplished by bromodomain protein inhibitors. Established, patient-derived xenograft and stem cell-like glioma cells were treated with the novel bromodomain protein inhibitors, JQ1 and OTX015, along with BH3-mimetics, ABT263 or Obatoclax. Synergy was assessed by calculation of CI values. Small interfering RNAs (siRNAs) were used for gene silencing and mechanistic studies. In vivo experiments were performed in a glioblastoma xenograft model. Single treatments with JQ1 and OTX015 had only moderate effects on the reduction of cellular viability. However, the combination treatment of BH3-mimetics along with JQ1 or OTX015 resulted in a highly synergistic reduction of cellular viability in a broad range of different model systems of malignant glioma. Similarly, knockdown of c-myc sensitized glioma cells for ABT263 mediated cell death. The enhanced loss of cellular viability in the combination treatment was mediated by activation of apoptosis with dissipation of mitochondrial membrane potential and caspase cleavage. The combination treatment led to a modulation of anti- and pro-apoptotic Bcl-2 family members with an increase in pro-apoptotic Noxa mediated by ATF4. Small interfering RNA mediated knockdown of Bak and Noxa protected glioma cells from ABT263/JQ1 mediated apoptosis. Finally, the combination treatment of ABT263 and OTX015 resulted in a regression of tumors and a significantly smaller tumor size as compared to single or vehicle treated tumors. Thus, these results warrant clinical testing for the drug combination of BH3-mimetics along with bromodain protein inhibitors.
Topics: Acetanilides; Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Azepines; Bcl-2-Like Protein 11; Caspases; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Synergism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glioma; Heterocyclic Compounds, 3-Ring; Humans; Membrane Potential, Mitochondrial; Mice; Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; RNA, Small Interfering; Sulfonamides; Triazoles; Xenograft Model Antitumor Assays
PubMed: 28418907
DOI: 10.18632/oncotarget.16365