Exploring the causal relationship between antihypertensive drugs and glioblastoma by combining drug target Mendelian randomization study, eQTL colocalization, and single-cell RNA sequencing.

Recent reports indicate a potential oncogenic role of antihypertensive drugs in common cancers. However, it remains uncertain whether this phenomenon influences the risk of glioblastoma multiforme (GBM). This study aimed to assess the potential causal effects of blood pressure (BP) and antihypertensive drugs on GBM. Genome-wide association study (GWAS) summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), and GBM in Europeans were downloaded. To represent the effects of antihypertensive drugs, we utilized single nucleotide polymorphisms (SNPs) associated with SBP/DBP adjacent to the coding regions of different antihypertensive drugs as instrumental variables to model five antihypertensive drugs, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, ß-receptor blockers (BBs), and thiazide diuretics. Positive control studies were performed using GWAS data in chronic heart failure. The primary method for causality estimation was the inverse-variance-weighted method. Mendelian randomization analysis showed that BBs with the ß1-adrenergic receptor (ADRB1) as a therapeutic target could significantly reduce the risk of GBM by mediating DBP (OR = 0.431, 95% CI: 0.267-0.697, p < .001) and that they could also significantly reduce the risk of GBM by mediating SBP (OR = 0.595, 95% CI: 0.422-0.837, p = .003). Sensitivity analysis and colocalization analysis reinforced the robustness of these findings. Finally, the low expression of the ADRB1 gene in malignant gliomas was found by GBM data from TCGA and single-cell RNA sequencing, which most likely contributed to the poor prognosis of GBM patients. In summary, our study provides preliminary evidence of some causal relationship between ADRB1-targeted BBs and glioblastoma development. However, more studies are needed to validate these findings and further reveal the complex relationship between BP and GBM.

Interplay of Sphingolipid Metabolism in Predicting Prognosis of GBM Patients: Towards Precision Immunotherapy.

Background: In spite of numerous existing bio-surveillance systems for predicting glioma (GBM) prognosis, enhancing the efficacy of immunotherapy remains an ongoing conundrum. The continual scrutiny of the dynamic interplay between the sphingolipid metabolic pathway and tumor immunophenotypes has unveiled potential implications. However, the intricate orchestration of functional and regulatory mechanisms by long non-coding RNAs (lncRNAs) in GBM, particularly in the context of sphingolipid metabolism, remains cryptic. Methods: We harnessed established R packages to intersect gene expression profiles of GBM patients within the The Cancer Genome Atlas (TCGA) database with the compilation of sphingolipid metabolism genes from GeneCards. This enabled us to discern markedly distinct lncRNAs, which were subsequently deployed to construct a robust prognostic model utilizing Lasso-Cox regression analysis. We then scrutinized the immune microenvironment across various risk strata using the ssGSEA and CIBERSORT algorithms. To evaluate mutation patterns and drug resistance profiles within patient subgroups, we devised the "Prophytic" and "Maftools" packages, respectively. Results: Our investigation scrutinized lncRNAs linked to sphingolipid metabolism, utilizing glioma specimens from TCGA. We meticulously curated 1224 sphingolipid-associated genes gleaned from GeneCards and pinpointed 272 differentially expressed mRNAs via transcriptomic analysis. Enrichment analyses underscored their significance in sphingolipid processes. A prognostic model founded on 17 meticulously selected lncRNAs was systematically constructed and validated. This model adeptly stratified GBM patients into high- and low-risk categories, yielding highly precise prognostic insights. We also discerned correlations between immune cell infiltration and genetic mutation discrepancies, along with distinct therapeutic responses through drug sensitivity analysis. Notably, computational findings were corroborated through experimental validation by RT-PCR. Conclusion: In summation, our exhaustive inquiry underscores the multifaceted utility of the sphingolipid metabolic pathway as an autonomous diagnostic and prognostic indicator for glioma patients. Furthermore, we amalgamate a profusion of substantiated evidence concerning immune infiltration and gene mutations, thereby reinforcing the proposition that sphingolipid metabolism may function as a pivotal determinant in the panorama of immunotherapeutic interventions.

IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy.

Introduction: Copper metabolism encompasses all cellular metabolic processes involving copper ions and plays a significant role in the pathogenesis of diseases, including cancer. Furthermore, copper is intricately involved in various processes related to nucleotide metabolism. However, a comprehensive analysis of copper metabolism in gliomas remains lacking despite its importance. Methods: To address this gap, glioma patients were stratified based on the expression levels of copper metabolism-related genes. By utilizing machine learning techniques, a novel copper metabolism-associated biomarker was developed. The potential of this biomarker in prognosis, mutation analysis, and predicting immunotherapy response efficiency in gliomas was systematically investigated. Results: Notably, IGFBP2, identified as a glioma tumor promoter, was found to promote disease progression and influence immunotherapy response. Additionally, glioma-derived IGFBP2 was observed to enhance microglial migration. High IGFBP2 expression in GBM cells facilitated macrophage interactions through the EGFR, CD63, ITGB1, and CD44 signaling pathways. Discussion: Overall, the copper metabolism-associated biomarker shows promising potential to enhance the clinical management of gliomas, offering valuable insights into disease prognosis and treatment strategies.

GPX8 regulates pan-apoptosis in gliomas to promote microglial migration and mediate immunotherapy responses.

Introduction: Gliomas have emerged as the predominant brain tumor type in recent decades, yet the exploration of non-apoptotic cell death regulated by the pan-optosome complex, known as pan-apoptosis, remains largely unexplored in this context. This study aims to illuminate the molecular properties of pan-apoptosis-related genes in glioma patients, classifying them and developing a signature using machine learning techniques. Methods: The prognostic significance, mutation features, immunological characteristics, and pharmaceutical prediction performance of this signature were comprehensively investigated. Furthermore, GPX8, a gene of interest, was extensively examined for its prognostic value, immunological characteristics, medication prediction performance, and immunotherapy prediction potential. Results: Experimental techniques such as CCK-8, Transwell, and EdU investigations revealed that GPX8 acts as a tumor accelerator in gliomas. At the single-cell RNA sequencing level, GPX8 appeared to facilitate cell contact between tumor cells and macrophages, potentially enhancing microglial migration. Conclusions: The incorporation of pan-apoptosis-related features shows promising potential for clinical applications in predicting tumor progression and advancing immunotherapeutic strategies. However, further in vitro and in vivo investigations are necessary to validate the tumorigenic and immunogenic processes associated with GPX8 in gliomas.

Integrating machine learning and bioinformatics analysis to m6A regulator-mediated methylation modification models for predicting glioblastoma patients' prognosis and immunotherapy response.

BACKGROUND: Epigenetic regulations of immune responses are essential for cancer development and growth. As a critical step, comprehensive and rigorous explorations of m6A methylation are important to determine its prognostic significance, tumor microenvironment (TME) infiltration characteristics and underlying relationship with glioblastoma (GBM). METHODS: To evaluate m6A modification patterns in GBM, we conducted unsupervised clustering to determine the expression levels of GBM-related m6A regulatory factors and performed differential analysis to obtain m6A-related genes. Consistent clustering was used to generate m6A regulators cluster A and B. Machine learning algorithms were implemented for identifying TME features and predicting the response of GBM patients receiving immunotherapy. RESULTS: It is found that the m6A regulatory factor significantly regulates the mutation of GBM and TME. Based on Europe, America, and China data, we established m6Ascore through the m6A model. The model accurately predicted the results of 1206 GBM patients from the discovery cohort. Additionally, a high m6A score was associated with poor prognoses. Significant TME features were found among the different m6A score groups, which demonstrated positive correlations with biological functions (i.e., EMT2) and immune checkpoints. CONCLUSIONS: m6A modification was important to characterize the tumorigenesis and TME infiltration in GBM. The m6Ascore provided GBM patients with valuable and accurate prognosis and prediction of clinical response to various treatment modalities, which could be useful to guide patient treatments.

NAP1L1 promotes proliferation and chemoresistance in glioma by inducing CCND1/CDK4/CDK6 expression through its interaction with HDGF and activation of c-Jun.

The prognosis of glioma is poor as its pathogenesis and mechanisms underlying cisplatin chemoresistance remain unclear. Nucleosome assembly protein 1 like 1 (NAP1L1) is regarded as a hallmark of malignant tumors. However, the role of NAP1L1 in glioma remains unknown. In this study, we aimed to investigate the molecular functions of NAP1L1 in glioma and its involvement in cisplatin chemoresistance, if any. NAP1L1 was found to be upregulated in samples from The Cancer Genome Atlas (TCGA) database. Immunohistochemistry indicated that NAP1L1 and hepatoma-derived growth factor (HDGF) were enhanced in glioma as compared to the para-tumor tissues. High expressions of NAP1L1 and HDGF were positively correlated with the WHO grade, KPS, Ki-67 index, and recurrence. Moreover, NAP1L1 expression was also positively correlated with the HDGF expression in glioma tissues. Functional studies suggested that knocking down NAP1L1 could significantly inhibit glioma cell proliferation both in vitro and in vivo, as well as enhance the sensitivity of glioma cells to cisplatin (cDDP) in vitro. Mechanistically, NAP1L1 could interact with HDGF at the protein level and they co-localize in the cytoplasm. HDGF knockdown in NAP1L1-overexpressing glioma cells significantly inhibited cell proliferation. Furthermore, HDGF could interact with c-Jun, an oncogenic transcription factor, which eventually induced the expressions of cell cycle promoters, CCND1/CDK4/CDK6. This finding suggested that NAP1L1 could interact with HDGF, and the latter recruited c-Jun, a key oncogenic transcription factor, that further induced CCND1/CDK4/CDK6 expression, thereby promoting proliferation and chemoresistance in glioma cells. High expression of NAP1L1 in glioma tissues indicated shorter overall survival in glioma patients.

circ_PTN contributes to -cisplatin resistance in glioblastoma via PI3K/AKT signaling through the miR-542-3p/PIK3R3 pathway.

Glioblastoma has been identified as the most common and aggressive primary brain tumor in adults. Recently, it has been found that cisplatin (DDP) treatment is a common chemotherapeutic method for GBM patients. circ_PTN (ID number: hsa_circ_0003949) is a newly found circular (circRNA) which has been proved to be highly expressed in GBM cells, while its role in GBM remains unclear. Therefore, our study focused on investigating the role of circ_PTN in the DDP resistance of GBM cells. The expression of circ_PTN in DDP-sensitive and DDP-resistant GBM cells was detected in our assay. Functional experiments were utilized to unveil the effects of circ_PTN on the DDP resistance of GBM cells. Moreover, mechanism assays were conducted to confirm the mechanism of how circ_PTN affected the DDP resistance of GBM cells. According to the results, we found that circ_PTN promoted the DDP resistance of GBM cells through activation of the PI3K/AKT pathway. Moreover, circ_PTN silencing inhibited the DDP resistance of GBM tumors in vivo. To conclude, our study unveiled the influence of circ_PTN on the DDP resistance of GBM cells, which might provide a therapeutic target for GBM treatment via DDP.

Upregulation of DEAD box helicase 5 and 17 are correlated with the progression and poor prognosis in gliomas.

Recent researches indicated Ddx5 and Ddx17 play crucial roles in tumorigenesis. However, the study of Ddx5 and Ddx17 in glioma remains a little. Our study investigated their expression in glioma and evaluated its association with clinical factors and prognostic significance. The expression of Ddx5 and Ddx17 were both upregulated in glioma tissues compared to normal brain tissues, and a significant positive correlation between Ddx5 and Ddx17 expression was identified by statistical analysis. Immunohistochemical staining verified the expression of Ddx5 and Ddx17 in peritumoral zone was lower than that in core zone but higher than normal brain tissues. Moreover, the increased expression of Ddx5 and Ddx17 was markedly correlated with WHO Grade and histological type, and high Ddx5 and Ddx17 were found to be significantly associated with the worse overall survival of glioma patients. In additional, higher expression of both Ddx5 and Ddx17 predicted shorter clinical survival time for high-grade glioma patients with radiotherapy or with chemotherapy. In conclusion, overexpressed Ddx5 and Ddx17 are involved in the clinical progression and poor prognosis of glioma patients, suggesting that their upregulation can be used as a reliable clinical predictor for tumor diagnosis and to predict survival in patients with glioma.

[Curcumin suppresses invasiveness and migration of human glioma cells in vitro by inhibiting HDGF/ß-catenin complex].

OBJECTIVE: To investigate the effect of curcumin on the invasion and migration of human glioma cells in vitro and explore the molecular mechanisms. METHODS: MTT assay was used for screening the optimal curcumin concentrations. The effects of curcumin on the invasion and metastasis of human glioma cell lines U251 and LN229 were tested using Transwell assay, Boyden assay and wound-healing assays. The expression of the related proteins and their interactions were determined using Western blotting and coimmunoprecipitation assay. RESULTS: Curcumin at the concentration of 20 µmol/L for 48 h was used as the optimal condition for subsequent cell treatment. In the two glioma cell lines, curcumin significantly suppressed the invasion and migration of the cells (P < 0.05) and lowered the expressions of hepatoma-derived growth factor (HDGF), Ncadherin, vimentin, Snail and Slug, but increased the expression of E-cadherin. Interference of HDGF in curcumin-treated glioma cells synergistically inhibited the epithelial-mesenchymal transition (EMT) signals, while overexpression of HDGF significantly reversed the inhibitory effect of curcumin on EMT; curcumin treatment could significantly reduce the binding of HDGF to ß-catenin. CONCLUSIONS: Curcumin suppresses EMT signal by reducing HDGF/ß-catenin complex and thereby lowers the migration and invasion abilities of human glioma cells in vitro.

Phytanoyl-CoA 2-Hydroxylase-Interacting Protein-Like Gene Is a Therapeutic Target Gene for Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common primary CNS cancer and has a poor prognosis. This study searched for significant genes and the mechanisms involved in GBM. We used the Gene Expression Omnibus (GEO) to test the WHO normal and IV glioma database, used R tool to identify the significant gene, and finally, combined these with The Cancer Genome Atlas (TCGA) to verify the significant genes. Subsequently, we explored the biological mechanisms involved. Phytanoyl-CoA 2-hydroxylase-interacting protein-like gene (PHYHIPL) is downregulated in grade IV glioma (GBM). The downregulation of PHYHIPL in GBM is accompanied by poor overall survival in the TCGA database, which indicates that PHYHIPL is a protection gene in GBM development. Bioinformatics analysis shows that the poor prognosis with downregulated PHYHIPL may be the result of the TNF signaling pathway and the IL-17 signaling pathway, but good prognosis accompanied by upregulated PHYHIPL may be the result of retrograde endocannabinoid signaling and the cAMP signaling pathway. Protein-protein interactions (PPI) net indicated that PHYHIPL may play a vital role in cell metabolism, and we hypothesize that the downregulation mechanism may be the result of mutations of the ß-catenin gene and the endogenous siRNA, as shown in previous studies. PHYHIPL may be a target gene for the treatment and prognosis of GBM.

The expression of MMP19 and its clinical significance in glioma.

AIMS: The expression of phosphoglycerate kinase 1 (MMP19) is elevated in some cancers. However, the clinical features and prognostic value of glioma patients with MMP19 expression are unclear. In this study, the expression level of MMP19 and the correlation between the level of MMP19 expression and the clinicopathologic data in glioma patients including survival were examined. METHODS AND RESULTS: Using real-time PCR, the mRNA expression of MMP19 was examined in 61 fresh glioma tissues and 32 brain samples. The result indicated that MMP19 mRNA was obviously elevated in glioma tissues compared to brain tissues. Further, we observed that MMP19 mRNA was much higher in stage III patients than it was in stage I-II patients. The expression of the MMP19 protein was determined by immunohistochemical analysis in 156 paraffin-embedded glioma samples and 35 normal paraffin-embedded brain samples. The MMP19 protein level was significantly increased in glioma tissues compared to brain tissues (P = 0.008). Furthermore, we observed that a high expression of MMP19 protein was positively associated with clinical stage (P = 0.008) but did not correlate with age, gender, or histological type. An increased MMP19 protein expression was associated with poor overall survival rates (P = 0.001). A stratified analysis showed that patients with high MMP19 protein expression indicated a worse prognosis occurring in WHO III-IV stages (P = 0.001). A Multivariate analysis indicated that a high expression of the MMP19 protein was an independent prognostic indicator of patient survival (P = 0.009). CONCLUSIONS: MMP19 is overexpressed and plays a significant role in disease progression and poor outcome in glioma patients.

Intracranial meningioma surgery in the elderly (over 65 years): prognostic factors and outcome.

BACKGROUND: Meningiomas are more prevalent in elderly individuals; however, the surgical outcome and prognostic factors in this age group are unclear. This retrospective study aimed to identify the prognostic factors of elderly patients with intracranial meningiomas who underwent surgical resection. METHODS: Eighty-six patients (aged ≥ 65) diagnosed with an intracranial meningioma were surgically treated at our department. The clinical, radiological, and follow-up data were retrospectively reviewed. Univariate and multivariate logistic analyses were performed to identify relationships between factors [age, sex, neurological condition, concomitant disease, American Society of Anesthesiology (ASA) classification, preoperative Karnofsky Performance Scale (KPS) score, tumor location and size, peritumoral edema, and Simpson resection grade] and outcome. RESULTS: One patient (1.2 %) died within 30 days of surgery. The morbidity rate was 37.2 %. Postoperative morbidities occurred more frequently in the patients with preoperative neurological deficits than in those without (p = 0.049). Univariate analysis identified significant relationships between a low KPS score (≤ 70) at discharge and preoperative neurological deficits, low preoperative KPS score (≤ 70), and critical tumor location (p < 0.001, p < 0.001, and p = 0.04, respectively). In the multivariate logistic analysis, only the preoperative KPS score remained significant for the KPS score at discharge (p = 0.005); there was no significant association with the most recent KPS score. CONCLUSION: The outcome of intracranial meningioma resection in elderly individuals is favorable if the preoperative KPS score is >70 and no neurological deficits are present. Treatment decisions should be patient-specific, and additional factors should be considered when operations are performed in patients with a low preoperative KPS score or neurological deficits.