Invasive Ability Of Glioma Cells Research Articles

Multifaceted bioinformatic analysis of m6A-related ferroptosis and its link with gene signatures and tumour-infiltrating immune cells in gliomas.

Whether N6-Methyladenosine (m6A)- and ferroptosis-related genes act on immune responses to regulate glioma progression remains unanswered. Data of glioma and corresponding normal brain tissues were fetched from the TCGA database and GTEx. Differentially expressed genes (DEGs) were identified for GO and KEGG enrichment analyses. The FerrDb database was based to yield ferroptosis-related DEGs. Hub genes were then screened out using the cytoHubba database and validated in clinical samples. Immune cells infiltrating into the glioma tissues were analysed using the CIBERSORT R script. The association of gene signature underlying the m6A-related ferroptosis with tumour-infiltrating immune cells and immune checkpoints in low-grade gliomas was analysed. Of 6298 DEGs enriched in mRNA modifications, 144 were ferroptosis-related; NFE2L2 and METTL16 showed the strongest positive correlation. METTL16 knockdown inhibited the migrative and invasive abilities of glioma cells and induced ferroptosis invitro. NFE2L2 was enriched in the anti-m6A antibody. Moreover, METTL16 knockdown reduced the mRNA stability and level of NFE2L2 (both p < 0.05). Proportions of CD8+ T lymphocytes, activated mast cells and M2 macrophages differed between low-grade gliomas and normal tissues. METTL16 expression was negatively correlated with CD8+ T lymphocytes, while that of NFE2L2 was positively correlated with M2 macrophages and immune checkpoints in low-grade gliomas. Gene signatures involved in the m6A-related ferroptosis in gliomas were identified via bioinformatic analyses. NFE2L2 interacted with METTL16 to regulate the immune response in low-grade gliomas, and both molecules may be novel therapeutic targets for gliomas.

Pan-cancer analysis of the disulfidptosis-related gene RPN1 and its potential biological function and prognostic significance in gliomas

BackgroundNumerous studies have shown a strong correlation between disulfidptosis and various cancers. However, the expression and function of RPN1, a crucial gene in disulfidptosis, remain unclear in the context of cancer. MethodsGene expression and clinical information on lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. RPN1 expression was analyzed using the Timer2.0 and the Human Protein Atlas (HPA) databases. Prognostic significance was assessed using Cox regression analysis and Kaplan–Meier curves. Genetic mutations and methylation levels were examined using the cBioPortal and UALCAN platforms, respectively. The relationship between RPN1 and tumor mutation burden (TMB) and microsatellite instability (MSI) across different cancer types was analyzed using the Spearman correlation coefficient. The relationship between RPN1 and immune cell infiltration was analyzed using the Timer2.0 database, whereas variations in drug sensitivity were explored using the CellMiner database. Receiver operating characteristic curves validated RPN1’s diagnostic potential in glioma, and its correlation with immune checkpoint inhibitors (ICIs) was assessed using Spearman’s correlation coefficient. Single-sample gene set enrichment analysis elucidated a link between RPN1 and immune cells and pathways. In addition, a nomogram based on RPN1 was developed to predict patient prognosis. The functional impact of RPN1 on glioma cells was confirmed using scratch and Transwell assays. ResultRPN1 was aberrantly expressed in various cancers and affected patient prognosis. The main mutation type of RPN1 in the cancer was amplified. RPN1 exhibited a positive correlation with myeloid-derived suppressor cells, neutrophils, and macrophages, and a negative correlation with CD8+ T cells and hematopoietic stem cells. RPN1 expression was associated with TMB and MSI in various cancers. The expression of RPN1 affected drug sensitivity in cancer cells. RPN1 was positively correlated with multiple ICIs in gliomas. RPN1 also affected immune cell infiltration into the tumor microenvironment. RPN1 was an independent prognostic factor for gliomas, and the nomogram demonstrated excellent predictive performance. Interference with RPN1 expression reduces the migratory and invasive ability of glioma cells. ConclusionRPN1 exerts multifaceted effects on different stages of cancer, including immune infiltration, prognosis, and treatment outcomes. RPN1 expression affects the prognosis and immune microenvironment infiltration in patients with glioma, making RPN1 a potential target for the treatment of glioma.

High expression of RTEL1 predicates worse progression in gliomas and promotes tumorigenesis through JNK/ELK1 cascade

Gliomas are the most common primary intracranial tumor worldwide. The maintenance of telomeres serves as an important biomarker of some subtypes of glioma. In order to investigate the biological role of RTEL1 in glioma. Relative telomere length (RTL) and RTEL1 mRNA was explored and regression analysis was performed to further examine the relationship of the RTL and the expression of RTEL1 with clinicopathological characteristics of glioma patients. We observed that high expression of RTEL1 is positively correlated with telomere length in glioma tissue, and serve as a poor prognostic factor in TERT wild-type patients. Further in vitro studies demonstrate that RTEL1 promoted proliferation, formation, migration and invasion ability of glioma cells. In addition, in vivo studies also revealed the oncogene role of RTEL1 in glioma. Further study using RNA sequence and phospho-specific antibody microarray assays identified JNK/ELK1 signaling was up-regulated by RTEL1 in glioma cells through ROS. In conclusion, our results suggested that RTEL1 promotes glioma tumorigenesis through JNK/ELK1 cascade and indicate that RTEL1 may be a prognostic biomarker in gliomas.

NPS-2143 inhibit glioma progression by suppressing autophagy through mediating AKT-mTOR pathway.

Gliomas are the most common tumours in the central nervous system. In the present study, we aimed to find a promising anti-glioma compound and investigate the underlying molecular mechanism. Glioma cells were subjected to the 50 candidate compounds at a final concentration of 10 μM for 72 h, and CCK-8 was used to evaluate their cytotoxicity. NPS-2143, an antagonist of calcium-sensing receptor (CASR), was selected for further study due to its potent cytotoxicity to glioma cells. Our results showed that NPS-2143 could inhibit the proliferation of glioma cells and induce G1 phase cell cycle arrest. Meanwhile, NPS-2143 could induce glioma cell apoptosis by increasing the caspase-3/6/9 activity. NPS-2143 impaired the immigration and invasion ability of glioma cells by regulating the epithelial-mesenchymal transition process. Mechanically, NPS-2143 could inhibit autophagy by mediating the AKT-mTOR pathway. Bioinformatic analysis showed that the prognosis of glioma patients with low expression of CASR mRNA was better than those with high expression of CASR mRNA. Gene set enrichment analysis showed that CASR was associated with cell adhesion molecules and lysosomes in glioma. The nude mice xenograft model showed NPS-2143 could suppress glioma growth invivo. In conclusion, NPS-2143 can suppress the glioma progression by inhibiting autophagy.

The prognostic and immune significance of PLBD1 in pan-cancer and its roles in proliferation and invasion of glioma.

Cancer is a destructive disease and is currently the leading cause of major threats to human health. PLBD1 is a transcription factor that regulates phospholipid metabolism, but its role in tumors is unknown. We assessed pan-cancer expression, methylation, and mutation data of PLBD1 by multiple databases to investigate its clinical prognostic value. In addition, we examined the pan-cancer immunological signature of PLBD1, particularly in gliomas. Furthermore, we assessed the impact of PLBD1 knockdown on the proliferation and invasive capacity of glioma cells by in vitro experiments. Our results suggest that PLBD1 is highly expressed in multiple types of cancers, and it can serve as an independent prognostic factor for gliomas. In addition, we found that the epigenetic alterations of PLBD1 were highly heterogeneous in a variety of cancers, including gliomas, and that its high methylation was associated with poor prognosis in a broad range of cancers. Immunological profiling demonstrated that PLBD1 was significantly associated with immune cell infiltration and multiple immune checkpoints in gliomas and is a potential biomarker for gliomas. Furthermore, cellular experiments showed that knockdown of PLBD1 significantly inhibited the proliferation and invasive ability of glioma cells. In conclusion, PLBD1 is a potential tumor prognostic biomarker and immunotherapeutic target that plays a crucial role in glioma cell proliferation, invasion and immunotherapy.

CTSC promoted the migration and invasion of glioma cells via activation of STAT3/SERPINA3 axis

Cathepsin C (CTSC) has been reported to be upregulated in several cancers, however, there are still many missing links about the role of CTSC in glioma. To address this knowledge gap, the present study employed bioinformatics analysis, Transwell assay, RT-qPCR and Western blot assays to investigate the expression level of CTSC in glioma tissues, its relationship with survival period, and its effect on the migration and invasion ability of glioma cells. The findings revealed that CTSC was upregulated in glioma and was associated with poor prognosis. Moreover, CTSC was found to promote cell migration and invasion abilities as well as epithelial-mesenchymal transition (EMT). A further study found that CTSC induced SERPINA3 and STAT3 expression in glioma cells. Additionally, we demonstrated that STAT3 signaling mediated upregulation of SERPINA3 expression by CTSC. In sum, our findings suggest that CTSC activates the STAT3/SERPINA3 axis to promote migration and invasion of glioma cells, which may lead to new potential therapeutic approaches for humans with cancer.

Systematic pan-cancer analysis identifies SLC35C1 as an immunological and prognostic biomarker

GDP-amylose transporter protein 1 (SLC35C1) plays an important role in many types of cancer. Therefore, it is clinically important to further investigate the expression profile of SLC35C1 in human tumors to provide new molecular clues for the pathogenesis of glioma. In this study, we performed a comprehensive pan-cancer analysis of SLC35C1 using a series of bioinformatics approaches and validated its differential tissue expression and biological function. The results showed that SLC35C1 was aberrantly expressed in different types of tumors and significantly correlated with overall survival (OS) and progression-free interval (PFI). More importantly, the expression level of SLC35C1 was closely correlated with Tumor Microenvironment (TME), immune infiltration and immune-related genes. In addition, we found that SLC35C1 expression was also closely related to Tumor Mutation Burden (TMB), Microsatellite Instability (MSI) and antitumor drug sensitivity in various cancer types. Functional bioinformatics analysis indicated that SLC35C1 may be involved in multiple signaling pathways and biological processes in glioma. Based on SLC35C1 expression, a risk factor model was found to predict OS of glioma. In addition, in vitro experiments showed that SLC35C1 knockdown significantly inhibited the proliferation, migration and invasive ability of glioma cells, while SLC35C1 overexpression promoted proliferation, migration, invasion and colony formation of glioma cells. Finally, quantitative real-time PCR confirmed that SLC35C1 was highly expressed in gliomas.

The PODNL1/AKT/β-catenin signaling axis mediates glioma progression and sensitivity to temozolomide

Abnormal expression of small leucine-rich repeat proteins (SLRP) in tumor tissues has been reported as a critical trigger for tumorigenesis and progression. However, the molecular mechanism of PODNL1, a novel member of SLRP family, in glioma remains largely unknown. Therefore, this study aimed to investigate its correlation with clinical factors by glioma cohort and to identify the molecular mechanisms of aberrant PODNL1 gene expression in glioma. Our findings revealed that both PODNL1 mRNA and protein levels were markedly upregulated in glioma tissues, and high PODNL1 mRNA level was significantly associated with poor prognosis of glioma patients. In functional assays, PODNL1 knockdown significantly suppressed the proliferation and invasion abilities of glioma cells, while overexpression of PODNL1 had the opposite effect both in vitro and in vivo. Mechanistically, PODNL1 knockdown suppressed the activation of AKT/mTOR signaling and inhibited nuclear translocation of β-catenin protein in the glioma cells. Our results suggest that PODNL1 acts as an oncogenic factor in glioma by promoting glioma progression through the activation of the kinase AKT, which indeces β-catenin nuclear translocation. Additionally, PODNL1 knockdown enhanced the sensitivity of glioma cells to temozolomide, a chemotherapeutic agent commonly used in the treatment of glioma. The PODNL1/AKT/β-catenin signaling axis represents a new potential therapeutic target against glioma. Furthermore, our data showed the combination of temozolomide and MK-2206, an AKT inhibitor, had a synergistic antitumor effect against glioma cells.

Kaempferol suppresses glioma progression and synergistically enhances the antitumor activity of gefitinib by inhibiting the EGFR/SRC/STAT3 signaling pathway.

Kaempferol (Kae) is a natural flavonoid that has multiple biological activities, such as anti-inflammatory and antitumor activities. However, few studies have been reported on antiglioma effects of Kae. This study aimed to explore the effects and potential mechanisms of Kae and synergistic antitumor activities with gefitinib (Gef) on glioma. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were used to detect cytotoxicity and cell proliferation. Cell apoptosis and the cell cycle were detected by flow cytometry. Transwell assays were used to detect the migratory and invasive abilities of glioma cells. Network pharmacology and molecular docking analysis were used to screen for core targets of Kae in glioma therapy. Xenograft tumor nude mice were established with U251 cells to verify the antiglioma effects of Kae in vivo. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to detect apoptosis in tumor tissues. The expression of proteins was detected by immunohistochemistry and western blot analysis. Kae inhibited cell proliferation, promoted apoptosis, and induced cell cycle arrest in the G2/M phase of glioma cells in a concentration-dependent manner. Kae inhibited the migration and invasion of glioma cells at low concentrations. Network pharmacology analyses showed that epidermal growth factor receptor (EGFR) and SRC proto-oncogene (SRC) might be direct molecular-binding targets of Kae. Our results showed that Kae inhibited the levels of phosphorylated EGFR, phosphorylated SRC (p-SRC), and phosphorylated signal transducer and activator of transcription 3 (STAT3). In addition, the combination of Kae with Gef significantly inhibited the proliferation of glioma cells. Kae further inhibited EGFR phosphorylation after treatment with Gef. Similarly, Kae further enhanced the inhibition of p-SRC caused by SU6656. Finally, we demonstrated that Kae exerted great antitumor activities and enhanced the antitumor effect of Gef by inhibiting EGFR/SRC/STAT3 signaling pathway in vivo. Kae played a potential role and synergistic antiglioma effects with Gef by inhibiting the phosphorylation of EGFR/SRC dual targets. Kae is expected to be a candidate drug or chemosensitizer in glioma therapy.

CUX2 prevents the malignant progression of gliomas by enhancing ADCY1 transcription.

Gliomas are one of the most prevalent brain tumors. This study sought to elucidate the mechanism of CUX2 in glioma development via ADCY1. CUX2 and ADCY1 expression in glioma predicted by bioinformatics analysis. Subsequent to gain- and loss-of-function experiments in glioma cells, cell proliferation was tested by CCK8 and plate clone formation assays, and cell migration and invasion by Transwell assay. The binding between CUX2 and ADCY1 was examined with dual-luciferase gene reporter and ChIP assays. The xenograft mouse model was established to verify the effect of the CUX2/ADCY1 axis on glioma cell growth in vivo. CUX2 and ADCY1 expression was low in glioma. The overexpression of CUX2 repressed the proliferative, migrating, and invasive abilities of glioma cells. Moreover, CUX2 was enriched in the ADCY1 promoter to enhance ADCY1 expression. ADCY1 upregulation diminished glioma cell proliferative, migrating, and invasive properties. Silencing of ADCY1 abrogated and upregulation of ADCY1 promoted the inhibitory influence of CUX2 upregulation on the malignant behaviors of glioma cells in vitro and gliomas cell growth in vivo. Collectively, CUX2 promoted ADCY1 transcription to delay glioma cell migration, proliferation, and invasion.

CircKIF4A promotes glioma growth and temozolomide resistance by accelerating glycolysis

Circular RNAs (circRNAs) are a kind of noncoding RNAs that have different biological functions. CircRNAs play very important parts in the progression of cancers. Nevertheless, the exact mechanism and function of many circRNAs in glioma are not clear. In our study, circKIF4A was identified as a remarkably upregulated circRNA expressed in glioma tissues and cell lines. We performed loss-off function and gain-of-function experiments to inquire into the biological function of circKIF4A in the progression of glioma. We discovered that knockdown of circKIF4A remarkably decreased the proliferation and invasion ability of glioma cells. Moreover, subcutaneous tumorigenesis model and intracranial injection of orthotopic glioma model were established to investigate the functions of circKIF4A in vivo. Suppression of circKIF4A remarkably enhanced the sensitivity of glioma to temozolomide treatment. The glycolysis rate was accelerated by circKIF4A overexpression, which promoted glioma growth and temozolomide resistance. The glycolysis regulating enzyme ALDOA was regulated by circKIF4A through the mechanism of interactivity with miR-335-5p in glioma cells. In a word, our data showed that the upregulation of circKIF4A facilitates glioma progression by means of binding miR-335-5p and upregulating ALDOA expression.

Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target

Simple SummaryGlioma is one of the most common intracranial malignancies and is incurable due to strong aggressiveness and resistance to radiotherapy and chemotherapy. The lack of effective therapeutic targets is a major problem in current treatment. In the present study, we found that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the occurrence and development of glioma. High NNMT expression in glioma is a predictor of short overall survival and poor patient outcome. NNMT knockdown reduced the volume of mice xenograft glioma and the viability of glioma cells. Additionally, overexpression of NNMT epigenetically silenced GAP43 through DNA methylation, histone methylation, and deacetylation modification processes. GAP43 can inhibit the formation of microtubules in tumor and intertumor cell network connections and induce apoptosis through the SIRT1 signaling pathway. Therefore, NNMT could be a potential candidate for the clinical diagnosis and treatment of glioma.Purpose: Increasing evidence has revealed that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the prognosis of tumors. The present study aimed to investigate the role of NNMT in glioma and to elucidate the associated functional mechanisms. Methods: Clinical samples were analyzed by immunohistochemical staining and Western blotting to evaluate NNMT expression in glioma and normal brain tissues. The correlation between NNMT expression and glioma was analyzed using the Cancer Genome Atlas (TCGA) database. Additionally, NNMT was knocked down in two types of glioma cells, U87 and U251, to evaluate the invasive ability of these cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate NNMT knockdown in the cells. Furthermore, ELISA was used to determine the balance between nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogen (NAD/NADH ratio), which verified the altered methylation patterns in the cells. The glioma xenograft mouse models were used to verify the regulatory role of NNMT, GAP43, and SIRT1. Results: Analysis based on our clinical glioma samples and TCGA database revealed that overexpression of NNMT was associated with poor prognosis of patients. Knockdown of NNMT reduced the invasive ability of glioma cells, and downregulation of its downstream protein GAP43 occurred due to altered cellular methylation caused by NNMT overexpression. Gene Set Enrichment Analysis confirmed that NNMT modulated the NAD-related signaling pathway and showed a negative association between NNMT and SIRT1. Moreover, the regulatory roles of NNMT, GAP43, and SIRT1 were confirmed in glioma xenograft mouse models. Conclusion: Overexpression of NNMT causes abnormal DNA methylation through regulation of the NAD/NADH ratio, which in turn leads to the downregulation of GAP43 and SIRT1, eventually altering the biological behavior of tumor cells.

Protein Disulfide-Isomerase A3 Is a Robust Prognostic Biomarker for Cancers and Predicts the Immunotherapy Response Effectively.

BackgroundProtein disulfide isomerase A3 (PDIA3) is a member of the protein disulfide isomerase (PDI) family that participates in protein folding through its protein disulfide isomerase function. It has been reported to regulate the progression of several cancers, but its function in cancer immunotherapy is unknown.MethodsThe RNA-seq data of cancer and normal tissues were downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. The Cbioportal dataset was used to explore the genomic alteration information of PDIA3 in pan-cancer. Human Protein Atlas (HPA) and ComPPI websites were employed to mine the protein information of PDIA3, and western blot assay was performed to monitor the upregulated PDIA3 expression in clinical GBM samples. The univariate Cox regression and the Kaplan–Meier method were utilized to appraise the prognostic role of PDIA3 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was applied to search the associated cancer hallmarks with PDIA3 expression. TIMER2.0 was the main platform to investigate the immune cell infiltrations related to PDIA3 in pan-cancer. The associations between PDIA3 and immunotherapy biomarkers were performed by Spearman correlation analysis. The immunoblot was used to quantify the PDIA3 expression levels, and the proliferative and invasive ability of glioma cells was determined by colony formation and transwell assays.FindingsPDIA3 is overexpressed in most cancer types and exhibits prognosis predictive ability in various cancers, and it is especially expressed in the malignant cells and monocytes/macrophages. In addition, PDIA3 is significantly correlated with immune-activated hallmarks, cancer immune cell infiltrations, and immunoregulators, and the most interesting finding is that PDIA3 could significantly predict anti-PDL1 therapy response. Besides, specific inhibitors that correlated with PDIA3 expression in different cancer types were also screened by using Connectivity Map (CMap). Finally, knockdown of PDIA3 significantly weakened the proliferative and invasive ability of glioma cells.InterpretationThe results revealed that PDIA3 acts as a robust tumor biomarker. Its function in protein disulfide linkage regulation could influence protein synthesis, degradation, and secretion, and then shapes the tumor microenvironment, which might be further applied to develop novel anticancer inhibitors.

Valproic Acid Inhibits Glioma and Its Mechanisms.

Glioma is one of the most common intracranial tumors worldwide, and metastasis and chemoresistance remain a challenge in glioma treatment. This study aims to investigate the effect of sodium valproate on the invasion and metastasis of glioma cells and its mechanism. Glioma cell lines were stimulated with VPA at different concentrations and for different durations of action. U87 glioma cells were transfected with Smad4 plasmid and small interfering RNA, and the changes of EMT-related protein indexes in U87 cells after up- or downregulation of Smad4 were detected by Western blotting. Immunohistochemistry was used to detect the differences in the expression of Smad4, TIF1-γ, and TGF-β proteins in 39 glioma clinical specimens from the Department of Pathology of our hospital. Based on the regulation of EMT-related transcription factors by VPA, our study indicates that VPA inhibits the EMT process of glioma by altering the expression level of Smad4, which is induced by TGF-β1 to form a Smad3/4 complex, thus inducing the EMT process of the tumor and acting as an antitumor target to inhibit the invasive ability of glioma cells. Sodium valproate inhibits glioma invasion and metastasis through the regulation of Smad4 expression.

WDR34 affects PI3K/Akt and Wnt/β-catenin pathways to regulates malignant biological behaviors of glioma cells.

Glioma is the most prevalent primary intracranial tumor globally. WDR34, a member of the WDR superfamily with five WD40 repeats, is involved in the pathogenesis of several tumors. However, the role of WDR34 in glioma progression is unknown. The expression and prognostic significance of WDR34 in glioma patients were analyzed using GEPIA. WDR34 expression was detected by qRT-PCR. Western blot was employed to determine the expression of Ki67, proliferating cell nuclear antigen (PCNA), matrix metallopeptidase (MMP)2, MMP9, phosphatase and tensin homolog, protein kinase B (Akt), phosphorylated Akt, β-catenin, and c-Myc. CCK-8, BrdU incorporation assay, Transwell invasion assay, flow cytometry analysis, and measurement of caspase-3 and caspase-9 activities were conducted to examine the effects of WDR34 knockdown on glioma cells. WDR34 was upregulated in glioma, which predicted a poor prognosis in glioma patients. WDR34 knockdown inhibited cell proliferation and reduced the expression of Ki67 and PCNA in glioma cells. WDR34 knockdown repressed the invasive ability of glioma cells by decreasing MMP-2 and MMP-9 expression. WDR34 knockdown increased the apoptotic rate and caspase-3 and caspase-9 activities in glioma cells. The PI3K/Akt and Wnt/β-catenin pathways were inhibited after WDR34 knockdown in glioma cells. Moreover, overexpression of Akt or β-catenin reversed the function of WDR34 knockdown on proliferation, invasion, and apoptosis. WDR34 knockdown reduced tumor growth in vivo. WDR34 knockdown inhibited malignant biological behaviors of glioma cells by inactivating the PI3K/Akt and Wnt/β-catenin signaling cascades.

Inhibition of FABP6 Reduces Tumor Cell Invasion and Angiogenesis through the Decrease in MMP-2 and VEGF in Human Glioblastoma Cells.

Malignant glioma is one of the most lethal cancers with rapid progression, high recurrence, and poor prognosis in the central nervous system. Fatty acid-binding protein 6 (FABP6) is a bile acid carrier protein that is overexpressed in colorectal cancer. This study aimed to assess the involvement of FABP6 expression in the progression of malignant glioma. Immunohistochemical analysis revealed that FABP6 expression was higher in glioma than in normal brain tissue. After the knockdown of FABP6, a decrease in the migration and invasion abilities of glioma cells was observed. The phosphorylation of the myosin light chain was inhibited, which may be associated with migration ability. Moreover, expression levels of invasion-related proteins, matrix metalloproteinase-2 (MMP-2) and cathepsin B, were reduced. Furthermore, tube formation was inhibited in the human umbilical vein endothelial cells with a decreased concentration of vascular endothelial growth factor (VEGF) in the conditioned medium after the knockdown of FABP6. The phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p65 were also decreased after FABP6 reduction. Finally, the bioluminescent images and immunostaining of MMP-2, cluster of differentiation 31 (CD31), and the VEGF receptor 1 (VEGFR1) revealed attenuated tumor progression in the combination of the FABP6-knocked-down and temozolomide (TMZ)-treated group in an orthotopic xenograft mouse tumor model. This is the first study that revealed the impact of FABP6 on the invasion, angiogenesis, and progression of glioma. The results of this study show that FABP6 may be a potential therapeutic target combined with TMZ for malignant gliomas.

Highly Expressed CYBRD1 Associated with Glioma Recurrence Regulates the Immune Response of Glioma Cells to Interferon.

Invasiveness, resistance to treatment, and recurrence of gliomas are significant hurdles to successful treatment regimens. Data sets from Gene Expression Omnibus (GEO), CGGA-RNAseq, and The Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) were analyzed, and an increased expression of Cytochrome B Reductase 1 (CYBRD1) was identified and could be associated with aggravated clinical outcomes. Gene ontology (GO) enrichment analysis indicated that CYBRD1 co-expressed genes are enriched during an immune response. CYBRD1 overexpression in glioma cell lines is enhanced, whereas CYBRD1 silencing attenuated the aggressiveness of glioma cells. In IFN-α-treated glioma cells, IFN-α suppressed the viability and migratory ability and invasive ability of glioma cells, whereas CYBRD1 overexpression attenuated the antitumor effects of IFN-α. CYBRD1 could potentially serve as a biomarker for glioma recurrence. CYBRD1 overexpression enhances glioma cell aggressiveness and attenuates glioma cell response to IFN-α.

Ultrasound-responsive nutlin-loaded nanoparticles for combined chemotherapy and piezoelectric treatment of glioblastoma cells

Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, represents the most aggressive primary brain tumor. The complex genetic heterogeneity, the acquired drug resistance, and the presence of the blood-brain barrier (BBB) limit the efficacy of the current therapies, with effectiveness demonstrated only in a small subset of patients. To overcome these issues, here we propose an anticancer approach based on ultrasound-responsive drug-loaded organic piezoelectric nanoparticles. This anticancer nanoplatform consists of nutlin-3a-loaded ApoE-functionalized P(VDF-TrFE) nanoparticles, that can be remotely activated with ultrasound-based mechanical stimulations to induce drug release and to locally deliver anticancer electric cues. The combination of chemotherapy treatment with chronic piezoelectric stimulation resulted in activation of cell apoptosis and anti-proliferation pathways, induction of cell necrosis, inhibition of cancer migration, and reduction of cell invasiveness in drug-resistant GBM cells. Obtained results pave the way for the use of innovative multifunctional nanomaterials in less invasive and more focused anticancer treatments, able to reduce drug resistance in GBM. Statement of significancePiezoelectric hybrid lipid-polymeric nanoparticles, efficiently encapsulating a non-genotoxic drug (nutlin-3a) and functionalized with a peptide (ApoE) that enhances their passage through the BBB, are proposed. Upon ultrasound stimulation, nanovectors resulted able to reduce cell migration, actin polymerization, and invasion ability of glioma cells, while fostering apoptotic and necrotic events. This wireless activation of anticancer action paves the way to a less invasive, more focused and efficient therapeutic strategy.

The nuclear transporter importin-11 regulates the Wnt/β-catenin pathway and acts as a tumor promoter in glioma

Karyopherins mediate the macromolecular transport between the cytoplasm and the nucleus and participate in cancer progression. However, the role and mechanism of importin-11 (IPO11), a member of the karyopherin family, in glioma progression remain undefined. Effects of IPO11 on glioma progression were detected using CCK-8, colony formation assay, flow cytometry analysis, caspase-3 activity assay, and Transwell invasion assay. Western blot analysis was used to detect the expression of active caspase-3, active caspase-7, active caspase-9, N-cadherin, Vimentin, E-cadherin, β-catenin, and c-Myc. The activity of Wnt/β-catenin pathway was evaluated by the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor reporter assay. Results showed that IPO11 knockdown inhibited proliferation and reduced colony number in glioma cells. IPO11 silencing promoted the apoptotic rate, increased expression levels of active caspase-3, caspase-7, and caspase-9, and enhanced caspase-3 activity. Moreover, IPO11 silencing inhibited glioma cell invasion by suppressing epithelial-to-mesenchymal transition (EMT). Mechanistically, IPO11 knockdown inactivated the Wnt/β-catenin pathway. β-Catenin overexpression abolished the effects of IPO11 silencing on the proliferation, apoptosis, and invasion in glioma cells. Furthermore, IPO11 silencing blocked the malignant phenotypes and repressed the Wnt/β-catenin pathway in vivo. In conclusion, IPO11 knockdown suppressed the malignant phenotypes of glioma cells by inactivating the Wnt/β-catenin pathway.

Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide

Glioblastoma multiforme (GBM; grade IV glioma) is the most malignant type of primary brain tumor and is characterized by rapid proliferation and invasive growth. Intermedin (IMD) is an endogenous peptide belonging to the calcitonin gene-related peptide family and has been reported to play an important role in cell survival and invasiveness in several types of cancers. In this study, we found that the expression level of IMD was positively related to the malignancy grade of gliomas. The highest expression of IMD was found in GBM, indicating that IMD may play an important role in glioma malignancy. IMD increased the invasive ability of glioma cells by promoting filopodia formation, which is dependent on ERK1/2 activation. IMD-induced ERK1/2 phosphorylation also promoted GBM cell proliferation. In addition, IMD enhanced mitochondrial function and hypoxia-induced responses in GBM cells. Treatment with anti-IMD monoclonal antibodies not only inhibited tumor growth in both ectopic and orthotopic models of GBM but also significantly enhanced the antitumor activity of temozolomide. Our study may provide novel insights into the mechanism of GBM cell invasion and proliferation and provide an effective strategy to improve the therapeutic effect of GBM treatments.