Target For Treatment Of Glioma Research Articles

CHIP-mediated ubiquitin degradation of BCAT1 regulates glioma cell proliferation and temozolomide sensitivity

Glioma, a malignant and infiltrative neoplasm of the central nervous system, poses a significant threat due to its high mortality rates. Branched-chain amino acid transaminase 1 (BCAT1), a key enzyme in branched-chain amino acid (BCAA) catabolism, exhibits elevated expression in gliomas and correlates strongly with poor prognosis. Nonetheless, the regulatory mechanisms underlying this increased BCAT1 expression remains incompletely understood. In this study, we reveal that ubiquitination at Lys360 facilitates BCAT1 degradation, with low ubiquitination levels contributing to high BCAT1 expression in glioma cells. The Carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, interacts with BCAT1 via its coiled-coil (CC) domain, promoting its K48-linkage ubiquitin degradation through proteasomal pathway. Moreover, CHIP-mediated BCAT1 degradation induces metabolic reprogramming, and impedes glioma cell proliferation and tumor growth both in vitro and in vivo. Furthermore, a positive correlation is observed between low CHIP expression, elevated BCAT1 levels, and unfavorable prognosis among glioma patients. Additionally, we show that the CHIP/BCAT1 axis enhances glioma sensitivity to temozolomide by reducing glutathione (GSH) synthesis and increasing oxidative stress. These findings underscore the critical role of CHIP/BCAT1 axis in glioma cell proliferation and temozolomide sensitivity, highlighting its potential as a diagnostic marker and therapeutic target in glioma treatment.

Prognostic value and drug sensitivity of F‑box and leucine‑rich repeat protein 6 in glioma.

Gliomas are highly malignant and invasive tumors lacking clear boundaries. Previous bioinformatics and experimental analyses have indicated that F-box and leucine-rich repeat protein 6 (FBXL6), a protein crucial for the cell cycle and tumorigenesis, is highly expressed in certain types of tumors. The high expression level of FBXL6 is reported to promote tumor growth and adversely affect patient survival. However, the molecular mechanism, prognostic value and drug sensitivity of FBXL6 in glioma remain unclear. To address this, the present study analyzed FBXL6 expression in gliomas, utilizing data from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Analysis of FBXL6 mRNA expression levels, combined with patient factors such as age, sex and tumor grade using Kaplan-Meier plots and nomograms, demonstrated a strong correlation between FBXL6 expression and glioma progression. Co-expression networks provided further insights into the biological function of FBXL6. Additionally, using CIBERSORT and TISDB tools, the correlation between FBXL6 expression correlation tumor-infiltrating immune cells and immune genes was demonstrated to be statistically significant. These findings were validated by examining FBXL6 mRNA and protein levels in glioma tissues using various techniques, including western blot, reverse transcription-quantitative PCR and immunohistochemistry. These assays demonstrated the role of FBXL6 in glioma progression. Furthermore, drug sensitivity analysis demonstrated a strong correlation between FBXL6 expression and various drugs, which indicated that FBXL6 may potentially act as a future promising therapeutic target in glioma treatment. Therefore, the present study identified FBXL6 as a diagnostic and prognostic marker in patients with gliomas and highlighted its potential role in glioma progression.

HIF-1α facilitates glioma proliferation and invasion by activating pyroptosis signaling axis

BackgroundHIF-1α is thought to be a novel regulator which contributes to carcinogenesis. However, the mechanism underlying the effect of HIF-1α in gliomas remains largely unknown.MethodsIn the research, we demonstrate that HIF-lα mRNA and protein levels are elevated in glioma cells. The colony formation assays, transwell assays, and wound-healing assays showed that overexpression of HIF-1α promoted proliferation and invasion of glioma cells.ResultsOverexpression of HIF-lα also increased the expression of inflammatory factors related to pyrolysis (TNF-α, IL-10, and IL-1β) and protein related to pyrolysis signal pathway (NLRP3, ASC, caspase-1, GSDMD, and GSDME).ConclusionsTherefore, we speculate that HIF-1α promotes the proliferation and invasion of glial cells by regulating pyrolysis pathway. These results might provide a novel strategy and target for treatment of glioma.

TENT5A Increases Glioma Malignancy and Promotes its Progression.

Recent studies reported that terminal nucleotidyltransferase 5A (TENT5A) is highly expressed in glioblastoma and associated with poor prognosis. In this work, we aim to specify the expression level of TENT5A in different grades of glioma and explore its role in glioma progression. GEPIA online tools were used to perform the bioinformatic analysis. qRT-PCR, Western blot, and Immunohistochemistry were performed in glioma cells or tissues. Furthermore, CCK8, colony formation, transwell, flow cytometry and scratch assays were performed. TENT5A was highly expressed in glioma and its level was associated with the pathological grade of glioma. Knockdown of TENT5A suppressed cell proliferation, colony formation ability, cell invasion and migration. Overexpression of TENT5A was lethal to the glioma cells. Our data showed that the expression of TENT5A is associated with the pathological grade of glioma. Knockdown of TENT5A decreased the ability of proliferation, invasion and migration of glioma cells. High levels of TENT5A in glioma cells are lethal. Therefore, TENT5A could be a new target for glioma treatment.

PTEN-Long inhibits the biological behaviors of glioma cells.

PTEN-Long is a translational variant of phosphatase and tensin homolog (PTEN). This study aimed to assess the effect of PTEN-Long on the biological characteristics of glioma cells and related mechanisms. A vector stably expressing PTEN-Long was established and transfected into cells, serving as the overexpression group, while a set of empty vectors served as the negative control group. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to detect the expression of PTEN-Long and phosphatidylinositol 3-kinase, Protein kinase B, andnuclear factor-κB (PI3K-AKT-NF-κB). Cell proliferation was assessed with the Cell Counting Kit 8 (CCK8) assay, migration through the scratch test, and invasion by the transwell chamber assay. Cell cycle analysis was performed using flow cytometry. The volume and weight of subcutaneous tumors in nude mice were also evaluated. PTEN-Long expression led to downregulation of p-Akt, NF-κB p65, p-NF-κB p65, and Bcl-xl, and up-regulation of IκBα. In addition, it inhibited glioma cell proliferation, induced cell cycle arrest in the G0/G1 phase, and reduced cell migration and invasion. Moreover, PTEN-Long inhibited the growth of subcutaneous glioma in nude mice. PTEN-Long inhibits the proliferation, migration, and invasion and induces apoptosis in glioma cells by inhibiting PI3K-AKT-NF-κb signaling, implying that PTEN-Long may be a new target for glioma treatment.

TMIC-37. AN ADVANCED PHAGOCYTOSIS GLIOMA THERAPY BASED ON MICROGLIA: INSIGHT FROM AD THERAPY

Abstract INTRODUCTION Alzheimer's disease (AD) has an inverse correlation with glioma incidence. AD brain present a suppressive environment for glioma initiation and progression caused by amyloid β42 (Aβ42) activation of microglia. However, the underlying mechanisms remain elusive. METHODS Public database of patients with AD and brain cancer were collected and analyzed for the correlation between the two distinct diseases. The level of Aβ42 expression was examined by IHC staining in lower-grade glioma (LGG) and higher-grade glioma (HGG). Glioma-bearing mice were applied to evaluate the tumor suppressive effect induced by oligomer Aβ42 (OAβ42) in vivo. The co-culture system was applied to study the mechanism of OAβ42 activated microglia and enhanced tumor cell phagocytosis. RNA sequencing was performed to identify the underlying molecular mechanism involved in OAβ42 potentiated microglial phagocytosis. RESULTS OAβ42 is an innate peptide and a favorable prognostic biomarker of glioma with a prolonged OS in LGG than HGG (P=0.04). Injection of OAβ42 could inhibit the growth of glioma (P=0.0003) through enhancing microglial phagocytosis in the allogeneic mouse model. And the overall survival of the OAβ42 treated mice was longer than the vehicle group (P=.037). The OAβ42 primed microglia phagocytized more glioma cells than vehicle control in a co-culture system (P=0.0007). Autocrine of insulin-like growth factor 1(IGF-1) from OAβ42 activated microglia is essential for engulfing tumor cells. CONCLUSIONS Our findings proved OAβ42 modulated microglia could serve as a cellular target for treatment of glioma. Furthermore, our study provides a novel conceptual therapeutic strategy through modulating the function of existing immune cells in the microenvironment.

SPI1 activates TGF-β1/PI3K/Akt signaling through transcriptional upregulation of FKBP12 to support the mesenchymal phenotype of glioma stem cells.

Glioma stem cells (GSCs) exhibit diverse molecular subtypes with the mesenchymal (MES) population representing the most malignant variant. The oncogenic potential of Salmonella pathogenicity island 1 (SPI1), an oncogenic transcription factor, has been established across various human malignancies. In this study, we explored the association between the SPI1 pathway and the MES GSC phenotype. Through comprehensive analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas glioma databases, along with patient-derived GSC cultures, we analyzed SPI1 expression. Using genetic knockdown and overexpression techniques, we assessed the functional impact of SPI1 on GSC MES marker expression, invasion, proliferation, self-renewal, and sensitivity to radiation in vitro, as well as its influence on tumor formation in vivo. Additionally, we investigated the downstream signaling cascades activated by SPI1. Our findings revealed a positive correlation between elevated SPI1 expression and the MES phenotype, which in turn, correlated with poor survival. SPI1 enhanced GSC MES differentiation, self-renewal, and radioresistance in vitro, promoting tumorigenicity in vivo. Mechanistically, SPI1 augmented the transcriptional activity of both TGF-β1 and FKBP12 while activating the non-canonical PI3K/Akt pathway. Notably, inhibition of TGF-β1/PI3K/Akt signaling partially attenuated SPI1-induced GSC MES differentiation and its associated malignant phenotype. Collectively, our results underscore SPI1's role in activating TGF-β1/PI3K/Akt signaling through transcriptional upregulation of FKBP12, thereby supporting the aggressive MES phenotype of GSCs. Therefore, SPI1 emerges as a potential therapeutic target in glioma treatment.

Knockdown of circEXOC6 inhibits cell progression and glycolysis by sponging miR-433-3p and mediating FZD6 in glioma.

The effect of circular RNA in many human cancers is widely studied. Nevertheless, their specific biological functions and mechanisms in glioma remain unclear. CircEXOC6, miR-433-3p, and frizzled class receptor 6 (FZD6) mRNA expression levels were measured by quantitative reverse transcription polymerase chain reaction assay. Cell proliferation, migration, invasion, apoptosis, and angiogenesis were tested by colony formation, cell-light 5-ethynyl-2'-deoxyuridine, transwell, and tube formation assays, respectively. Moreover, glucose consumption and lactate production were calculated to evaluate the glycolytic metabolism using the respective kits. Western blot assay was carried out to measure the protein levels of apoptotic markers (Bcl-2 and Bax), glycolytic markers (HK2 and GLUT1), and FZD6. The targeted relationship of miR-433-3p and circEXOC6 or FZD6 was verified by dual-luciferase reporter or RNA immunoprecipitation assays. In vivo, xenograft and immunohistochemistry assay was conducted to discriminate the effect of circEXOC6. CircEXOC6 and FZD6 were highly expressed, while miR-433-3p was significantly lowly expressed in glioma tissues or cells. Deficiency of circEXOC6 inhibited cell proliferation, migration, invasion, angiogenesis, and glycolysis, and triggered cell apoptosis ratio in glioma; simultaneously, it could block the growth of tumor in vivo. In addition, miR-433-3p was a target of circEXOC6, and downregulated miR-433-3p could partly weaken the inhibitory effect of circEXOC6 deficiency. Besides, miR-433-3p enrichment inhibited cell progression and glycolysis in glioma, and the effect was reversed by overexpression of FZD6. Deletion of circEXOC6 restrained cell progression and glycolysis by sponging miR-433-3p and interacting with FZD6, which might provide an underlying target for glioma treatment.

Multiscale imaging of peroxynitrite in gliomas with a blood-brain barrier permeable probe reveals its potential as a biomarker and target for glioma treatment

Cancer development is driven by diverse processes, and metabolic alterations are among the primary characteristics. Multiscale imaging of aberrant metabolites in cancer is critical to understand the pathology and identify new targets for treatment. While peroxynitrite (ONOO−) is reported being enriched in some tumors and plays important tumorigenic roles, whether it is upregulated in gliomas remains unexplored. To determine the levels and roles of ONOO− in gliomas, efficient tools especially those with desirable blood-brain barrier (BBB) permeability and can realize the in situ imaging of ONOO− in multiscale glioma-related samples are indispensable. Herein, we proposed a strategy of physicochemical property-guided probe design, which resulted in the development of a fluorogenic probe NOSTracker for smartly tracking ONOO−. The probe showed sufficient BBB permeability. ONOO− triggered oxidation of its arylboronate group was automatically followed by a self-immolative cleavage of a fluorescence-masking group, liberating its fluorescence signal. The probe was not only highly sensitive and selective towards ONOO−, but its fluorescence favored desirable stability in various complex biological milieus. Guaranteed by these properties, multiscale imaging of ONOO− was realized in vitro in patient-derived primary glioma cells, ex vivo in clinical glioma slices, and in vivo in the glioma of live mice. The results showed the upregulation of ONOO− in gliomas. Furthermore, a specific ONOO− scavenger uric acid (UA) was pharmaceutically used to downregulate ONOO− in glioma cell lines, and an anti-proliferative effect was observed. These results taken together imply the potential of ONOO− as a biomarker and target for glioma treatment, and propose NOSTracker as a reliable tool to further explore the role of ONOO− in glioma development.

PA2G4P4 Promotes Glioma Cell Migration and Tumorigenesis through the PTEN/AKT/mTOR Signaling Pathway

Dysregulation of pseudogene expression is closely related to the progression of various cancers, including glioma. Proliferation-associated 2G4 pseudogene 4 (PA2G4P4) could affect cell viability and apoptosis of glioma cells. However, the specific regulatory mechanism of PA2G4P4 is not clear. In this paper, we found that PA2G4P4 overexpres-sion promoted glioma cell proliferation, migration and cell cycle progression, whereas PA2G4P4 knockdown inhibited cancer progression. Knockdown of PA2G4P4 also suppressed the tumorigenesis of glioma cells in vivo. Furthermore, knockdown of PA2G4 after overexpression of PA2G4P4 decreased the cell viability and migration ability to normal level. The protein level of a tumor suppressor gene phosphatase and tensing homolog (PTEN) was greatly decreased in U87 cells after PA2G4P4 overexpression, while increased after PA2G4 knockdown; on the contrary, the protein levels of P-AKT and P-S6 were obviously induced in U87 cells after PA2G4P4 overexpression, and decreased after PA2G4 knockdown. The cell ability, colony formation ability and cell migration ability were all recovered to normal level by adding an AKT inhibitor MK2206 to the glioma cells, which were induced by PA2G4P4 overexpression. Our results revealed that PA2G4P4 could regulate glioma cell proliferation and migration through PTEN/AKT/mTOR signaling pathway by targeting PA2G4 gene. PA2G4P4 may become a target for glioma treatment.

SLC1A5 enhances malignant phenotypes through modulating ferroptosis status and immune microenvironment in glioma

Glioma is the most common type of primary malignant tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients classified into the high-risk group had more immuno-suppressive status and worse prognosis. Among these 7 genes, we screened solute carrier family 1 member 5 (SLC1A5), an FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation and invasion, and reduce the sensitivity of ferroptosis via the GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages. Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could apply to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.

Emerging roles of ferroptosis in glioma.

Glioma is the most common primary malignant tumor in the central nervous system, and directly affects the quality of life and cognitive function of patients. Ferroptosis, is a new form of regulated cell death characterized by iron-dependent lipid peroxidation. Ferroptosis is mainly due to redox imbalance and involves multiple intracellular biology processes, such as iron metabolism, lipid metabolism, and antioxidants synthesis. Induction of ferroptosis could be a new target for glioma treatment, and ferroptosis-related processes are associated with chemoresistance and radioresistance in glioma. In the present review, we provide the characteristics, key regulators and pathways of ferroptosis and the crosstalk between ferroptosis and other programmed cell death in glioma, we also proposed the application and prospect of ferroptosis in the treatment of glioma.

CDH6 as a prognostic indicator and marker for chemotherapy in gliomas.

Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore, new targets for glioma treatment are needed. This study examined the cadherin-6 (CDH6) expression in gliomas using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. CDH6 expression positively correlated with the World Health Organization (WHO) tumor grade and negatively correlated with patient prognosis. A significant decrease in CDH6 promoter methylation was identified with an increase in the WHO grade severity. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that CDH6 might be involved in cell–cell interactions and immune processes in the glioma microenvironment. Weighted gene co-expression network analysis revealed a correlation between CDH6 and cell adhesion molecules, focal adhesions, phosphatidylinositol 3-kinase-protein kinase B signaling pathways, nuclear division, chromosome segregation, mitotic nuclear division, and immune-related pathways. CDH6 strongly correlated with immunosuppressive cells, including regulatory T cells, monocytes, macrophages, tumor-associated macrophages, and myeloid-derived suppressor cells. It also showed correlations with immune-active cells such as B cells, CD8+ T cells, and dendritic cells. Single-cell analysis showed that CDH6 was expressed mainly in astrocyte (AC)-like malignant cells. Differentially expressed genes of AC-like malignant cells were found to be associated with stress response, membranous processes, viral infections, and several types of cancers. Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy.

Gp96 Expression in Gliomas and Its Association with Tumor Malignancy and T Cell Infiltrating Level

Heat shock protein glycoprotein 96 kDa (gp96) implicates in glioma invasiveness and engages antitumor immune response, representing a potential target for glioma treatment. However, its expression in different types of gliomas, its association with glioma-infiltrating T cells (GITs), and their clinical significance remain unknown. Herein, we utilized multiplex immunofluorescence staining (MIS) to detect gp96 expression and GIT levels on a tissue microarray (TMA), that comprises 234 glioma cases. We then validated the TMA results and explored possible mechanisms by investigating the RNA-seq data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We observed that gp96 was ubiquitously expressed in all types of gliomas whereas overexpressed in grade IV gliomas. Also, high gp96 expression predicted unfavorable outcomes independent of the malignancy grade. Meanwhile, gp96 expression positively correlated CD8+, CD4+, and PD-1+ cell densities, and especially associated with increased infiltration of CD4+ PD-1+ GITs. Clinically, the gp96-immune cell score (GI score), by summing the values measuring gp96 expression and immune cell densities, is capable of stratifying patients into four outcome-distinct groups (hazard ratio, 1.945; 95% CI, 1.521–2.486; P < 0.0001). Mechanistically, the interferon-γ/α response pathways were revealed to engage in the association between gp96 and GITs. Taken together, gp96 was ubiquitously expressed in gliomas, overexpressed in grade IV gliomas, and increased with GIT infiltrative levels. The GI score, that integrates levels of gp96 expression and GIT infiltration, is a potential prognostic classification system for gliomas.

Analysis of the Mechanism of RAD18 in Glioma

Introduction: This study aimed to evaluate the regulatory mechanism of RAD18 in glioma development. Methods: RAD18 expression was compared in glioma tumors and normal samples. Furthermore, we investigated the association between gene transcription and clinical factors in glioma samples, followed by functional enrichment analysis, screening for key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, immune infiltration analysis of high and low RAD18 expression groups, and correlation analysis of quantified KEGG signaling pathways and immune cell types. Results: The expression of RAD18 was upregulated in gliomas. Moreover, RAD18 expression was significantly correlated with age, tumor grade, and histological subtype. Notably, patients with gliomas with high RAD18 expression levels had worse overall survival. Functional enrichment analysis showed that RAD18 was significantly related to biological processes, such as cell division, chemical synaptic transmission, and mitotic nuclear division, and KEGG pathways such as cell cycle, oxidative phosphorylation, and extracellular matrix (ECM)-receptor interaction. The infiltration of five immune cells (plasma B cells, naive B cells, resting CD4+ memory T cells, monocytes, and M1 macrophages) was significantly different between the high and low RAD18 expression groups, and this difference was significantly related to key KEGG pathways, such as neuroactive ligand-receptor interaction and ECM-receptor interaction. Conclusion: RAD18 may serve as a target for glioma treatment and as a key regulator of glioma development.

Pseudogene RPL32P3 regulates the blood\u2013tumor barrier permeability via the YBX2/HNF4G axis

The existence of the blood–tumor barrier (BTB) severely hinders the transport of anti-tumor drugs to brain tumor tissues. Selectively opening BTB is of great significance to improve the chemotherapy effect of glioma. Pseudogenes have been recognized as important regulators in various biologic processes. In this study, we identified that ribosomal protein L32 pseudogene 3 (RPL32P3) was highly expressed in glioma-exposed endothelial cells (GECs). Knockdown of RPL32P3 decreased the expression of tight junction-related proteins (TJPs) and increased BTB permeability. Subsequent analysis of the underlying mechanism indicated that RPL32P3 recruited lysine methyltransferase 2 A (KMT2A) to the Y-box binding protein 2 (YBX2) promoter region and mediated H3K4me3 to promote YBX2 transcription. Highly expressed YBX2 bound and stabilized hepatocyte nuclear factor 4 gamma (HNF4G) mRNA. Highly expressed HNF4G directly bound to the promoters of TJPs ZO-1, occludin and claudin-5 to promote their transcriptional activities and regulated BTB permeability. The simultaneous knockdown of RPL32P3, YBX2, and HNF4G combined with doxorubicin (DOX) increased the apoptosis of glioma cells. In conclusion, the current study indicated that RPL32P3 knockdown increased BTB permeability through the YBX2/HNF4G pathway. These findings may provide new targets for the comprehensive treatment of glioma.

TRIP4 transcriptionally activates DDIT4 and subsequent mTOR signaling to promote glioma progression

In spite of significant advances in the understanding of glioma biology and pathology, survival remains poor. Therefore, it is still of great significance to further explore the key factors involved in tumorigenesis and development in glioma and find potential new therapeutic targets. Here, we show that thyroid hormone receptor interactor 4 (TRIP4) is highly expressed in glioma cells and tissues. Patients of glioma with high expression of TRIP4 possess poor overall survival. Knockdown of TRIP4 inhibited tumor cell proliferation, metastasis, and apoptosis suppression, whereas overexpression of TRIP4 displays the opposite effects. Further research showed that TRIP4 promoted glioma progression through regulating DDIT4 expression and subsequent activation of mTOR signaling. DDIT4 overexpression restored the inhibition of tumor growth by TRIP4 knockdown in vitro and in vivo. Consistently, mTOR activity inhibition reversed TRIP4 overexpression-mediated tumor promotion in vitro and in vivo. Moreover, molecular mechanism exploration demonstrates that TRIP4 functions as a specific transcriptional activator to anchor at the promoter region of DDIT4 gene (−196 to −11) to regulate its transcription and such regulation was affected by HIF1α. Clinically, TRIP4 expression is positively correlated with DDIT4 expression in glioma samples based on tissue microarray analysis and both of their high expression predicts the malignancy of the disease. Altogether, our findings identify TRIP4 as a critical promoter of glioma progression by targeting DDIT4 and mTOR signaling successively and suggest that TRIP4-DDIT4 axis has potential to be a novel therapeutic target in glioma treatment.

Heterogeneity of subsets in glioblastoma mediated by Smad3 palmitoylation

Glioblastoma (GBM) is the most common and deadly of the primary intracranial tumors and is comprised of subsets that show plasticity and marked heterogeneity, contributing to the lack of success in genomic profiling to guide development of precision medicine for these tumors. In this study, a mutation in isocitrate dehydrogenase 1 was found to suppress the transforming growth factor-beta signaling pathway and E2F4 interacted with Smad3 to inhibit expression of mesenchymal markers. However, palmitoylation of Smad3 mediated by palmitoyltransferase ZDHHC19 promoted activation of the transforming growth factor-beta signaling pathway, and its interaction with EP300 promoted expression of mesenchymal markers in the mesenchymal subtype of GBM. Smad3 and hypoxia-inducible factor 1-alpha may be important molecular targets for treatment of glioma because they appear to coordinate the basic aspects of cancer stem cell biology.

Long Noncoding RNA PVT1 Promotes Stemness and Temozolomide Resistance through miR-365/ELF4/SOX2 Axis in Glioma.

Long non-coding RNA (lncRNA) are a class of non-coding RNAs demonstrated to play pivotal roles in regulating tumor progression. Therefore, deciphering the regulatory role of lncRNA in the development of glioma may offer a promising therapeutic target for treatment of glioma. We performed RT-qPCR analysis on the expression of lncRNA plasmacytoma variant translocation 1 (PVT1) and miR-365 in glioma tissues and cell lines. Cell proliferation and viability was assessed with CCK8 assay. Cell migration was assessed by wound healing assay. Transwell assay was used to assess cell invasion capacity. Expression of CD133+ cells was detected by flow cytometry. Western blot assay was used to detection the expression of ELF4 and stemness-related protein SOX2, Oct4 and Nanog. Bioinformatics and dual-luciferase assay were used to predict and validate the interaction between PVT1 and miR-365. Elevated PVT1 expression was observed in glioma tissues and cells. Knockdown of PVT1 and overexpression of miR-365 inhibited proliferation, migration, invasion and promoted stemness and Temozolomide (TMZ) resistance of glioma cells. PVT1 regulated ELF4 expression by competitively binds to miR-365. PVT1 regulated the stemness and sensitivity of TMZ of glioma cells through miR-365/ELF4/SOX2 axis. This study identified that PVT1 promoted glioma stemness through miR-365/ELF4/SOX2 axis.

MiR-451 suppresses EMT and metastasis in glioma cells

ABSTRACT The metastasis of tumor cells is a challenge for the clinical treatment of glioma. Epithelial-mesenchymal transition (EMT) contributes to glioma cell invasiveness. Our previous study confirmed that the expression of miRNA-451, which inhibits the PI3K/Akt signaling pathway by directly targeting CAB39 and plays a repressive role in glioma, is downregulated in glioma. However, the specific mechanism of miRNA-451 regulation in glioma is unclear. In this study, we investigated whether miRNA-451 blocks the processes of EMT and metastasis in glioma cells in vivo and in vitro. By targeting CAB39, miRNA-451 likely triggers the PI3K/Akt/Snail signaling pathway to reduce glioma proliferation, invasion, migration and EMT. We used Western blotting experiments to demonstrate that overexpression of miRNA-451 significantly reduced p-AKT(Ser473), N-cadherin, Vimentin, Twist, Snail and Cyclin D1 expression and increased E-cadherin expression. We demonstrated that overexpression of miR-451 suppressed glioma cell proliferation, invasion, migration and EMT by MTT and colony formation assays, Transwell assays, wound healing assays and animal experiments. Taken together, these results suggest that miRNA-451 can reduce EMT and metastasis in glioma cells through the suppression of the PI3K/Akt/Snail signaling pathway by targeting CAB39 in vitro and in vivo. miR-451 may be a new target for glioma treatment.