Glioblastoma multiforme (GBM) is a devastating brain tumour without effective treatment. Recent studies have shown that autophagy is a promising therapeutic strategy for GBM. Therefore, it is necessary to identify novel biomarkers associated with autophagy in GBM. In this study, we downloaded autophagy-related genes from Human Autophagy Database (HADb) and Gene Set Enrichment Analysis (GSEA) website. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were performed to identify genes for constructing a risk signature. A nomogram was developed by integrating the risk signature with clinicopathological factors. Time-dependent receiver operating characteristic (ROC) curve and calibration plot were used to evaluate the efficiency of the prognostic model. Finally, four autophagy-related genes (DIRAS3, LGALS8, MAPK8 and STAM)were identified and were used for constructing a risk signature, which proved to be an independent risk factor for GBM patients. Furthermore, a nomogram was developed based on the risk signature and clinicopathological factors (IDH1 status, age and history of radiotherapy or chemotherapy). ROC curve and calibration plot suggested the nomogram could accurately predict 1-, 3-and 5-year survival rate of GBM patients.For function analysis, the risk signature was associated with apoptosis, necrosis, immunity, inflammation response and MAPK signalling pathway. In conclusion, the risk signature with 4 autophagy-related genes could serve as an independent prognostic factor for GBM patients. Moreover, we developed a nomogram based on the risk signature and clinical traits which was validated to perform better for predicting 1-, 3-and 5-year survival rate of GBM. K E Y W O R D Sautophagy, glioblastoma multiform, nomogram, prognosis, risk signature
Background Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment and immunotherapy is still poorly understood. Methods Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma. Results Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with PD-1/L1 blockade generated a synergistic therapeutic outcome in GBM murine models. Conclusions This work provides a molecular, clinical and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade (ICB) treatment with ferroptosis inhibition.
Objective: Glioblastoma (GBM) is the most common and fatal primary brain tumor in adults. It is necessary to identify novel and effective biomarkers or risk signatures for GBM patients. Methods: Differentially expressed genes (DEGs) between GBM and low-grade glioma (LGG) in TCGA samples were screened out and weight correlation network analysis (WGCNA) was performed to confirm WHO grade-related genes. Five genes were selected via multivariate Cox proportional hazards regression analysis and were used to construct a risk signature. A nomogram composed of the risk signature and clinical characters (age, radiotherapy, and chemotherapy experience) was established to predict 1, 3, 5-year survival rate for GBM patients. Results: One hundred ninety-four DEGs in blue gene module were found to be positively related to WHO grade via WGCNA. Five genes (DES, RANBP17, CLEC5A, HOXC11, POSTN) were selected to construct a risk signature for GBM via R language. This risk signature was identified to independently predict the outcome of GBM patients, as well as stratified by IDH1 status, MGMT promoter status, and radio-chemotherapy. The nomogram was established which combined the risk signature with clinical factors. The results of c-index, ROC curve and calibration plot revealed the nomogram showing a good accuracy for predicting 1, 3, or 5-year survival of GBM patients. Conclusion: The risk signature with five genes could serve as an independent factor for predicting the prognosis of patients with GBM. Moreover, the nomogram with the risk signature and clinical traits proved to perform better for predicting 1, 3, 5-year survival rate.
Glioma is the most prevalent primary brain tumour in adults. As well as being highly invasive, it is characterized by diffuse infiltration, fuzzy boundaries and aggressive proliferation. 1 With the development of molecular biological techniques, our understanding of the pathogenesis of glioma has greatly improved, and clinically, important genetic changes have been identified. In the revised classification of central nervous system (CNS) tumours proposed by the World Health Organization (WHO) in 2016, gliomas were classified based on a combination of histological findings and molecular findings, namely isocitrate dehydrogenase (IDH) mutations, 1p19q codeletion, H3 Lys27Met and RELA-fusion. 2 However, although the diagnosis and treatment of gliomas have been greatly improved, the outcome of glioma patients is still unfavourable, with a mortality rate of nearly 80% during the first year of diagnosis. 3 For glioblastomas (GBMs), median survival is only approximately 15 months. 4 Thus, there is an urgent need to improve the diagnosis and treatment of glioma.
Background: Interferon treatment, as an important approach of anti-tumor immunotherapy, has been implemented in multiple clinical trials of glioma. However, only a small number of gliomas benefit from it. Therefore, it is necessary to investigate the clinical role of interferons and to establish robust biomarkers to facilitate its application. Materials and methods: This study reviewed 1,241 glioblastoma (GBM) and 1,068 lower grade glioma (LGG) patients from six glioma cohorts. The transcription matrix and clinical information were analyzed using R software, GraphPad Prism 7 and Medcalc, etc. Immunohistochemical (IHC) staining were performed for validation in protein level. Results: Interferon signaling was significantly enhanced in GBM. An interferon signature was developed based on five interferon genes with prognostic significance, which could reflect various interferon statuses. Survival analysis showed the signature could serve as an unfavorable prognostic factor independently. We also established a nomogram model integrating the risk signature into traditional prognostic factors, which increased the validity of survival prediction. Moreover, high-risk group conferred resistance to chemotherapy and high IFNB1 expression levels. Functional analysis showed that the high-risk group was associated with overloaded immune response. Microenvironment analysis and IHC staining found that high-risk group occupied a disorganized microenvironment which was characterized by an enrichment of M0 macrophages and neutrophils, but less infiltration of activated nature killing (NK) cells and M1 type macrophages. Conclusion: This interferon signature was an independent indicator for unfavorable prognosis and showed great potential for screening out patients who will benefit from chemotherapy and interferon treatment.
Background: Glioblastoma (GBM) is the most lethal cancer of the central nervous system. Integrin beta 5 (ITGB5) is thought to be involved in intercellular signal transduction and regulation of tumor initiation and progression. However, the function of ITGB5 in GBM is not known.Methods: To address this question, we evaluated the expression level of ITGB5 in clinical specimens by immunohistochemistry and western blotting, as well as the association between ITGB5 expression and GBM patient survival using data from Chinese Glioma Genome Atlas and The Cancer Genome Atlas. The biological function of ITGB5 in GBM was investigated by Gene Ontology, gene set enrichment, and in vitro loss-of-function experiments using glioma cells.Results: Among integrin family members, ITGB5 showed the greatest difference in expression between low-grade glioma and GBM. Elevated ITGB5 expression was highly correlated with glioma progression and a mesenchymal subtype and poor survival in GBM patients. ITGB5 was found to be associated with regulation of the immune response and angiogenesis in GBM, and was required for migration and invasion of glioma cells and tube formation by endothelial cells.Conclusions: These data indicate that ITGB5 can serve as a predictive biomarker for GBM patient survival and is a potential therapeutic target in GBM treatment.
Background: Glioma is the most common primary brain tumor with a dismal prognosis. It is urgent to develop novel molecular biomarkers and conform to individualized schemes.Methods: Differentially expressed pseudogenes between low grade glioma (LGG) and glioblastoma multiforme (GBM) were identified in the training cohort. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox proportional hazards regression analyses were used to select pseudogenes associated with prognosis of glioma. A risk signature was constructed based on the selected pseudogenes for predicting the survival of glioma patients. A pseudogene-miRNA-mRNA regulatory network was established and visualized using Cytoscape 3.5.1. Gene Oncology (GO) and signaling pathway analyses were performed on the targeted genes to investigate functional roles of the risk signature.Results: Five pseudogenes (ANXA2P2, EEF1A1P9, FER1L4, HILS1, and RAET1K) correlating with glioma survival were selected and used to establish a risk signature. Time-dependent receiver operating characteristic (ROC) curves revealed that the risk signature could accurately predict the 1, 3, and 5-year survival of glioma patients. GO and signaling pathway analyses showed that the risk signature was involved in regulation of proliferation, migration, angiogenesis, and apoptosis in glioma.Conclusions: In this study, a risk signature with five pseudogenes was constructed and shown to accurately predict 1-, 3-, and 5-year survival for glioma patient. The risk signature may serve as a potential target against glioma.
BackgroundGlioma is the most common primary brain tumor in adults with a poor prognosis. As a member of ARF subfamily GTPase, ARL2 plays a key role in regulating the dynamics of microtubules and mitochondrial functions. Recently, ARL2 has been identified as a prognostic and therapeutic target in a variety range of malignant tumors. However, the biological functional role of ARL2 in glioma still remains unknown. The aim of this study was to explore the expression and functional role of ARL2 in glioma.MethodsIn this study, we investigated the expression of ARL2 in glioma samples by using RT-PCR, immunohistochemistry and western blot. The correlation between ARL2 expression and the outcomes of glioma patients was evaluated with survival data from TCGA, CGGA and Rembrandt dataset. Lentiviral technique was used for ARL2 overexpression in U87 and U251 cells. CCK8 assay, colony formation assay, wound healing test, transwell invasion assay and in vivo subcutaneous xenograft model were performed to investigated the biological functions of ARL2.ResultsARL2 expression was down-regulated in glioma, and was inversely associated with poor prognosis in glioma patients. Furthermore, exogenous ARL2 overexpression attenuated the growth and colony-formation abilities of glioma cells, as well as their migration and invasive capabilities. Moreover, elevated expression of ARL2 inhibited in vivo tumorigenicity of glioma cells. Mechanistically, ARL2 regulated AXL expression, which was known as an important functional regulator of proliferation and tumorigenicity in glioma cells.ConclusionOur study suggests that ARL2 inhibits the proliferation, migration and tumorigenicity of glioma cells by regulating the expression of AXL and may conduct as a new prognostic and therapeutic target for glioma.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4517-0) contains supplementary material, which is available to authorized users.
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