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Yuan H, Cheng J, Xia J, Yang Z, Xu L. Identification of critical biomarkers and immune landscape patterns in glioma based on multi-database. Discov Oncol 2025; 16:35. [PMID: 39800804 PMCID: PMC11725551 DOI: 10.1007/s12672-024-01653-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/28/2024] [Indexed: 01/16/2025] Open
Abstract
PURPOSE Glioma is the most prevalent tumor of the central nervous system. The poor clinical outcomes and limited therapeutic efficacy underscore the urgent need for early diagnosis and an optimized prognostic approach for glioma. Therefore, the aim of this study was to identify sensitive biomarkers for glioma. PATIENTS AND METHODS Differentially expressed genes (DEGs) of glioma were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The potential biomarkers were identified using weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression. The prognostic ability of the potential biomarkers was evaluated by Cox regression and survival curve. CellMiner was used to access the correlation between the expression of potential biomarkers and anticancer drug sensitivity. We then explored the association of potential biomarkers and tumor immune infiltration by single-sample GSEA (ssGSEA) and CIBERSORT. Immune staining in glioma patient samples and cell experiments of potential biomarkers further verified their expression and function. RESULTS Ultimately, we identified three potential biomarkers: SLC8A2, ATP2B3, and SRCIN1. These 3 genes were found significantly correlated with clinicopathological features (age, WHO grade, IDH mutation status, 1p19q codeletion status). Furthermore, the overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were found to be positively correlated with high expression of these 3 potential biomarkers. Besides, there was a substantial relationship between the sensitivity of anticancer drugs and these biomarkers expression. More importantly, the negative association between the 3 genes with most tumor immune cells was also established. Moreover, the decreased expression of the biomarkers was also verified in glioma patient samples. Finally, we confirmed that these 3 genes might promotes glioma proliferation and migration in vitro. CONCLUSION SLC8A2, ATP2B3, and SRCIN1 were identified as underlying biomarkers for glioma associated with prognosis assessments and personal immunotherapy.
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Affiliation(s)
- Hanzhang Yuan
- Department of Neurosurgery, Yueyang Central Hospital, Yueyang, 414020, Hunan, China
| | - Jingsheng Cheng
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, 415003, Hunan, China
| | - Jun Xia
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, 415003, Hunan, China
| | - Zeng Yang
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, 415003, Hunan, China
| | - Lixin Xu
- Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, 415003, Hunan, China.
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Reiche L, Plaack B, Lehmkuhl M, Weyers V, Gruchot J, Picard D, Perron H, Remke M, Knobbe-Thomsen C, Reifenberger G, Küry P, Kremer D. HERV-W envelope protein is present in microglial cells of the human glioma tumor microenvironment and differentially modulates neoplastic cell behavior. Microbes Infect 2024:105460. [PMID: 39577621 DOI: 10.1016/j.micinf.2024.105460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 10/28/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
Gliomas are the most common parenchymal tumors of the central nervous system (CNS). With regard to their still unclear etiology, several recent studies have provided evidence of a new category of pathogenic elements called human endogenous retroviruses (HERVs) which seem to contribute to the evolution and progression of many neurological diseases such as amyotrophic lateral sclerosis (ALS), schizophrenia, chronic inflammatory polyneuropathy (CIDP) and, particularly, multiple sclerosis (MS). In these diseases, HERVs exert effects on cellular processes such as inflammation, proliferation, and migration. In previous studies, we demonstrated that in MS, the human endogenous retrovirus type-W envelope protein (HERV-W ENV) interferes with lesion repair through the activation of microglia (MG), the innate myeloid immune cells of the CNS. Here, we now show that HERV-W ENV is also present in the microglial cells (MG) of the tumor microenvironment (TME) in gliomas. It modulates the behavior of glioblastoma (GBM) cell lines in GBM/MG cocultures by altering their gene expression, secreted cytokines, morphology, proliferation, and migration properties and could thereby contribute to key tumor properties.
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Affiliation(s)
- Laura Reiche
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Benedikt Plaack
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Maike Lehmkuhl
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Vivien Weyers
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Joel Gruchot
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Daniel Picard
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Hervé Perron
- R&D Division, GeNeuro Innovation, Lyon, France; GeNeuro, Plan-les-Ouates, Switzerland
| | - Marc Remke
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Christiane Knobbe-Thomsen
- Institute of Neuropathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany; ViraTherapeutics GmbH, Rum, Austria
| | - Guido Reifenberger
- Institute of Neuropathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Patrick Küry
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany; Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - David Kremer
- Department of Neurology and Neurorehabilitation, Hospital Zum Heiligen Geist, Academic Teaching Hospital of the Heinrich-Heine-University Düsseldorf, Kempen, Germany.
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Atanaki FF, Mirsadeghi L, Manesh MR, Kavousi K. Integrative analysis of single-cell transcriptomic and multilayer signaling networks in glioma reveal tumor progression stage. Front Genet 2024; 15:1446903. [PMID: 39606019 PMCID: PMC11599185 DOI: 10.3389/fgene.2024.1446903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
Introduction Tumor microenvironments (TMEs) encompass complex ecosystems of cancer cells, infiltrating immune cells, and diverse cell types. Intercellular and intracellular signals within the TME significantly influence cancer progression and therapeutic outcomes. Although computational tools are available to study TME interactions, explicitly modeling tumor progression across different cancer types remains a challenge. Methods This study introduces a comprehensive framework utilizing single-cell RNA sequencing (scRNA-seq) data within a multilayer network model, designed to investigate molecular changes across glioma progression stages. The heterogeneous, multilayered network model replicates the hierarchical structure of biological systems, from genetic building blocks to cellular functions and phenotypic manifestations. Results Applying this framework to glioma scRNA-seq data allowed complex network analysis of different cancer stages, revealing significant ligand‒receptor interactions and key ligand‒receptor-transcription factor (TF) axes, along with their associated biological pathways. Differential network analysis between grade III and grade IV glioma highlighted the most critical nodes and edges involved in interaction rewiring. Pathway enrichment analysis identified four essential genes-PDGFA (ligand), PDGFRA (receptor), CREB1 (TF), and PLAT (target gene)-involved in the Receptor Tyrosine Kinases (RTK) signaling pathway, which plays a pivotal role in glioma progression from grade III to grade IV. Discussion These genes emerged as significant features for machine learning in predicting glioma progression stages, achieving 87% accuracy and 93% AUC in a 3-year survival prediction through Kaplan-Meier analysis. This framework provides deeper insights into the cellular machinery of glioma, revealing key molecular relationships that may inform prognosis and therapeutic strategies.
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Affiliation(s)
- Fereshteh Fallah Atanaki
- Laboratory of Complex Biological Systems and Bioinformatics (CBB), Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Leila Mirsadeghi
- Laboratory of Complex Biological Systems and Bioinformatics (CBB), Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | | | - Kaveh Kavousi
- Laboratory of Complex Biological Systems and Bioinformatics (CBB), Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
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Liu Z, Zang M, Li K, Qi W, Yuan H, Chen L, Zhang Y. The immunotherapy-based combination associated score as a robust predictor for outcome and response to combination of immunotherapy and VEGF inhibitors in renal cell carcinoma. Comput Biol Med 2024; 182:109210. [PMID: 39341105 DOI: 10.1016/j.compbiomed.2024.109210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 08/10/2024] [Accepted: 09/23/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Over the past decade, the realm of immunotherapy-based combination therapy has witnessed rapid growth for renal cell carcinoma (RCC), however, success has been constrained thus far. This limitation primarily stems from the absence of biomarkers essential for identifying patients likely to derive benefits from such treatments. METHODS In this study, the immunotherapy-based combination associated score (IBCS) was established using single-sample gene set enrichment analysis (ssGSEA) based on the genes identified in the key modules extracted by weighted correlation network analysis (WGCNA) in the IMmotion151 dataset, a randomized, global phase III trial. RESULTS High IBCS patients showed better responses to immunotherapy-based combinations and had longer progression-free survival (PFS). Further transcriptomic analysis revealed that IBCS was negatively correlated to TIDE score, identifying a subset of RCC patients characterized by enrichment of T-effector and moderate cell-cycle/angiogenesis gene expression. Our analysis of hub genes unveiled a novel molecule that could potentially serve as a target antigen in RCC. Validation through multiplex immunofluorescence assays on tissue microarrays (TMAs) containing 180 samples confirmed the pivotal role of this hub gene in immunoregulation. Furthermore, we developed an independent risk score model, which is significant for prognostic evaluation and patient stratification. Notably, we devised a forecasting nomogram using this risk score model, surpassing the IMDC score (a widely accepted risk score for predicting survival in patients undergoing VEGF-targeted therapy) in prognostic accuracy for patients treated with immunotherapy-based combinations. CONCLUSION This study has collectively developed an immunotherapy-based combination associated score, pinpointed effective biomarkers for prognostic and responsiveness of kidney cancer patients to immunotherapy-based combinations, and delved into their potential biological mechanisms, offering promising targets for further exploration.
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Affiliation(s)
- Zhengfang Liu
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Maolin Zang
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Kaiyue Li
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Wenqiang Qi
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Huiyang Yuan
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Lipeng Chen
- Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yan Zhang
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Shenzhen Research Institute, Shandong University, Shenzhen, Guangdong, 518057, China.
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Zhu C, Chen X, Liu TQ, Cheng L, Cheng W, Cheng P, Wu AH. Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma. Nat Commun 2024; 15:8506. [PMID: 39353936 PMCID: PMC11445535 DOI: 10.1038/s41467-024-52888-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 09/24/2024] [Indexed: 10/03/2024] Open
Abstract
Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn't induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.
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Affiliation(s)
- Chen Zhu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Xin Chen
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Tian-Qi Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Lin Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Wen Cheng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
- Institute of Health Sciences, China Medical University, Shenyang, China.
| | - Peng Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
- Institute of Health Sciences, China Medical University, Shenyang, China.
| | - An-Hua Wu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
- Institute of Health Sciences, China Medical University, Shenyang, China.
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Azimi P, Yazdanian T, Ahmadiani A. mRNA markers for survival prediction in glioblastoma multiforme patients: a systematic review with bioinformatic analyses. BMC Cancer 2024; 24:612. [PMID: 38773447 PMCID: PMC11106946 DOI: 10.1186/s12885-024-12345-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 05/06/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is a type of fast-growing brain glioma associated with a very poor prognosis. This study aims to identify key genes whose expression is associated with the overall survival (OS) in patients with GBM. METHODS A systematic review was performed using PubMed, Scopus, Cochrane, and Web of Science up to Journey 2024. Two researchers independently extracted the data and assessed the study quality according to the New Castle Ottawa scale (NOS). The genes whose expression was found to be associated with survival were identified and considered in a subsequent bioinformatic study. The products of these genes were also analyzed considering protein-protein interaction (PPI) relationship analysis using STRING. Additionally, the most important genes associated with GBM patients' survival were also identified using the Cytoscape 3.9.0 software. For final validation, GEPIA and CGGA (mRNAseq_325 and mRNAseq_693) databases were used to conduct OS analyses. Gene set enrichment analysis was performed with GO Biological Process 2023. RESULTS From an initial search of 4104 articles, 255 studies were included from 24 countries. Studies described 613 unique genes whose mRNAs were significantly associated with OS in GBM patients, of which 107 were described in 2 or more studies. Based on the NOS, 131 studies were of high quality, while 124 were considered as low-quality studies. According to the PPI network, 31 key target genes were identified. Pathway analysis revealed five hub genes (IL6, NOTCH1, TGFB1, EGFR, and KDR). However, in the validation study, only, the FN1 gene was significant in three cohorts. CONCLUSION We successfully identified the most important 31 genes whose products may be considered as potential prognosis biomarkers as well as candidate target genes for innovative therapy of GBM tumors.
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Affiliation(s)
- Parisa Azimi
- Neurosurgeon, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, 19839- 63113, Iran.
| | | | - Abolhassan Ahmadiani
- Neurosurgeon, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran, 19839- 63113, Iran.
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Yang YP, Bai M, Cheng YX, Feng X, Zhang YY, Zhang YY, Liu MY, Duan YQ. Based on the prognosis model of immunogenes, the prognosis model was constructed to predict the invasion of immune genes and immune cells related to primary liver cancer and its experimental validation. Heliyon 2024; 10:e27362. [PMID: 38560168 PMCID: PMC10980948 DOI: 10.1016/j.heliyon.2024.e27362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 04/04/2024] Open
Abstract
Background Primary liver cancer (PLC) is a prevalent malignancy of the digestive system characterized by insidious symptom onset and a generally poor prognosis. Recent studies have highlighted a significant correlation between the initiation and prognosis of liver cancer and the immune function of PLC patients. Purpose Revealing the expression of PLC-related immune genes and the characteristics of immune cell infiltration provides assistance for the analysis of clinical pathological parameters and prognosis of PLC patients. Methods PLC-related differentially expressed genes (DEGs) with a median absolute deviation (MAD > 0.5) were identified from TCGA and GEO databases. These DEGs were intersected with immune-related genes (IRGs) from the ImmPort database to obtain PLC-related IRGs. The method of constructing a prognostic model through immune-related gene pairs (IRGPs) is used to obtain IRGPs and conduct the selection of central immune genes. The central immune genes obtained from the selection of IRGPs are validated in PLC. Subsequently, the relative proportions of 22 types of immune cells in different immune risk groups are evaluated, and the differential characteristics of PLC-related immune cells are verified through animal experiments. Results Through database screening and the construction of an IRGP prognosis model, 84 pairs of IRGPs (P < 0.001) were ultimately obtained. Analysis of these 84 IRGPs revealed 11 central immune genes related to PLC, showing differential expression in liver cancer tissues compared to normal liver tissues. Results from the CiberSort platform indicate differential expression of immune cells such as naive B cells, macrophages, and neutrophils in different immune risk groups. Animal experiments demonstrated altered immune cell proportions in H22 tumor-bearing mice, validating findings from peripheral blood and spleen homogenate analyses. Conclusion Our study successfully predicted and validated PLC-related IRGs and immune cells, suggesting their potential as prognostic indicators and therapeutic targets for PLC.
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Affiliation(s)
- Yu-Ping Yang
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Min Bai
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yin-Xia Cheng
- Ningxia Medical University, College of Traditional Chinese Medicine, Yinchuan, 750000, PR China
| | - Xin Feng
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yan-Ying Zhang
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yuan-Yuan Zhang
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Meng-Ya Liu
- Gansu University of Traditional Chinese Medicine, College of Basic Medical Sciences, Lanzhou, 730000, PR China
| | - Yong-Qiang Duan
- Ningxia Medical University, College of Traditional Chinese Medicine, Yinchuan, 750000, PR China
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Luo Z, Liu X, Chen Y, Shen L, Qin H, Zha Q, Hu F, Wang Y. Gene features of tumor-specific T cells relevant to immunotherapy, targeted therapy and chemotherapy in lung cancer. Heliyon 2024; 10:e28374. [PMID: 38590880 PMCID: PMC10999884 DOI: 10.1016/j.heliyon.2024.e28374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 04/10/2024] Open
Abstract
1 Background In lung cancer, the use of small-molecule inhibitors, chemotherapy and immunotherapy has led to unprecedented survival benefits in selected patients. Considering most patients will experience a relapse within a short period of time due to single drug resistance, combination therapy is also particularly important to improve patient prognosis. Therefore, more robust biomarkers to predict responses to immunotherapy, targeted therapy, chemotherapy and rationally drug combination therapies may be helpful in clinical treatment choices. 2 Methods We defined tumor-specific T cells (TSTs) and their features (TSTGs) by single-cell RNA sequencing. We applied LASSO regression to filter out the most survival-relevant TSTGs to form the Tumor-specific T cell score (TSTS). Immunological characteristics, enriched pathways, and mutation were evaluated in high- and low TSTS groups. 3 Results We identified six clusters of T cells as TSTs in lung cancer, and four most robust genes from 9 feature genes expressed only on tumor-specific T cells were screened to construct a tumor-specific T cells score (TSTS). TSTS was positively correlated with immune infiltration and angiogenesis and negatively correlated with malignant cell proliferation. Moreover, potential vascular-immune crosstalk in lung cancer provides the theoretical basis for combined anti-angiogenic and immunotherapy. Noticeable, patients in high TSTS had better response to ICB and targeted therapy and patients in the low TSTS group often benefit from chemotherapy. 4 Conclusion The proposed TSTS is a promising indicator to predict immunotherapy, targeted therapy and chemotherapy responses in lung cancer patients for helping clinical treatment choices.
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Affiliation(s)
- Ziwei Luo
- Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200120, China
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xuefei Liu
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China
- Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital, Shenzhen, Guangdong, 518038, China
| | - Ying Chen
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Lize Shen
- LC-Bio Technology Co.ltd, Hangzhou, 310018, China
| | - Hui Qin
- Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200120, China
| | - Qiongfang Zha
- Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200120, China
| | - Feng Hu
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200120, China
| | - Yali Wang
- Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200120, China
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Zhang C, Wang Y, Shao W, Zhou D, Yu D, Hou S, Lin N. A novel NFAT1-IL6/JAK/STAT3 signaling pathway related nomogram predicts overall survival in gliomas. Sci Rep 2023; 13:11401. [PMID: 37452092 PMCID: PMC10349126 DOI: 10.1038/s41598-023-38629-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023] Open
Abstract
The NFAT1-mediated IL6/JAK-STAT signaling pathway has been observed to contribute to malignant progression in glioma patients. To predict the overall survival (OS) rate of these patients, a prognostic model was developed based on this pathway. Two datasets, mRNAseq_325 and mRNAseq_693, were obtained from the China Glioma Genome Atlas (CGGA), excluding some patients with a lack of survival information, resulting in the inclusion of 684 glioma cases. The two groups were randomly divided into training and validation groups to analyze the differential expression of NFAT1 in pan-cancer and investigate the relationship between differential NFAT1 expression and glioma clinicopathological factors and Transcriptional subtypes. A prediction model based on the IL6/JAK/STAT signaling pathway was constructed using the LASSO-COX dimension reduction analysis to predict the OS of glioma patients. Pearson correlation analysis was utilized to identify gene sets associated with patient risk scores and to perform GO and KEGG analyses. NFAT1 is differentially expressed in a variety of cancers and is enriched in the more malignant potential glioma subtypes. It is an independent prognostic factor in glioma patients, and its expression is significantly positively correlated with the IL6/JAK/STAT signalling pathway in glioma patients. The final prediction model incorporating the seven candidate genes together with other prognostic factors showed strong predictive performance in both the training and validation groups. Risk scores of glioma patients were correlated with processes such as NF-κB and protein synthesis in glioma patients. This individualized prognostic model can be used to predict the OS rate of patients with glioma at 1, 2, 3, 5, and 10 years, providing a reference value for the treatment of glioma patients.
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Affiliation(s)
- Chao Zhang
- Department of Neurosurgery, The Affliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, 239000, China
| | - Yu Wang
- Department of Neurosurgery, The Affliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, 239000, China
| | - Wei Shao
- Department of Neurosurgery, The Affliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, 239000, China
| | - Dongrui Zhou
- Department of Neurosurgery, The Affliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, 239000, China
| | - Dong Yu
- Department of Neurosurgery, The Affliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, 239000, China
| | - Shiqiang Hou
- Department of Neurosurgery, The Affliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, 239000, China
| | - Ning Lin
- Department of Neurosurgery, The Affliated Chuzhou Hospital of Anhui Medical University, The First People's Hospital of Chuzhou, Chuzhou, 239000, China.
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Xu C, Wang P, Guo H, Shao C, Liao B, Gong S, Zhou Y, Yang B, Jiang H, Zhang G, Wu N. MiR-146a-5p deficiency in extracellular vesicles of glioma-associated macrophages promotes epithelial-mesenchymal transition through the NF-κB signaling pathway. Cell Death Discov 2023; 9:206. [PMID: 37391426 DOI: 10.1038/s41420-023-01492-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 06/05/2023] [Accepted: 06/15/2023] [Indexed: 07/02/2023] Open
Abstract
Glioma-associated macrophages (GAMs) are pivotal chains in the tumor immune microenvironment (TIME). GAMs mostly display M2-like phenotypes with anti-inflammatory features related to the malignancy and progression of cancers. Extracellular vesicles derived from immunosuppressive GAMs (M2-EVs), the essential components of the TIME, greatly impact the malignant behavior of GBM cells. M1- or M2-EVs were isolated in vitro, and human GBM cell invasion and migration were reinforced under M2-EV treatment. Signatures of the epithelial-mesenchymal transition (EMT) were also enhanced by M2-EVs. Compared with M1-EVs, miR-146a-5p, considered the key factor in TIME regulation, was deficient in M2-EVs according to miRNA-sequencing. When the miR-146a-5p mimic was added, EMT signatures and the invasive and migratory abilities of GBM cells were correspondingly weakened. Public databases predicted the miRNA binding targets and interleukin 1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were screened as miR-146a-5p binding genes. Bimolecular fluorescent complementation and coimmunoprecipitation confirmed interactions between TRAF6 and IRAK1. The correlation between TRAF6 and IRAK1 was evaluated with immunofluorescence (IF)-stained clinical glioma samples. The TRAF6-IRAK1 complex is the switch and the brake that modulates IKK complex phosphorylation and NF-κB pathway activation, as well as the EMT behaviors of GBM cells. Furthermore, a homograft nude mouse model was explored and mice transplanted with TRAF6/IRAK1-overexpressing glioma cells had shorter survival times while mice transplanted with glioma cells with miR-146a-5p overexpression or TRAF6/IRAK1 knockdown lived longer. This work indicated that in the TIME of GBM, the deficiency of miR-146a-5p in M2-EVs enhances tumor EMT through disinhibition of the TRAF6-IRAK1 complex and IKK-dependent NF-κB signaling pathway providing a novel therapeutic strategy targeting the TIME of GBM.
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Affiliation(s)
- Chao Xu
- Chongqing Medical University, Chongqing, China
- Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China
- Chongqing School, University of Chinese Academy of Sciences, Chongqing, China
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Pan Wang
- Chongqing Medical University, Chongqing, China
- Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China
- Chongqing School, University of Chinese Academy of Sciences, Chongqing, China
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Haiyan Guo
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Chuan Shao
- Chongqing Medical University, Chongqing, China
- Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China
- Chongqing School, University of Chinese Academy of Sciences, Chongqing, China
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Bin Liao
- Chongqing Medical University, Chongqing, China
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Sheng Gong
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Yanghao Zhou
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Bingjie Yang
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Haotian Jiang
- Chongqing Medical University, Chongqing, China
- Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China
- Chongqing School, University of Chinese Academy of Sciences, Chongqing, China
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Gang Zhang
- Chongqing Medical University, Chongqing, China
- Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China
- Chongqing School, University of Chinese Academy of Sciences, Chongqing, China
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China
| | - Nan Wu
- Chongqing Medical University, Chongqing, China.
- Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China.
- Chongqing School, University of Chinese Academy of Sciences, Chongqing, China.
- Department of Neurosurgery, Chongqing General Hospital, Chongqing, China.
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11
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Roddy AC, McInerney CE, Flannery T, Healy EG, Stewart JP, Spence VJ, Walsh J, Salto-Tellez M, McArt DG, Prise KM. Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification. Biomedicines 2023; 11:biomedicines11041219. [PMID: 37189838 DOI: 10.3390/biomedicines11041219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM.
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Affiliation(s)
- Aideen C Roddy
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Caitríona E McInerney
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Tom Flannery
- Department of Neurosurgery, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast BT12 6BA, UK
| | - Estelle G Healy
- Regional Service for Neuropathology, Institute of Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast BT12 6BA, UK
| | - James P Stewart
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Veronica J Spence
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Jamie Walsh
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Manuel Salto-Tellez
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
- Integrated Pathology Unit, Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK
| | - Darragh G McArt
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
| | - Kevin M Prise
- Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, Belfast BT9 7AE, UK
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12
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Cheng X, Liu Z, Liang W, Zhu Q, Wang C, Wang H, Zhang J, Li P, Gao Y. ECM2, a prognostic biomarker for lower grade glioma, serves as a potential novel target for immunotherapy. Int J Biochem Cell Biol 2023; 158:106409. [PMID: 36997057 DOI: 10.1016/j.biocel.2023.106409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
Extracellular matrix protein 2 (ECM2), which regulates cell proliferation and differentiation, has recently been reported as a prognostic indicator for multiple cancers, but its value in lower grade glioma (LGG) remains unknown. In this study, LGG transcriptomic data of 503 cases in The Cancer Genome Atlas (TCGA) database and 403 cases in The Chinese Glioma Genome Atlas (CGGA) database were collected to analyze ECM2 expression patterns and the relationship with clinical characteristics, prognosis, enriched signaling pathways, and immune-related markers. In addition, a total of 12 laboratory samples were used for experimental validation. Wilcoxon or Kruskal-Wallis tests demonstrated highly expressed ECM2 in LGG was positively associated with malignant histological features and molecular features such as recurrent LGG and isocitrate dehydrogenase (IDH) wild-type. Also, Kaplan-Meier (KM) curves proved high ECM2 expression could predict shorter overall survival in LGG patients, as multivariate analysis and meta-analysis claimed ECM2 was a deleterious factor for LGG prognosis. In addition, the enrichment of immune-related pathways for ECM2, for instance JAK-STAT pathway, was obtained by Gene Set Enrichment Analysis (GSEA) analysis. Furthermore, positive relationships between ECM2 expression with immune cells infiltration and cancer-associated fibroblasts (CAFs), iconic markers (CD163), and immune checkpoints (CD274, encoding PD-L1) were proved by Pearson correlation analysis. Finally, laboratory experiments of RT-qPCR and immunohistochemistry showed high expression of ECM2, as well as CD163 and PD-L1 in LGG samples. This study identifies ECM2, for the first time, as a subtype marker and prognostic indicator for LGG. ECM2 could also provide a reliable guarantee for further personalized therapy, synergizing with tumor immunity, to break through the current limitations and thus reinvigorating immunotherapy for LGG. AVAILABILITY OF DATA AND MATERIALS: Raw data from all public databases involved in this study are stored in the online repository (chengMD2022/ECM2 (github.com)).
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13
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A transcriptome-based analysis reveals functional differences among Dendrobium officinale Kimura & Migo species from different growing regions and with different quality levels. MEDICINE IN NOVEL TECHNOLOGY AND DEVICES 2022. [DOI: 10.1016/j.medntd.2022.100163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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14
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Duhamel M, Drelich L, Wisztorski M, Aboulouard S, Gimeno JP, Ogrinc N, Devos P, Cardon T, Weller M, Escande F, Zairi F, Maurage CA, Le Rhun É, Fournier I, Salzet M. Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival. Nat Commun 2022; 13:6665. [PMID: 36333286 PMCID: PMC9636229 DOI: 10.1038/s41467-022-34208-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Molecular heterogeneity is a key feature of glioblastoma that impedes patient stratification and leads to large discrepancies in mean patient survival. Here, we analyze a cohort of 96 glioblastoma patients with survival ranging from a few months to over 4 years. 46 tumors are analyzed by mass spectrometry-based spatially-resolved proteomics guided by mass spectrometry imaging. Integration of protein expression and clinical information highlights three molecular groups associated with immune, neurogenesis, and tumorigenesis signatures with high intra-tumoral heterogeneity. Furthermore, a set of proteins originating from reference and alternative ORFs is found to be statistically significant based on patient survival times. Among these proteins, a 5-protein signature is associated with survival. The expression of these 5 proteins is validated by immunofluorescence on an additional cohort of 50 patients. Overall, our work characterizes distinct molecular regions within glioblastoma tissues based on protein expression, which may help guide glioblastoma prognosis and improve current glioblastoma classification.
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Affiliation(s)
- Marie Duhamel
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France.
| | - Lauranne Drelich
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France
| | - Maxence Wisztorski
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France
| | - Soulaimane Aboulouard
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France
| | - Jean-Pascal Gimeno
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France
| | - Nina Ogrinc
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France
| | - Patrick Devos
- Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des technologies de santé et des pratiques médicales, F-59000, Lille, France
| | - Tristan Cardon
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France
| | - Michael Weller
- Department of Neurology & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Fabienne Escande
- CHU Lille, Service de biochimie et biologie moléculaire, CHU Lille, F-59000, Lille, France
| | - Fahed Zairi
- CHU Lille, Service de neurochirurgie, F-59000, Lille, France
| | - Claude-Alain Maurage
- CHU Lille, Service de biochimie et biologie moléculaire, CHU Lille, F-59000, Lille, France
| | - Émilie Le Rhun
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France.
- Department of Neurology & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
- CHU Lille, Service de biochimie et biologie moléculaire, CHU Lille, F-59000, Lille, France.
| | - Isabelle Fournier
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France.
- Institut Universitaire de France (IUF), 75000, Paris, France.
| | - Michel Salzet
- Univ.Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), F-59000, Lille, France.
- Institut Universitaire de France (IUF), 75000, Paris, France.
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15
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Cancer cell intrinsic TIM-3 induces glioblastoma progression. iScience 2022; 25:105329. [DOI: 10.1016/j.isci.2022.105329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 11/30/2021] [Accepted: 10/07/2022] [Indexed: 11/17/2022] Open
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16
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Tan L, Liu X, Gao W, Zhao Q. Identification of Four Hub Genes as Promising Biomarkers for the Evaluation of Ovarian Cancer Prognosis. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Ovarian malignant growth is perhaps the most lethal disease in females. There are no exact biomarkers for the early determination of ovarian disease. We obtained a total of 12 gene clusters through WGCNA and studied the azure gene modules related to the lymphatic infiltration of ovarian
cancer further. What’s more, endurance investigation was utilized to decide three qualities connected with the by and large and infection-free endurance in ovarian disease patients, including GOGA8B [Hazard Ratio (HR)=1.53, p=0.037, 95% CI: 1.05–2.24], LRRC26
(HR=0.7, p =0.045, 95% CI: 0.48–1.01), and CCDC114 (HR = 0.72, p = 0.042, 95% CI: 0.53–0.98). A prognostic risk score model was built to anticipate the endurance pace of patients at 1, 3, and 5 years, individually. The area under the receiver operating characteristic
(ROC) curve (AUC) of the training set was 0.749, 0.764, and 0.784, respectively; the test AUC was 0.601, 0.623, and 0.709. Our review gives a point of view on significant possible biomarkers for the determination, anticipation, and therapy of ovarian malignant growth.
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Affiliation(s)
- Li Tan
- Department of Gynaecology and Obstetrics, The Second People’s Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, China
| | - Xiaoting Liu
- Department of Gynaecology and Obstetrics, The Second People’s Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, China
| | - Wei Gao
- Department of Orthopedics, The Second People’s Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, Hunan, 470007, China
| | - Qiong Zhao
- Department of Gynaecology and Obstetrics, The Second People’s Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, China
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17
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Zeng J, Hua S, Liu J, Mungur R, He Y, Feng J. Identification of core genes as potential biomarkers for predicting progression and prognosis in glioblastoma. Front Genet 2022; 13:928407. [PMID: 36238156 PMCID: PMC9552700 DOI: 10.3389/fgene.2022.928407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Glioblastoma is a common malignant neuroepithelial neoplasm with poor clinical outcomes and limited treatment options. It is extremely important to search and confirm diverse hub genes that are effective in the advance and prediction of glioblastoma. Methods: We analyzed GSE50161, GSE4290, and GSE68848, the three microarray datasets retrieved from the GEO database. GO function and KEGG pathway enrichment analyses for differentially expressed genes (DEGs) were performed using DAVID. The PPI network of the DEGs was analyzed using the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape software. Hub genes were identified through the PPI network and a robust rank aggregation method. The Cancer Genome Atlas (TCGA) and the Oncomine database were used to validate the hub genes. In addition, a survival curve analysis was conducted to verify the correlation between the expression of hub genes and patient prognosis. Human glioblastoma cells and normal cells were collected, and then RT-PCR, Western blot, and immunofluorescence were conducted to validate the expression of the NDC80 gene. A cell proliferation assay was used to detect the proliferation of glioma cells. The effects of NDC80 expression on migration and invasion of GBM cell lines were evaluated by conducting scratch and transwell assays. Results: A total of 716 DEGs were common to all three microarray datasets, which included 188 upregulated DEGs and 528 downregulated DEGs. Furthermore, we found that among the common DEGs, 10 hub genes showed a high degree of connectivity. The expression of the 10 hub genes in TCGA and the Oncomine database was significantly overexpressed in glioblastoma compared with normal genes. Additionally, the survival analysis showed that the patients with low expression of six genes (BIR5C, CDC20, NDC80, CDK1, TOP2A, and MELK) had a significantly favorable prognosis (p < 0.01). We discovered that NDC80, which has been shown to be important in other cancers, also has an important role in malignant gliomas. The RT-PCR, Western blot, and immunofluorescence results showed that the expression level of NDC80 was significantly higher in human glioblastoma cells than in normal cells. Moreover, we identified that NDC80 increased the proliferation and invasion abilities of human glioblastoma cells. Conclusion: The six genes identified here may be utilized to form a panel of disease progression and predictive biomarkers of glioblastoma for clinical purposes. NDC80, one of the six genes, was discovered to have a potentially important role in GBM, a finding that needs to be further studied.
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Affiliation(s)
- Jianping Zeng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Jianping Zeng,
| | - Shushan Hua
- Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Liu
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Rajneesh Mungur
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Yongsheng He
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiugeng Feng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
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18
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Ye S, Yang B, Zhang T, Wei W, Li Z, Chen J, Li X. Identification of an Immune-Related Prognostic Signature for Glioblastoma by Comprehensive Bioinformatics and Experimental Analyses. Cells 2022; 11:cells11193000. [PMID: 36230961 PMCID: PMC9562700 DOI: 10.3390/cells11193000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/13/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Glioblastoma (GBM), which has a poor prognosis, accounts for 31% of all cancers in the brain and central nervous system. There is a paucity of research on prognostic indicators associated with the tumor immune microenvironment in GBM patients. Accurate tools for risk assessment of GBM patients are urgently needed. Methods: In this study, we used weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) methods to screen out GBM-related genes among immune-related genes (IRGs). Then, we used survival analysis and Cox regression analysis to identify prognostic genes among the GBM-related genes to further establish a risk signature, which was validated using methods including ROC analysis, stratification analysis, protein expression level validation (HPA), gene expression level validation based on public cohorts, and RT-qPCR. In order to provide clinicians with a useful tool to predict survival, a nomogram based on an assessment of IRGs and clinicopathological features was constructed and further validated using DCA, time-dependent ROC curve, etc. Results: Three immune-related genes were found: PPP4C (p < 0.001, HR = 0.514), C5AR1 (p < 0.001, HR = 1.215), and IL-10 (p < 0.001, HR = 1.047). An immune-related prognostic signature (IPS) was built to calculate risk scores for GBM patients; patients classified into different risk groups had significant differences in survival (p = 0.006). Then, we constructed a nomogram based on an assessment of the IRG-based signature, which was validated as a potential prediction tool for GBM survival rates, showing greater accuracy than the nomogram without the IPS when predicting 1-year (0.35 < Pt < 0.50), 3-year (0.65 < Pt < 0.80), and 5-year (0.65 < Pt < 0.80) survival. Conclusions: In conclusion, we integrated bioinformatics and experimental approaches to construct an IPS and a nomogram based on IPS for predicting GBM prognosis. The signature showed strong potential for prognostic prediction and could help in developing more precise diagnostic approaches and treatments for GBM.
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Singh M, Raghav A, Gautam KA. Role of the circulatory interleukin-6 in the pathogenesis of gliomas: A systematic review. World J Methodol 2022; 12:428-437. [PMID: 36186749 PMCID: PMC9516551 DOI: 10.5662/wjm.v12.i5.428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/01/2022] [Accepted: 07/25/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Glioma is the most common primary tumor in the brain originating from glial cells. In spite of extensive research, the overall survival rate is not enhanced. A number of published articles observed differentially circulating levels of cytokines in glioma. Interleukin-6 (IL-6) protein coded by IL-6 gene is regulated by the immune system and it has been found to have a significant role in progression and apoptosis resistance of glioma.
AIM To review the role of circulatory IL-6 in the development and progression of glioma and its utility as a biomarker.
METHODS Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were applied to filter the relevant studies based on inclusion and exclusion criteria. We used a combination of keywords and the Reference Citation Analysis (RCA) tool to search the potential studies and performed data extraction from selected studies.
RESULTS The published results were inconsistent; however, most studies showed a significantly higher IL-6 level in glioma cases as compared to controls. Comparative IL-6 level among the different grades of glioma showed a higher level with low-grade gliomas and lower level with high-grade gliomas.
CONCLUSION IL-6 level significantly differed between cases and controls, and among different cancer stages, which shows its potential as a diagnostic and prognostic marker.
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Affiliation(s)
- Manish Singh
- Department of Neurosurgery, GSVM Medical College, Kanpur 208001, India
| | - Alok Raghav
- Department of Neurosurgery, GSVM Medical College, Kanpur 208001, India
| | - Kirti Amresh Gautam
- Department of Basic and Applied Science, GD Goenka University, Gurugram 122103, Haryana, India
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20
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Lerond J, Morisse MC, Letourneur Q, Gimonnet C, Navarro S, Gaspar C, Idbaih A, Bielle F. Immune Microenvironment and Lineage Tracing Help to Decipher Rosette-Forming Glioneuronal Tumors: A Multi-Omics Analysis. J Neuropathol Exp Neurol 2022; 81:873-884. [PMID: 35984315 DOI: 10.1093/jnen/nlac074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Rosette-forming glioneuronal tumors (RGNT) are rare low-grade primary central nervous system (CNS) tumors. The methylation class (MC) RGNT (MC-RGNT) delineates RGNT from other neurocytic CNS tumors with similar histological features. We performed a comprehensive molecular analysis including whole-exome sequencing, RNAseq, and methylome on 9 tumors with similar histology, focusing on the immune microenvironment and cell of origin of RGNT. Three RGNT in this cohort were plotted within the MC-RGNT and characterized by FGFR1 mutation plus PIK3CA or NF1 mutations. RNAseq analysis, validated by immunohistochemistry, identified 2 transcriptomic groups with distinct immune microenvironments. The "cold" group was distinguishable by a low immune infiltration and included the 3 MC-RGNT and 1 MC-pilocytic astrocytoma; the "hot" group included other tumors with a rich immune infiltration. Gene set enrichment analysis showed that the "cold" group had upregulated NOTCH pathway and mainly oligodendrocyte precursor cell and neuronal phenotypes, while the "hot" group exhibited predominantly astrocytic and neural stem cell phenotypes. In silico deconvolution identified the cerebellar granule cell lineage as a putative cell of origin of RGNT. Our study identified distinct tumor biology and immune microenvironments as key features relevant to the pathogenesis and management of RGNT.
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Affiliation(s)
- Julie Lerond
- Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université, AP-HP, SIRIC Curamus, Paris, France
| | - Mony Chenda Morisse
- AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France
| | | | | | - Soledad Navarro
- AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurochirurgie, Paris, France
| | - Cassandra Gaspar
- Sorbonne Université, Inserm, UMS Production et Analyse des données en Sciences de la vie et en Santé, PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, Paris, France
| | - Ahmed Idbaih
- Sorbonne Université, AP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France
| | - Franck Bielle
- Sorbonne Université, AP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neuropathologie, Paris, France.,AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Onconeurotek, Paris, France
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21
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Bioinformatics Analysis for Constructing a Six-Immune-Related Long Noncoding RNA Signature as a Prognostic Model of Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2022; 2022:2093437. [PMID: 35845962 PMCID: PMC9283041 DOI: 10.1155/2022/2093437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/21/2022] [Indexed: 12/24/2022]
Abstract
The present study was aimed at identifying the potential prognostic biomarkers of the immune-related long noncoding RNA (IRL) signature for patients with hepatocellular carcinoma (HCC). RNA-sequencing data and clinical information about HCC were obtained from The Cancer Genome Atlas. The IRLs were determined with regard to the coexpression of immune-related genes and differentially expressed lncRNAs. The survival IRLs were obtained using the univariate Cox analysis. Subsequently, the prognosis model was constructed via the multivariate Cox analysis. Subsequently, functional annotation was conducted using Gene Set Enrichment Analysis (GSEA) and principal component analysis (PCA). In total, 341 IRLs were identified, and 6 IRLs were found to have a highly significant association with the prognosis of patients with HCC. The immune prognosis model was constructed with these 6 IRLs (AC099850.4, negative regulator of antiviral response, AL031985.3, PRRT3-antisense RNA1, AL365203.2, and long intergenic nonprotein coding RNA 1224) using the multivariate Cox regression analysis. In addition, immune-related prognosis signatures were confirmed as an independent prognostic factor. The association between prognostic signatures and immune infiltration indicated that the 6 lncRNAs could reflect the immune status of the tumor. Collectively, the present study demonstrates that six-lncRNA signatures may be potential biomarkers to predict the prognosis of patients with HCC.
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22
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Liu M, Wei D, Nie Q, Peng L, He L, Cui Y, Ye Y. Uncovering of potential molecular markers for cervical squamous cell carcinoma (CESC) based on analysis of methylated-differentially expressed genes. Taiwan J Obstet Gynecol 2022; 61:663-671. [PMID: 35779918 DOI: 10.1016/j.tjog.2022.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2022] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVE Cervical squamous cell carcinoma (CESC) is a cancer with high mortality caused by human papillomavirus. The aim of this study was to uncover potential CESC biomarkers to help early diagnosis and treatment. MATERIALS AND METHODS The mRNA transcriptome data and DNA methylation data were downloaded from database for the identification of differentially expressed mRNAs (DEmRNAs) and DNA methylation analysis. Functional analysis was used to reveal the molecular functions. Then, the association between differential methylation and DEmRNA was analyzed. Protein-protein interaction (PPI) network analysis was performed on the selected differentially methylated genes (DEGs). Subsequently, we analyzed the prognosis and constructed a prognostic risk model. We also performed diagnostic analyses of risk model genes. In addition, we verified the protein expression level of identified DEGs. RESULTS 1438 DEmRNAs, 1669 differentially methylated sites (DMSs), 46 differentially methylated CpG islands and 53 differential methylation genes (DMGs) were obtained. In PPI, the highest interaction scores were MX2 and IRF8, and their interaction score was 0.928. Interestingly, 5 DMGs were found to be associated with CESC prognosis. In addition, our results demonstrated that high risk score was associated with poor prognosis of CESC. Furthermore, it was found that ZIK1, ZNRF2, HHEX, VCAM1 could be diagnostic molecular markers for CESC. CONCLUSION Analysis of methylated-differentially expressed genes may contribute to the identification of early diagnosis and therapeutic targets of CESC. In addition, a prognostic model based on 5 DMGs can be used to predict the prognosis of CESC.
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Affiliation(s)
- Miaomiao Liu
- Department of Medical Imaging, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, China; The Fifth Department of Oncology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, China
| | - Dong Wei
- Department of Urology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, China
| | - Qian Nie
- China Physical Examination Center of Hebei General Hospital, 348 Heping West Road, Shijiazhuang, China
| | - Lili Peng
- The Fifth Department of Oncology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, China
| | - Liya He
- The Fifth Department of Oncology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, China
| | - Yujie Cui
- The Fifth Department of Oncology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, China
| | - Yuquan Ye
- Department of Medical Imaging, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, China; Department of Ultrasound, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, China.
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23
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The Potential Diagnostic Value of Immune-Related Genes in Interstitial Fibrosis and Tubular Atrophy after Kidney Transplantation. J Immunol Res 2022; 2022:7212852. [PMID: 35755170 PMCID: PMC9232312 DOI: 10.1155/2022/7212852] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/29/2022] [Accepted: 05/11/2022] [Indexed: 12/02/2022] Open
Abstract
Background Inflammation within areas of interstitial fibrosis and tubular atrophy (IF/TA) is associated with kidney allograft failure. The aim of this study was to reveal new diagnostic markers of IF/TA based on bioinformatics analysis. Methods Raw data of IF/TA samples after kidney transplantation and control samples after kidney transplantation were extracted from the Gene Expression Omnibus (GEO) database (GSE76882 and GSE120495 datasets), and genes that were differentially expressed between the two groups (DEGs) were screened. Gene Set Enrichment Analysis (GSEA), ESTIMATE and single sample GSEA (ssGSEA), least absolute shrinkage and selection operator (LASSO) regression analysis, and competing endogenous RNA (ceRNA) network were used to analyze the data. Results The results of GSEA revealed that multiple immune-related pathways were enriched in the IF/TA group, and subsequent immune landscape analysis also showed that the IF/TA group had higher immune and stromal scores and up to 15 types of immune cells occupied them, such as B cells, cytotoxic cells, and T cells. LASSO regression analysis selected 6 (including ANGPTL3, APOH, LTF, FCGR2B, HLA-DQA2, and EGF) out of 14 DE-IRGs as diagnostic genes to construct a diagnostic model. Then, receiver operating characteristic (ROC) curve analysis showed the powerful diagnostic value of the model, and the area under the curve (AUC) of a single diagnostic gene was greater than 0.75. The results of ingenuity pathway analysis (IPA) also indicated that DEGs were involved in the immune system and kidney disease-related pathways. Finally, we found multiple miRNAs that could regulate diagnostic genes from the ceRNA network. Conclusion This study identified 6 IF/TA-related genes, which might be used as a new diagnosis model in the clinical practice.
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24
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Tian C, Wang Y, Song X. Prognostic Characteristics of Immune-Related Genes and the Related Regulatory Axis in Patients With Stage N+M0 Breast Cancer. Front Oncol 2022; 12:878219. [PMID: 35785160 PMCID: PMC9243266 DOI: 10.3389/fonc.2022.878219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/24/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer (BRCA) has the highest incidence rate among female tumours. The function of the immune system affects treatment efficacy and prognosis in patients with BRCA. However, the exact role of immune-related genes (IRGs) in stage N+M0 BRCA is unknown. We constructed a predictive risk scoring model with five IRGs (CDH1, FGFR3, INHBA, S100B, and SCG2) based on the clinical, mutation, and RNA sequencing data of individuals with stage N+M0 BRCA sourced from The Cancer Genome Atlas. Results from the Shandong Cancer Hospital and Institute validation cohort suggested that regardless of clinical stage, tumour size, or the number of lymph node metastases, this model was able to reliably discriminate low-risk patients from high-risk ones and assess the prognosis of patients with stage N+M0 BRCA, and low-risk patients could benefit more from immunotherapy than high-risk patients. In addition, significant inter-group variations in immunocyte infiltration and the tumour microenvironment were observed. Moreover, risk score and age were found to be independent factors in multivariate COX regression analysis, which influenced the outcome of patients with stage N+M0 BRCA. Based on the above findings, we plotted a prognostic nomogram. Finally, we constructed a lncRNA KCNQ1OT1-LINC00665-TUG1/miR-9-5p/CDH1 regulatory axis of the ceRNA network to explore the mechanism of BRCA progression. In summary, we conducted a systemic and extensive bioinformatics investigation and established an IRG-based prognostic scoring model. Finally, we constructed a ceRNA regulatory axis that might play a significant role in BRCA development. More research is required to confirm this result. Scoring system-based patient grouping can help predict the outcome of patients with stage N+M0 BRCA more effectively and determine their sensitivity to immunotherapies, which will aid the development of personalised therapeutic strategies and inspire the research and development of novel medications.
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Affiliation(s)
- Chonglin Tian
- Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Burn and Plastic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yongsheng Wang
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Yongsheng Wang, ; Xianrang Song,
| | - Xianrang Song
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Yongsheng Wang, ; Xianrang Song,
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25
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Chen Z, Zhang W, Yan Z, Zhang M. Comprehensive analyses indicated the association between m6A related long non-coding RNAs and various pathways in glioma. Cancer Med 2022; 12:760-788. [PMID: 35668574 PMCID: PMC9844638 DOI: 10.1002/cam4.4913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 04/23/2022] [Accepted: 05/25/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Glioma is one of the most malignant brain tumors and diseases. N6-methyladenosine modification (m6A) is the most abundant and prevalent internal chemical modification of mRNA and long non-coding RNAs (lncRNAs) in eukaryotes. Nevertheless, the correlated pathways and clinical utilization of m6A-related lncRNAs have not been fully evaluated in glioma. METHODS Public RNA-sequencing and clinical annotation data were retrieved from TCGA, CGGA and GEO database. Differential expression analysis and univariate Cox regression analysis were performed to identify the m6A-related and differentially expressed lncRNAs with prognostic function (m6A-DELPF). The consensus clustering was performed to identify the expression pattern of m6A-DELPF. LASSO Cox regression analysis was performed to construct the lncRNA-based signature. The CIBERSORT and ESTIMATE algorithms were performed to analyze immune infiltration and tumor microenvironment, respectively. Immunotherapy sensitivity analysis was performed using data from TCIA. The small molecule drugs prediction analysis was performed using The Connectivity Map (CMap) database and STITCH database. A competing endogenous RNAs (ceRNA) network was constructed based on miRcode, miRDB, miRTarBase, TargetScan database. RESULTS Two clusters (cluster1 and cluster2) were identified after unsupervised cluster analysis based on m6A-DELPF. Additionally, a 15-gene prognostic signature namely m6A-DELPFS was constructed. Analyses of epithelial-mesenchymal-transition score, tumor microenvironment, immune infiltration, clinical characterization analysis, and putative drug prediction were performed to confirm the clinical utility and efficacy of m6A-DELPFS. The potential mechanisms including tumor immune microenvironment of m6A-DELPF influence the initiation and progression of glioma. A clinically accessible nomogram was also constructed based on the m6A-DELPF and other survival-relevant clinical parameters. Two miRNAs and 114 mRNAs were identified as the downstream of seven m6A-related lncRNAs in a ceRNA network. CONCLUSION Our present research confirmed the clinical value of m6A related lncRNAs and their high correlation with tumor immunity, tumor microenvironment, tumor mutation burden and drug sensitivity in glioma.
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Affiliation(s)
- Zhuohui Chen
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Wei Zhang
- Department of Neurosurgery, Xiangya HospitalCentral South UniversityChangshaChina
| | - Zhouyi Yan
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Mengqi Zhang
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina,National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
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26
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Gao W, Li Y, Zhang T, Lu J, Pan J, Qi Q, Dong S, Chen X, Su Z, Li J. Systematic Analysis of Chemokines Reveals CCL18 is a Prognostic Biomarker in Glioblastoma. J Inflamm Res 2022; 15:2731-2743. [PMID: 35509325 PMCID: PMC9059990 DOI: 10.2147/jir.s357787] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/12/2022] [Indexed: 12/30/2022] Open
Abstract
Background Glioblastoma (GBM) is the most common and aggressive brain tumor in adults, in which chemokines are often upregulated and may play pivotal roles in their development and progression. Chemokines are a large subfamily of cytokines with leukocyte chemotactic activities involved in various tumor progression. However, gene expression patterns of the chemokines on a global scale were not known in GBM. Methods Differentially expressed chemokine genes in glioma and normal samples were screened by using The Cancer Genome Atlas (TCGA) database. Cox regression identified the prognosis-related genes in each glioma subtype. The protein expression levels of chemokines in 72 glioma tissues were detected by ELISA. Results We found that the transcripts of seven chemokines, including CCL2, CCL8, CCL18, CCL28, CXCL1, CXCL5, and CXCL13, were highly expressed in GBM that evidenced by involving immune cell infiltration regulation and accompanied with worse outcomes of GBM patients. The prognostic nomogram construction demonstrated that CCL18 held the highest risk score in patients with GBM. Furthermore, experiments on 72 glioma tissue samples confirmed that CCL18 protein expression was positively associated with tumor grade and IDH1 status but inversely with glioma patients’ overall survival (OS). Conclusion Our study reveals comprehensive and comparable roles of chemokine members in glioblastoma, and identified CCL18 as a critical driver of GBM malignant behaviors, therefore providing a potential target for developing prognosis and therapy in human glioblastoma.
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Affiliation(s)
- Wenqing Gao
- State Key Laboratory of Genetic Engineering, Department of Neurology, Huashan Hospital and Institute of Neurology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, People's Republic of China
| | - Yuanyuan Li
- State Key Laboratory of Genetic Engineering, Department of Neurology, Huashan Hospital and Institute of Neurology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, People's Republic of China
| | - Teng Zhang
- State Key Laboratory of Genetic Engineering, Department of Neurology, Huashan Hospital and Institute of Neurology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, People's Republic of China
| | - Jianglong Lu
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Jiasong Pan
- State Key Laboratory of Genetic Engineering, Department of Neurology, Huashan Hospital and Institute of Neurology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, People's Republic of China
| | - Qi Qi
- State Key Laboratory of Genetic Engineering, Department of Neurology, Huashan Hospital and Institute of Neurology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, People's Republic of China
| | - Siqi Dong
- Department of Neurology, Huashan Hospital and Institute of Neurology, Fudan University, Shanghai, 200040, People's Republic of China
| | - Xiangjun Chen
- Department of Neurology, Huashan Hospital and Institute of Neurology, Fudan University, Shanghai, 200040, People's Republic of China.,National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Zhipeng Su
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Jixi Li
- State Key Laboratory of Genetic Engineering, Department of Neurology, Huashan Hospital and Institute of Neurology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, People's Republic of China.,National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
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27
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Khan K, Gogonea V, Fox PL. Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis. Transl Oncol 2022; 19:101392. [PMID: 35278792 PMCID: PMC8914993 DOI: 10.1016/j.tranon.2022.101392] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 12/16/2022] Open
Abstract
In mammalian cells, 20 aminoacyl-tRNA synthetases (AARS) catalyze the ligation of amino acids to their cognate tRNAs to generate aminoacylated-tRNAs. In higher eukaryotes, 9 of the 20 AARSs, along with 3 auxiliary proteins, join to form the cytoplasmic multi-tRNA synthetase complex (MSC). The complex is absent in prokaryotes, but evolutionary expansion of MSC constituents, primarily by addition of novel interacting domains, facilitates formation of subcomplexes that join to establish the holo-MSC. In some cases, environmental cues direct the release of constituents from the MSC which enables the execution of non-canonical, i.e., "moonlighting", functions distinct from their essential activities in protein translation. These activities are generally beneficial, but can also be deleterious to the cell. Elucidation of the non-canonical activities of several AARSs residing in the MSC suggest they are potential therapeutic targets for cancer, as well as metabolic and neurologic diseases. Here, we describe the role of MSC-resident AARSs in cancer progression, and the factors that regulate their release from the MSC. Also, we highlight recent developments in therapeutic modalities that target MSC AARSs for cancer prevention and treatment.
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Affiliation(s)
- Krishnendu Khan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America.
| | - Valentin Gogonea
- Department of Chemistry, Cleveland State University, Cleveland, OH 44115, United States of America
| | - Paul L Fox
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America.
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28
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Yang K, Shen Z, Yin N, Quan J, Wang M, Gao K. Development and Validation of a Novel Hypoxia Score for Predicting Prognosis and Immune Microenvironment in Rectal Cancer. Front Surg 2022; 9:881554. [PMID: 35548187 PMCID: PMC9081503 DOI: 10.3389/fsurg.2022.881554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/21/2022] [Indexed: 12/04/2022] Open
Abstract
Hypoxia plays a major role in various tumor types. However, few studies have concentrated on the prognostic model of hypoxia-related genes in rectal cancer and the effect of hypoxia on neutrophil-mediated immunosuppression. We performed Kaplan–Meier analysis, random survival forest analysis, and Cox regression analysis on 342 hypoxia-related genes, constructed hypoxia score in the Gene Expression Omnibus (GEO) cohort, and verified them in the Cancer Genome Atlas (TCGA) cohort. Then the patients were divided into two groups according to the risk level. The overall survival rate of the high-risk (HRisk) group was significantly higher than that of the low-risk (LRisk) group (GEO, p < 0.001; TCGA, p = 0.016). Through receiver operating characteristic and decision curve analysis, the nomogram based on hypoxia score has excellent prediction ability. Functional enrichment analysis showed that hypoxia, metastasis, inflammation, immunity, and other related pathways were enriched. The HRisk group was associated with lower tumor purity, higher immune and stromal score, higher neutrophils, and lower activated memory CD4 + T cells. More importantly, the checkpoint of neutrophil-mediated immunosuppression increased in the HRisk group. In conclusion, a hypoxia score based on 5 hypoxia-related genes can be used to predict the prognosis of rectal cancer and ANLN with a cancer-suppressing effect and SRPX (Sushi Repeat Containing Protein X-Linked) with a cancer-promoting effect may be potential therapeutic targets for rectal cancer.
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29
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Wu J, Shen S, Liu T, Ren X, Zhu C, Liang Q, Cui X, Chen L, Cheng P, Cheng W, Wu A. Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner. Oncogene 2022; 41:3024-3036. [PMID: 35459783 PMCID: PMC9122825 DOI: 10.1038/s41388-022-02295-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 03/14/2022] [Accepted: 03/23/2022] [Indexed: 11/18/2022]
Abstract
Glioblastoma multiforme (GBM) with mesenchymal features exhibits enhanced chemotherapeutic resistance and results in reduced overall survival. Recent studies have suggested that there is a positive correlation between the GBM mesenchymal status and immune cell infiltration. However, the mechanisms by which GBM acquires its mesenchymal features in a tumor immune microenvironment-dependent manner remains unknown. Here, we uncovered a chemerin-mediated autocrine and paracrine network by which the mesenchymal phenotype of GBM cells is strengthened. We identified chemerin as a prognostic secretory protein mediating the mesenchymal phenotype-promoting network between tumor-associated macrophages (TAMs) and tumor cells in GBM. Mechanistically, chemerin promoted the mesenchymal features of GBM by suppressing the ubiquitin-proteasomal degradation of CMKLR1, a chemerin receptor predominantly expressed on TAMs and partially expressed on GBM cells, thereby enhancing NF-κB pathway activation. Moreover, chemerin was found to be involved in the recruitment of TAMs in the GBM tumor microenvironment. We revealed that chemerin also enhances the mesenchymal phenotype-promoting ability of TAMs and promotes their M2 polarization via a CMKLR1/NF-κB axis, which further exacerbates the mesenchymal features of GBM. Blocking the chemerin/CMKLR1 axis with 2-(α-naphthoyl) ethyltrimethylammonium iodide disrupted the mesenchymal network and suppressed tumor growth in GBM. These results suggest the therapeutic potential of targeting the chemerin/CMKLR1 axis to block the mesenchymal network in GBM.
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Affiliation(s)
- Jianqi Wu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Shuai Shen
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Tianqi Liu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Xiufang Ren
- Departement of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chen Zhu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Qingyu Liang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Xiao Cui
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Ling Chen
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Medical School of Chinese PLA, Institute of Neurosurgery of Chinese PLA, Beijing, China
| | - Peng Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China
| | - Wen Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
| | - Anhua Wu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.
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Tian W, Yan G, Chen K, Han X, Zhang W, Sun L, Zhang Q, Zhang Y, Li Y, Liu M, Zhang Q. Development and Validation of a Novel Prognostic Model for Lower-Grade Glioma Based on Enhancer RNA-Regulated Prognostic Genes. Front Oncol 2022; 12:714338. [PMID: 35299740 PMCID: PMC8921558 DOI: 10.3389/fonc.2022.714338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 02/01/2022] [Indexed: 12/19/2022] Open
Abstract
Enhancer RNAs (eRNAs) are present specifically in tumors, where they affect the expression of eRNA-regulated genes (ERGs). Owing to this characteristic, ERGs were hypothesized to improve prognosis of overall survival in heterogeneous low-grade and intermediate-grade gliomas. This study aimed to construct and validate an ERG prognostic tool to facilitate clinical management, and offer more effective diagnostic and therapeutic biomarkers for glioma. Survival-related eRNAs were identified, and their ERGs were selected based on eRNA and target gene information. The ERG prognostic model was constructed and validated using internal and external validation cohorts. Finally, biological differences related to the ERG signature were analysed to explore the potential mechanisms influencing survival outcomes. Thirteen ERGs were identified and used to build an ERG risk signature, which included five super-enhancer RNA (seRNA)-regulated genes and five LGG-specific eRNA-regulated genes. The prognostic nomogram established based on combining the ERG score, age, and sex was evaluated by calibration curves, clinical utility, Harrell’s concordance index (0.86; 95% CI: 0.83-0.90), and time-dependent receiver operator characteristic curves. We also explored potential immune-related mechanisms that might cause variation in survival. The established prognostic model displayed high validity and robustness. Several immune-related genes regulated by seRNAs or specific eRNAs were identified, indicating that these transcripts or their genes were potential targets for improving immunotherapeutic/therapeutic outcomes. The functions of an important specific eRNA-regulated gene (USP28) were validated in robust vitro experiments. In addition, the ERG risk signature was significantly associated with the immune microenvironment and other immune-related features.
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Affiliation(s)
- Wei Tian
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Guangcan Yan
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Kegong Chen
- Department of Cardio-Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinhao Han
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Wei Zhang
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Lin Sun
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Qi Zhang
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Yafeng Zhang
- Department of Health Management, School of Health Management, Harbin Medical University, Harbin, China
| | - Yan Li
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Meina Liu
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Qiuju Zhang
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
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31
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Aminoacyl-tRNA Synthetase: A Non-Negligible Molecule in RNA Viral Infection. Viruses 2022; 14:v14030613. [PMID: 35337020 PMCID: PMC8955326 DOI: 10.3390/v14030613] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/08/2022] [Accepted: 03/13/2022] [Indexed: 02/01/2023] Open
Abstract
Infectious diseases such as the ongoing coronavirus disease 2019 (COVID-19) continue to have a huge impact on global health, and the host-virus interaction remains incompletely understood. To address the global threat, in-depth investigations in pathogenesis are essential for interventions in infectious diseases and vaccine development. Interestingly, aminoacyl-transfer RNA (tRNA) synthetases (aaRSs), an ancient enzyme family that was once considered to play housekeeping roles in protein synthesis, are involved in multiple viral infectious diseases. Many aaRSs in eukaryotes present as the components of a cytoplasmic depot system named the multi-synthetase complex (MSC). Upon viral infections, several components of the MSC are released and exert nonenzymatic activities. Host aaRSs can also be utilized to facilitate viral entry and replication. In addition to their intracellular roles, some aaRSs and aaRS-interacting multi-functional proteins (AIMPs) are secreted as active cytokines or function as “molecule communicators” on the cell surface. The interactions between aaRSs and viruses ultimately affect host innate immune responses or facilitate virus invasion. In this review, we summarized the latest advances of the interactions between aaRSs and RNA viruses, with a particular emphasis on the therapeutic potentials of aaRSs in viral infectious diseases.
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Markwell SM, Ross JL, Olson CL, Brat DJ. Necrotic reshaping of the glioma microenvironment drives disease progression. Acta Neuropathol 2022; 143:291-310. [PMID: 35039931 DOI: 10.1007/s00401-021-02401-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
Glioblastoma is the most common primary brain tumor and has a dismal prognosis. The development of central necrosis represents a tipping point in the evolution of these tumors that foreshadows aggressive expansion, swiftly leading to mortality. The onset of necrosis, severe hypoxia and associated radial glioma expansion correlates with dramatic tumor microenvironment (TME) alterations that accelerate tumor growth. In the past, most have concluded that hypoxia and necrosis must arise due to "cancer outgrowing its blood supply" when rapid tumor growth outpaces metabolic supply, leading to diffusion-limited hypoxia. However, growing evidence suggests that microscopic intravascular thrombosis driven by the neoplastic overexpression of pro-coagulants attenuates glioma blood supply (perfusion-limited hypoxia), leading to TME restructuring that includes breakdown of the blood-brain barrier, immunosuppressive immune cell accumulation, microvascular hyperproliferation, glioma stem cell enrichment and tumor cell migration outward. Cumulatively, these adaptations result in rapid tumor expansion, resistance to therapeutic interventions and clinical progression. To inform future translational investigations, the complex interplay among environmental cues and myriad cell types that contribute to this aggressive phenotype requires better understanding. This review focuses on contributions from intratumoral thrombosis, the effects of hypoxia and necrosis, the adaptive and innate immune responses, and the current state of targeted therapeutic interventions.
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Affiliation(s)
- Steven M Markwell
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA
| | - James L Ross
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Cheryl L Olson
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA
| | - Daniel J Brat
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA.
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Liu T, Zhu C, Chen X, Guan G, Zou C, Shen S, Wu J, Wang Y, Lin Z, Chen L, Cheng P, Cheng W, Wu A. Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance. Neuro Oncol 2022; 24:1113-1125. [PMID: 35148413 PMCID: PMC9248406 DOI: 10.1093/neuonc/noac033] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
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 Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand-1 (PD-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 treatment with ferroptosis inhibition.
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Affiliation(s)
| | | | | | - Gefei Guan
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Cunyi Zou
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shuai Shen
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianqi Wu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuhang Wang
- The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhiguo Lin
- Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China
| | - Ling Chen
- Department of Neurosurgery, Chinese People’s Liberation Army of China (PLA) General Hospital, Medical School of Chinese PLA, Institute of Neurosurgery of Chinese PLA, Beijing, China
| | - Peng Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wen Cheng
- Corresponding Authors: Wen Cheng, MD, PhD, Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang, Liaoning 110001, China ()
| | - Anhua Wu
- Corresponding Author: Anhua Wu, MD, PhD, Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang, Liaoning 110001, China ()
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A Risk Score Signature Consisting of Six Immune Genes Predicts Overall Survival in Patients with Lower-Grade Gliomas. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2558548. [PMID: 35186111 PMCID: PMC8856808 DOI: 10.1155/2022/2558548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 01/17/2022] [Indexed: 12/18/2022]
Abstract
Background. Lower-grade gliomas (LGGs) are less aggressive with a long overall survival (OS) time span. Because of individualized genomic features, a prognostic system incorporating molecular signatures can more accurately predict OS. Methods. Differential expression analysis between LGGs and normal tissues was performed using the Gene Expression Omnibus (GEO) datasets (GSE4290 and GSE12657). Immune-related differentially expressed genes (ImmPort-DEGs) were analyzed for functional enrichment. The least absolute shrinkage and selection operator (LASSO) analysis was performed to develop an immune risk score signature (IRSS). We extracted information from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) to establish and validate the model. The relationship of model gene sets with immune infiltration was analyzed based on gene set variation analysis (GSVA) scores. Patients were divided into low- and high-risk groups based on the median score. The time-dependent receiver-operating characteristic (ROC) curve and the Kaplan-Meier curve were used to evaluate the model. Then, a precise prognostic nomogram was established, and its efficacy was verified. Results. A total of 18 related immune genes were identified, building a 6-gene IRSS (BMP2, F2R, FGF13, PCSK1, PRKCB, and PTGER3). DEGs were enriched in T cell and NK cell regulatory pathways. Immune infiltration analysis confirmed that the gene signature correlated with a decrease in innate immune cells. In terms of model evaluation, ROC curves at 1, 3, and 5 years showed moderate predictive ability of IRSS (
, 0.797, and 0.728). The Cox regression analysis revealed that IRSS was an independent prognostic factor, and the nomogram model had good predictive ability (
). Meanwhile, the predictive power of IRSS was also confirmed in the training cohort. The Kaplan-Meier results showed that the prognosis of the high-risk group was significantly worse in all cohorts. Conclusion. IRSS may serve as a novel survival prediction tool in the classification of LGG patients.
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Tian W, Chen K, Yan G, Han X, Liu Y, Zhang Q, Liu M. A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes. Front Cell Dev Biol 2022; 9:798445. [PMID: 35127714 PMCID: PMC8811171 DOI: 10.3389/fcell.2021.798445] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/30/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Gliomas are the most malignant tumors of the nervous system. Even though their survival outcome is closely affected by immune-related genes (IRGs) in the tumor microenvironment (TME), the corresponding regulatory mechanism remains poorly characterized. Methods: Specific enhancer RNAs (eRNAs) can be found in tumors, where they control downstream genes. The present study aimed to identify eRNA-regulated IRGs, evaluate their influence on the TME, and use them to construct a novel prognostic model for gliomas. Results: Thirteen target genes (ADCYAP1R1, BMP2, BMPR1A, CD4, DDX17, ELN, FGF13, MAPT, PDIA2, PSMB8, PTPN6, SEMA6C, and SSTR5) were identified and integrated into a comprehensive risk signature, which distinguished two risk subclasses. Discrepancies between these subclasses were compared to explore potential mechanisms attributed to eRNA-regulated genes, including immune cell infiltration, clinicopathological features, survival outcomes, and chemotherapeutic drug sensitivity. Furthermore, the risk signature was used to construct a prognostic tool that was evaluated by calibration curve, clinical utility, Harrell’s concordance index (0.87; 95% CI: 0.84–0.90), and time-dependent receiver operator characteristic curves (AUCs: 0.93 and 0.89 at 3 and 5 years, respectively). The strong reliability and robustness of the established prognostic tool were validated in another independent cohort. Finally, potential subtypes were explored in patients with grade III tumors. Conclusion: Overall, eRNAs were associated with immune-related dysfunctions in the TME. Targeting of IRGs regulated by eRNAs could improve immunotherapeutic/therapeutic outcomes.
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Affiliation(s)
- Wei Tian
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Kegong Chen
- Department of Cardio-Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guangcan Yan
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Xinhao Han
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Yanlong Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qiuju Zhang
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
| | - Meina Liu
- Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China
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Yan Z, Chu S, Zhu C, Han Y, Liang Q, Shen S, Cheng W, Wu A. Development of a T-cell activation-related module with predictive value for the prognosis and immune checkpoint blockade therapy response in glioblastoma. PeerJ 2022; 9:e12547. [PMID: 35036121 PMCID: PMC8710057 DOI: 10.7717/peerj.12547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/04/2021] [Indexed: 11/20/2022] Open
Abstract
Background Despite the rise in the use of immune checkpoint blockade drugs (ICBs) in recent years, there are no ICB drugs that are currently approved or under large-scale clinical trials for glioblastoma (GBM). T-cells, which mainly mediate adaptive immunity, are an important part of the tumor immune microenvironment. The activation of T-cells in tumors plays a key role in evaluating the sensitivity of patients to immunotherapy. Therefore, we applied bioinformatics approaches to construct a T-cell activation related risk score to study the effect of the activation of T-cells on the prognosis and ICB response of patients with GBM. Materials and Methods This study collected TCGA, CGGA, and GSE16011 glioma cohorts, as well as the IMvigor210 immunotherapy dataset, with complete mRNA expression profiles and clinical information. GraphPad Prism 8 and R 3.6.3 were used for bioinformatics analysis and plotting. Results The activation of T-cells in patients with GBM is characterized by obvious heterogeneity. We established a T-cell activation-related risk score based on five univariate Cox regression prognostic genes (CD276, IL15, SLC11A1, TNFSF4, and TREML2) in GBM. The risk score was an independent risk factor for poor prognosis. The overall survival time of patients in the high-risk group was significantly lower than in the low-risk group. Moreover, the high-risk score was accompanied by a stronger immune response and a more complex tumor immune microenvironment. “Hot tumors” were mainly enriched in the high-risk group, and high-risk group patients highly expressed inhibitory immune checkpoints (PD1, PD-L1, TIM3 etc.). By combining the risk and priming scores we obtained the immunotherapy score, which was shown to be a good evaluation index for sensitivity to GBM immunotherapy. Conclusions As an independent risk factor for poor prognosis, the T-cell activation-related risk score, combined with other clinical characteristics, could efficiently evaluate the survival of patients with GBM. The immunotherapy score obtained by combining the risk and priming scores could evaluate the ICB response of patients with GBM, providing treatment opportunities.
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Affiliation(s)
- Zihao Yan
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Siwen Chu
- Department of Ultrasound, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chen Zhu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yunhe Han
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qingyu Liang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shuai Shen
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wen Cheng
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Anhua Wu
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
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Li Y, Liu H. Clinical powers of Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1) for head-neck squamous cell carcinoma. Cancer Biomark 2022; 34:359-374. [PMID: 35068446 DOI: 10.3233/cbm-210340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND: Head and neck squamous cell carcinoma (HNSC) is one of the most common cancer types in the world. The study in molecular markers for HNSC prognosis is of great significance. We hypothesized that Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1), a gene that encodes a cytokine, is a critical biomarker for HNSC. METHODS: We acquired clinical data, mRNA expression data, protein staining data, and single-cell expression data of HNSC from open databases and evaluated the clinical prognostic value of AIMP1, and explored the potential roles of AIMP1 in HNSC biology and tumor immune microenvironment. RESULTS: AIMP1 was overexpressed in HNSC compared to normal tissues. Higher AIMP1 expression was associated with a worse survival rate. A survival nomogram was constructed for HNSC patients. One thousand two hundred and eighty-one genes were identified as positively associated with AIMP1 and enriched in proliferation-related terminologies, while 303 genes were identified as negatively associated with AIMP1 and enriched in terminologies related to skin development and immune cell regulation. AIMP1 was positively correlated with stemness, cell cycle, and DNA repair, and negatively correlated with angiogenesis, quiescence, metastasis, hypoxia, inflammation, EMT, DNA damage, and invasion in single cells. AIMP1 was expressed higher in malignant cells than immune cells and there was no difference in AIMP1 expression among immune cell types. AIMP1 high group had a lower immune score, stroma score, and microenvironment score. CONCLUSION: AIMP1 is a potential diagnostic and prognostic biomarker for HNSC patients and can potentially affect the proliferation and tumor immune microenvironment of HNSC cells. This study provided a novel molecular marker for the improvement of clinical HNSC treatment.
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Affiliation(s)
- Yixue Li
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China
| | - Hengrui Liu
- Biocomma Limited, Shenzhen, Guangdong, China
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China
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Gonzalez N, Asad AS, Gómez Escalante J, Peña Agudelo JA, Nicola Candia AJ, García Fallit M, Seilicovich A, Candolfi M. Potential of IDH mutations as immunotherapeutic targets in gliomas: a review and meta-analysis. Expert Opin Ther Targets 2021; 25:1045-1060. [PMID: 34904924 DOI: 10.1080/14728222.2021.2017422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Gliomas are stratified by the presence of a hotspot mutation in the enzyme isocitrate dehydrogenase genes (IDH1/2). While mutated IDH (mIDH) correlates with better prognosis, the role of this mutation in antitumor immunity and the response to immunotherapy is not completely understood. Understanding the relationship between the genetic features of these tumors and the tumor immune microenvironment (TIME) may help to develop appropriate therapeutic strategies. AREAS COVERED In this review we discussed the available literature related to the potential role of IDH mutations as an immunotherapeutic target in gliomas and profiled the immune transcriptome of glioma biopsies. We aimed to shed light on the role of mIDH on the immunological landscape of the different subtypes of gliomas, taking into account the most recent WHO classification of tumors of the central nervous system (CNS). We also discussed different immunotherapeutic approaches to target mIDH tumors and to overcome their immunosuppressive microenvironment. EXPERT OPINION Data presented here indicates that the TIME not only differs in association with IDH mutation status, but also within glioma subtypes, suggesting that the cellular context affects the overall effect of this genetic lesion. Thus, specific therapeutic combinations may help patients diagnosed with different glioma subtypes.
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Affiliation(s)
- Nazareno Gonzalez
- Instituto de Investigaciones Biomédicas (Inbiomed, Uba-conicet), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Antonela S Asad
- Instituto de Investigaciones Biomédicas (Inbiomed, Uba-conicet), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - José Gómez Escalante
- Unidad Funcional de Neurooncologia y Banco de Tumores, Instituto de Oncología Ángel H. Roffo, Buenos Aires, Argentina
| | - Jorge A Peña Agudelo
- Instituto de Investigaciones Biomédicas (Inbiomed, Uba-conicet), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Alejandro J Nicola Candia
- Instituto de Investigaciones Biomédicas (Inbiomed, Uba-conicet), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Matías García Fallit
- Instituto de Investigaciones Biomédicas (Inbiomed, Uba-conicet), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Departamento de Química Biológica, Facultad de Ciencias Exactas Y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Adriana Seilicovich
- Instituto de Investigaciones Biomédicas (Inbiomed, Uba-conicet), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marianela Candolfi
- Instituto de Investigaciones Biomédicas (Inbiomed, Uba-conicet), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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Rajagopalan S, Singh A, Khiabanian H. Cilium Expression Score Predicts Glioma Survival. Front Genet 2021; 12:758391. [PMID: 34868236 PMCID: PMC8640099 DOI: 10.3389/fgene.2021.758391] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/02/2021] [Indexed: 01/29/2023] Open
Abstract
The accurate classification, prognostication, and treatment of gliomas has been hindered by an existing cellular, genomic, and transcriptomic heterogeneity within individual tumors and their microenvironments. Traditional clustering is limited in its ability to distinguish heterogeneity in gliomas because the clusters are required to be exclusive and exhaustive. In contrast, biclustering can identify groups of co-regulated genes with respect to a subset of samples and vice versa. In this study, we analyzed 1,798 normal and tumor brain samples using an unsupervised biclustering approach. We identified co-regulated gene expression profiles that were linked to proximally located brain regions and detected upregulated genes in subsets of gliomas, associated with their histologic grade and clinical outcome. In particular, we present a cilium-associated signature that when upregulated in tumors is predictive of poor survival. We also introduce a risk score based on expression of 12 cilium-associated genes which is reproducibly informative of survival independent of other prognostic biomarkers. These results highlight the role of cilia in development and progression of gliomas and suggest potential therapeutic vulnerabilities for these highly aggressive tumors.
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Affiliation(s)
- Srinivas Rajagopalan
- Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, United States
| | - Amartya Singh
- Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, United States
| | - Hossein Khiabanian
- Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, United States.,Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
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Zhang X, Ping S, Wang A, Li C, Zhang R, Song Z, Gao C, Wang F. Development and Validation of an Immune-Related Gene Pairs Signature in Grade II/III Glioma. Int J Gen Med 2021; 14:8611-8620. [PMID: 34849006 PMCID: PMC8627264 DOI: 10.2147/ijgm.s335052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/08/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Gliomas are prevalent primary intracerebral malignant tumors. Increasing evidence indicates an association between the immune signature and Grade II/III glioma prognosis. Thus, we aimed to develop an immune-related gene pair (IRGP) signature that can be used as a prognostic tool in Grade II/III glioma. METHODS The gene expression levels and clinical information of Grade II/III glioma patients were collected from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The TCGA data were randomly divided into a training cohort (n = 249) and a validation cohort (n = 162), and a CGGA dataset served as an external validation group (n = 605). IRGPs significantly associated with prognosis were selected by Cox regression. Gene set enrichment analysis and filtration were performed with the IRGPs. RESULTS Within a set of 1991 immune genes, 8 IRGPs including 15 unique genes that significantly affect survival constituted a gene signature. In the validation datasets, the IRGP signature significantly stratified patients with Grade II/III glioma into low- and high-risk groups (P < 0.001), and the IRGP index was found to be an independent prognostic factor through univariate and multivariate analyses (P < 0.05). Additionally, 26 functional pathways were identified through the intersection of Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) enrichment analysis. CONCLUSION The IRGP signature demonstrated good prognostic value for Grade II/III gliomas, which may provide new insights into individual treatment for glioma patients. The IRGPs might function through the identified 26 functional pathways.
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Affiliation(s)
- Xu Zhang
- Department of Neurosurgery, Baoding No.1 Central Hospital, Baoding, People’s Republic of China
| | - Shuai Ping
- Department of Orthopaedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Anni Wang
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China
| | - Can Li
- Department of Neurosurgery, Chengdu Sixth People’s Hospital, Chengdu, People’s Republic of China
| | - Rui Zhang
- Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, People’s Republic of China
| | - Zimu Song
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China
| | - Caibin Gao
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China
| | - Feng Wang
- Department of Neurosurgery, People's Hospital of Ningxia Hui Autonomous Region Yinchuan, Yinchuan, People’s Republic of China
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Barthel L, Hadamitzky M, Dammann P, Schedlowski M, Sure U, Thakur BK, Hetze S. Glioma: molecular signature and crossroads with tumor microenvironment. Cancer Metastasis Rev 2021; 41:53-75. [PMID: 34687436 PMCID: PMC8924130 DOI: 10.1007/s10555-021-09997-9] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/06/2021] [Indexed: 11/29/2022]
Abstract
In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas’ grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.
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Affiliation(s)
- Lennart Barthel
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany. .,Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany.
| | - Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
| | - Philipp Dammann
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany.,Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ulrich Sure
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany
| | - Basant Kumar Thakur
- Cancer Exosome Research Lab, Department of Pediatric Hematology and Oncology, University Hospital Essen, 45147, Essen, Germany
| | - Susann Hetze
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany.,Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
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Wu H, Zhou Y, Wu H, Xu L, Yan Y, Tong X, Yan H. CENPN Acts as a Novel Biomarker that Correlates With the Malignant Phenotypes of Glioma Cells. Front Genet 2021; 12:732376. [PMID: 34646306 PMCID: PMC8502822 DOI: 10.3389/fgene.2021.732376] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/15/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Gliomas are the most common intracranial malignant neoplasms and have high recurrence and mortality rates. Recent literatures have reported that centromere protein N (CENPN) participates in tumor development. However, the clinicopathologic significance and biological functions of CENPN in glioma are still unclear. Methods: Clinicopathologic data and gene expression profiles of glioma cases downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were utilized to determine the associations between the expression of CENPN and clinical features of glioma. Kaplan-Meier and ROC curves were plotted for prognostic analysis. Gene set enrichment analysis (GSEA) and single sample gene set enrichment analysis (ssGSEA) were applied to identify immune-related functions and pathways associated with CENPN’ differential expression. In vitro experiments were conducted to investigate the impacts of CENPN on human glioma cells. Results: Elevated CENPN expression was associated with unfavorable clinical variables of glioma patients, which was validated in clinical specimens obtained from our institution by immunohistochemical staining (IHC). The GSEA and ssGSEA results revealed that CENPN expression was strongly correlated with inflammatory activities, immune-related signaling pathways and the infiltration of immune cells. Cell experiments showed that CENPN deficiency impaired cell proliferation, migration and invasion ability and increased glioma apoptosis. Conclusion: CENPN could be a promising therapeutic target for glioma.
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Affiliation(s)
- Hailong Wu
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China.,Department of Neurosurgery, Shijiazhuang Third Hospital, Hebei, China
| | - Yan Zhou
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Haiyang Wu
- Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, China
| | - Lixia Xu
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, China
| | - Yan Yan
- Clinical Laboratory, Tianjin Huanhu Hospital, Tianjin, China
| | - Xiaoguang Tong
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, China.,Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Hua Yan
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, China
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Xu S, Li X, Tang L, Liu Z, Yang K, Cheng Q. CD74 Correlated With Malignancies and Immune Microenvironment in Gliomas. Front Mol Biosci 2021; 8:706949. [PMID: 34540893 PMCID: PMC8440887 DOI: 10.3389/fmolb.2021.706949] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/19/2021] [Indexed: 12/29/2022] Open
Abstract
Background: Cluster of differentiation 74 (CD74) is found to be highly involved in the development of various types of cancers and could affect the activities of infiltrated cells in the tumor microenvironment. However, these studies only focus on a few types of immune cells. Our study aims to comprehensively explore the role of CD74 in glioma prognosis and immune microenvironment. Methods: A total of 40 glioma specimens were collected in this study. We extracted data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene-Expression Omnibus (GEO) databases to explore the expression pattern of CD74 in gliomas. gene sets enrichment analysis and gene set variation analysis analyses were conducted to characterize the immune features of CD74. ESTIMATE, ssGSEA, Tumor IMmune Estimation Resource, and CIBERSORT algorithms were applied to assess the immune infiltration. Kaplan-Meier analysis was used for survival analysis. Receiver operating characteristic analysis was used to evaluate the predictive accuracy of CD74 in glioma diagnosis and prognosis. Results: A total of 2,399 glioma patients were included in our study. CD74 was highly expressed in glioma tissue compared to normal brain tissue and its expression was significantly higher in the high-grade glioma compared to the lower grade glioma at transcriptional and translational levels. Besides, CD74 was positively associated with immune checkpoints and inflammatory cytokines as well as immune processes including cytokine secretion and leukocyte activation. The high expression of CD74 indicated a high infiltration of immune cells such as macrophages, dendritic cells, and neutrophils. Moreover, patients with high expression of CD74 had poor prognoses. CD74 had moderate predictive accuracy in the diagnosis of glioblastoma and prediction of survival. Conclusions: In conclusion, our study revealed that the high expression of CD74 was associated with poor prognosis and high immune infiltration. CD74 could be used as a potential target for glioma treatment and as a biomarker to predict the prognosis of glioma patients.
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Affiliation(s)
- Shengchao Xu
- Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, China
| | - Xizhe Li
- Department of Thoracic Surgery, Xiangya Hospital of Central South University, Changsha, China
| | - Lu Tang
- Department of Thoracic Surgery, Xiangya Hospital of Central South University, Changsha, China
| | - Zhixiong Liu
- Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, China
| | - Kui Yang
- Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China
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Ding S, Sun X, Zhu L, Li Y, Chen W, Shen K. Identification of a novel immune-related prognostic signature associated with tumor microenvironment for breast cancer. Int Immunopharmacol 2021; 100:108122. [PMID: 34536743 DOI: 10.1016/j.intimp.2021.108122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND In the view that immune-related genes play a crucial role in breast cancer progression and long-term patient outcomes, we aimed to identify a novel gene signature based on immune-related genes to improve the prognostic prediction of breast cancer. METHODS RNA sequencing data and clinical information were obtained from The Cancer Genome Atlas (TCGA). Univariate and multivariate Cox regression analyses were conducted to establish the immune-related prognostic signature (IRPS). Then, the IRPS was validated by Kaplan-Meier analyses, time-dependent ROC curve analyses and multivariate Cox regression analyses. External validation was conducted in GSE96058. Nomogram combining IRPS with clinical factors was developed and then validated by time-dependent ROC curve analyses and calibration plots. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression level of immune-related genes in tumor and normal tissues. RESULTS The IRPS based on 4 immune-related genes (CCL1, VGF, TSLP, FABP9) were constructed. Patients in the low-risk group had significantly better overall survival than those in the high-risk group (p = 0.0011 in the training set, p = 0.0043 in the validation set, p < 0.0001 in the entire set, p < 0.001 in the external validation set). Multivariate analyses indicated that IRPS could independently predict OS in the training set (HR, 0.48; 95% CI, 0.24-0.83; p = 0.009), validation set (HR, 0.55; 95% CI, 0.34-0.90; p = 0.018), entire set (HR, 0.52; 95% CI, 0.36-0.75; p < 0.001) and external validation set (HR: 0.74, 95% CI: 0.59-0.92, p = 0.007). Sequentially, we establish a nomogram by integrating IRPS and clinical factors, which showed satisfactory predictive performance with 3-year, 5-year, 10-year AUC of 0.701, 0.706 and 0.694. Results of qRT-PCR validated that higher expression level of FABP9, CCL1 and VGF and lower expression level of TSLP in tumor samples compared to normal tissues. CONCLUSIONS Collectively, a four-gene based IRPS was developed and validated for patients with breast cancer. As an independent and robust predictor, the IRPS was constructive to risk stratification of breast cancer.
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Affiliation(s)
- Shuning Ding
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xi Sun
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li Zhu
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yafen Li
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weiguo Chen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Kunwei Shen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Identification of a Tumor Microenvironment-Related Gene Signature Indicative of Disease Prognosis and Treatment Response in Colon Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6290261. [PMID: 34497681 PMCID: PMC8420973 DOI: 10.1155/2021/6290261] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/24/2021] [Indexed: 01/05/2023]
Abstract
Background The tumor microenvironment (TME) is associated with disease outcomes and treatment response in colon cancer. Here, we constructed a TME-related gene signature that is prognosis of disease survival and may predict response to immunotherapy in colon cancer. Methods We calculated immune and stromal scores for 385 colon cancer samples from The Cancer Genome Atlas (TCGA) database using the ESTIMATE algorithm. We identified nine TME-related prognostic genes using Cox regression analysis. We evaluated associations between protein expression, extent of immune cell infiltrate, and patient survival. We calculated risk scores and built a clinical predictive model for the TME-related gene signature. Receiver operating characteristic (ROC) curves were generated to assess the predictive power of the signature. We estimated the half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs in patients using the pRRophetic algorithm. The expression of immune checkpoint genes was evaluated. Results High immune and stromal scores are significantly associated with poor overall survival (p < 0.05). We identified 773 differential TME-related prognostic genes associated with survival; these genes were enriched in immune-related pathways. Nine key prognostic genes were identified and were used to construct a TME-related prognostic signature: CADM3, LEP, CD1B, PDE1B, CCL22, ABI3BP, IGLON5, SELE, and TGFB1. This signature identified a high-risk group with worse survival outcomes, based on Kaplan-Meier analysis. A nomogram composed of clinicopathological factors and risk score exhibited good accuracy. Drug sensitivity analysis identified no difference in sensitivity between the high-risk and low-risk groups. High-risk patients had higher expression of PD-1, PDL-1, and CTLA-4 and lower expression of LAG-3 and VSIR. Infiltration of dendritic cells was higher in the high-risk group. Conclusions We identified a novel prognostic TME-related gene expression signature in colon cancer. Stratification of patients based on this gene signature could be used to improve outcomes and guide better therapy for colon cancer patients.
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Establishment of an Immune-Related Gene Signature for Risk Stratification for Patients with Glioma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:2191709. [PMID: 34497663 PMCID: PMC8420975 DOI: 10.1155/2021/2191709] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/14/2021] [Accepted: 08/11/2021] [Indexed: 12/14/2022]
Abstract
Glioma is a frequently seen primary malignant intracranial tumor, characterized by poor prognosis. The study is aimed at constructing a prognostic model for risk stratification in patients suffering from glioma. Weighted gene coexpression network analysis (WGCNA), integrated transcriptome analysis, and combining immune-related genes (IRGs) were used to identify core differentially expressed IRGs (DE IRGs). Subsequently, univariate and multivariate Cox regression analyses were utilized to establish an immune-related risk score (IRRS) model for risk stratification for glioma patients. Furthermore, a nomogram was developed for predicting glioma patients' overall survival (OS). The turquoise module (cor = 0.67; P < 0.001) and its genes (n = 1092) were significantly pertinent to glioma progression. Ultimately, multivariate Cox regression analysis constructed an IRRS model based on VEGFA, SOCS3, SPP1, and TGFB2 core DE IRGs, with a C-index of 0.811 (95% CI: 0.786-0.836). Then, Kaplan-Meier (KM) survival curves revealed that patients presenting high risk had a dismal outcome (P < 0.0001). Also, this IRRS model was found to be an independent prognostic indicator of gliomas' survival prediction, with HR of 1.89 (95% CI: 1.252-2.85) and 2.17 (95% CI: 1.493-3.14) in the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets, respectively. We established the IRRS prognostic model, capable of effectively stratifying glioma population, convenient for decision-making in clinical practice.
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Chen D, Li G, Ji C, Lu Q, Qi Y, Tang C, Xiong J, Hu J, Yasar FBA, Zhang Y, Hoon DSB, Yao Y, Zhou L. Enhanced B7-H4 expression in gliomas with low PD-L1 expression identifies super-cold tumors. J Immunother Cancer 2021; 8:jitc-2019-000154. [PMID: 32457124 PMCID: PMC7253052 DOI: 10.1136/jitc-2019-000154] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2020] [Indexed: 12/29/2022] Open
Abstract
Background Characterizing expression profiles of different immune checkpoint molecules are promising for personalized checkpoint inhibitory immunotherapy. Gliomas have been shown as potential targets for immune checkpoint inhibitors recently. Our study was performed to determine coexpression levels of two major B7 immune regulatory molecules programmed death ligand 1 (PD-L1) and B7-H4, both of which have been demonstrated to inhibit antitumor host immunity in gliomas. Methods We assessed tumor tissues from stage II–IV primary gliomas (n=505) by immunohistochemistry (IHC) for protein levels of both PD-L1 and B7-H4. Gene coexpression analysis assessing clusters based on extent of PD-L1/B7-H4 classifier genes expression were investigated in two transcriptome datasets (The Cancer Genome Atlas and Chinese Glioma Genome Atlas). In addition, levels of immune cell infiltrates were estimated with IHC and RNA-seq data for assessing the tumor immune microenvironment of PD-L1/B7-H4 subgroups. Results High expression of PD-L1 and B7-H4 in gliomas was 23% and 20%, respectively, whereas coexpression of two proteins at high levels was limited to 2% of the cases. Comparable results were seen in RNA-seq datasets where PD-L1 mRNA expression levels negatively correlated with that of B7-H4. Gene coexpression modules clustered within each grade of gliomas demonstrated lack of double-high modules (cluster with high expression of both PD-L1 and B7-H4 classifier genes). B7-H4 mRNA expression levels showed negative correlation with extent of immune cell infiltration and High-B7-H4 module gliomas (high B7-H4 but low PD-L1 classifier genes expression) had less tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). IHC assessment also showed few TILs and TAMs in High-B7-H4 subgroup gliomas. Conclusions The majority of gliomas express PD-L1 or B7-H4, however, coexpression of both at high levels is minimal. The high-B7-H4 patients could be considered as ‘super-cold’ gliomas with significantly deficient in TILs, suggesting that B7-H4 might inhibit T-cell trafficking into the central nervous system. This study demonstrated that PD-L1 and B7-H4 may serve as mutually compensatory immune checkpoint molecules in gliomas for immune targeted or active-specific immunotherapy. The distinct B7-H4 pathways modulating T-cell function and immune evasion in glioma patients deserved to be further explored in the future during immunotherapy.
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Affiliation(s)
- Di Chen
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Gaopeng Li
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences & and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
| | - Chunxia Ji
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.,Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China
| | - Qiqi Lu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.,Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China
| | - Ying Qi
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Tang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.,Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China
| | - Ji Xiong
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jian Hu
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Fatma Betul Aksoy Yasar
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yan Zhang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences & and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
| | - Dave S B Hoon
- Department of Translational Molecular Medicine, John Wayne Cancer Institute, Providence Health Systems, Santa Monica, California, USA
| | - Yu Yao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Liangfu Zhou
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.,Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China
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Chen X, Lan H, He D, Xu R, Zhang Y, Cheng Y, Chen H, Xiao S, Cao K. Multi-Omics Profiling Identifies Risk Hypoxia-Related Signatures for Ovarian Cancer Prognosis. Front Immunol 2021; 12:645839. [PMID: 34349753 PMCID: PMC8327177 DOI: 10.3389/fimmu.2021.645839] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 07/01/2021] [Indexed: 12/23/2022] Open
Abstract
Background Ovarian cancer (OC) has the highest mortality rate among gynecologic malignancy. Hypoxia is a driver of the malignant progression in OC, which results in poor prognosis. We herein aimed to develop a validated model that was based on the hypoxia genes to systematically evaluate its prognosis in tumor immune microenvironment (TIM). Results We identified 395 hypoxia-immune genes using weighted gene co-expression network analysis (WGCNA). We then established a nine hypoxia-related genes risk model using least absolute shrinkage and selection operator (LASSO) Cox regression, which efficiently distinguished high-risk patients from low-risk ones. We found that high-risk patients were significantly related to poor prognosis. The high-risk group showed unique immunosuppressive microenvironment, lower antigen presentation, and higher levels of inhibitory cytokines. There were also significant differences in somatic copy number alterations (SCNAs) and mutations between the high- and low-risk groups, indicating immune escape in the high-risk group. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms showed that low-risk patients are significantly responsive to programmed cell death protein-1 (PD-1) inhibitors. Conclusions In this study, we highlighted the clinical significance of hypoxia in OC and established a hypoxia-related model for predicting prognosis and providing potential immunotherapy strategies.
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Affiliation(s)
- Xingyu Chen
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Hua Lan
- Department of Obstetrics and Gynecology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Dong He
- Department of Respiration, The Second People's Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, China
| | - Runshi Xu
- Medical school, Hunan University of Chinese Medicine, Changsha, China
| | - Yao Zhang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Yaxin Cheng
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Haotian Chen
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Songshu Xiao
- Department of Obstetrics and Gynecology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Ke Cao
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
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Construction of Immune-Associated Nomogram for Predicting the Recurrence Survival Risk of Stage I Cervical Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6699131. [PMID: 34337046 PMCID: PMC8289578 DOI: 10.1155/2021/6699131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 06/24/2021] [Indexed: 12/24/2022]
Abstract
Background Various studies reported that the prognosis of patients with cervical cancer (CC) was significantly associated with immunity, whereas limited studies have explored whether immune-associated genes could be classifiers for recurrence-free survival (RFS) of stage I CC. Thus, an improved immune-related gene signature for stage I CC patients' prognosis is urgently required. Materials and Methods We retrospectively analyzed the gene expression profiles of stage I CC patients in the GSE44001 set from the Gene Expression Omnibus (GEO) database. The stage I CC patients were randomly divided into the training group and the internal validation group. The training patients were adopted to develop a prognostic immune gene-based signature; meanwhile, the internal validation patients were used to validate the power of the selected immune gene-related signature using univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis. The accuracy and reliability of the immune gene-related signature were evaluated based on Kaplan-Meier analysis and time-dependent receiver operating characteristic (ROC) curves. Results High power of the 8-immune gene signature was found on the basis of ROC analysis (AUC at 1, 3, and 5 years were exhibited in the internal validation group (0.702, 0.715, and 0.728, respectively), external validation group (0.702, 0.825, and 0.842, respectively), and entire GEO dataset (0.840, 0.894, and 0.852, respectively)). Besides, C-index, ROC, calibration plots, and decision curve analysis (DCA) also acted well in our nomogram, suggestive of a high ability of the nomogram to elevate the prognostic prediction of stage I CC patients. Conclusions In this study, we successfully constructed an integrated 8-immune gene-based signature which could accurately identify patients with low prognostic risk from those with high prognostic risk. In addition, we developed an immune-related nomogram which can elevate the prognostic prediction of stage I CC patients.
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Mockenhaupt K, Gonsiewski A, Kordula T. RelB and Neuroinflammation. Cells 2021; 10:1609. [PMID: 34198987 PMCID: PMC8307460 DOI: 10.3390/cells10071609] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/23/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Neuroinflammation within the central nervous system involves multiple cell types that coordinate their responses by secreting and responding to a plethora of inflammatory mediators. These factors activate multiple signaling cascades to orchestrate initial inflammatory response and subsequent resolution. Activation of NF-κB pathways in several cell types is critical during neuroinflammation. In contrast to the well-studied role of p65 NF-κB during neuroinflammation, the mechanisms of RelB activation in specific cell types and its roles during neuroinflammatory response are less understood. In this review, we summarize the mechanisms of RelB activation in specific cell types of the CNS and the specialized effects this transcription factor exerts during neuroinflammation.
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Affiliation(s)
| | | | - Tomasz Kordula
- Department of Biochemistry and Molecular Biology, School of Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VI 23298, USA; (K.M.); (A.G.)
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