Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 4 944
Страница 376 из 495-
Multi-Omics and Single-Cell Dissection of Exostosin Glycosyltransferases (EXT1/EXT2) Reveals Divergent Oncogenic Roles and Therapeutic Vulnerabilities in Gliomas.
Exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2) catalyze heparan sulfate chain elongation and are increasingly implicated in cancer biology, but their roles in gliomas remain incompletely defined. Here, we performed an integrative multi-omics analysis to dissect the transcriptional, epigenetic, and microenvironmental landscape of EXT1 and EXT2 across gliomas. Bulk transcriptomic data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) revealed that both EXT1 and EXT2 are upregulated in high-grade gliomas and associate with adverse survival, with EXT1 showing the strongest and most consistent prognostic impact. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) indicated that EXT1-high tumors are enriched for DNA damage and replication stress programs, cell cycle progression, inflammatory response, and stromal activation pathways, whereas EXT2 expression is preferentially linked to extracellular matrix remodeling, cytoskeletal organization and angiogenesis-related signaling. Single-cell RNA sequencing and Immune deconvolution using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) showed that EXT1 correlates with increased stromal and immune scores, and reduced cytotoxic T cell signatures, consistent with an immunosuppressive tumor microenvironment. EXT2 expression is enriched in gliomas with pronounced vascular and mesenchymal features, supporting a complementary role in invasive growth and tissue remodeling. Immunohistochemistry on a glioma tissue microarray validated the upregulation of EXT1 protein in high-grade tumors. The study findings identified EXT1 as a central glycosylation-linked regulator of replication stress tolerance and immune remodeling in gliomas, and suggest that EXT2 contributes to extracellular matrix and cytoskeletal reprogramming. The exostosin axis represents a promising source of prognostic biomarkers and potential therapeutic targets in glioma.
-
METTL2B m3C RNA transferase: oncogenic role in ovarian cancer progression via regulation of the mTOR/AKT pathway and its link to the tumor immune microenvironment.
BACKGROUND: Aberrant expression of N3-methylcytidine methyltransferase 2B (METTL2B) has been observed in various human malignancies, including those of the prostate, liver, breasts, and bladder. However, its role in ovarian cancer (OC) remains largely unexplored. This research preliminarily investigated METTL2B expression in OC and elucidated the associated molecular mechanisms. METHODS: We utilized three publicly available cancer-related databases (Genotype-Tissue Expression, Gene Expression Omnibus, and The Cancer Genome Atlas) to identify gene signatures in patients with OC and normal individuals with a specific focus on METTL2B. The role of METTL2B in OC was evaluated using patient survival data, and its impact on oncogenic behaviors in both cell and animal models, including growth potential, migration, invasion, and the tumor microenvironment, was examined. This assessment was conducted using bioinformatics tools such as Gene Set Cancer Analysis, GeneMANIA, and Tumor Immune Single-cell Hub 2. Additionally, the association between drug sensitivity and METTL2B expression was analyzed using CellMiner. RESULTS: METTL2B expression was significantly elevated in OC, highlighting its potential clinical value in the diagnosis and prognosis of OC. Patients with lower METTL2B expression exhibited favorable survival. Furthermore, METTL2B knockdown significantly disrupted oncogenic behaviors in OC cell lines by suppressing the mTOR/AKT signaling pathway. Additionally, bioinformatics-based Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses suggested a close correlation between METTL2B and immune responses. CONCLUSIONS: Our research confirmed the upregulation of METTL2B in OC, suggesting its oncogenic function. However, METTL2B expression was negatively correlated with the infiltration scores of multiple immune cells, including cytotoxic cells and T cells, indicating its complex role in the tumor immune microenvironment. These findings highlight the significant clinical value of METTL2B in the diagnosis and prognosis of OC.
-
A single-cell type transcriptomics map of human tissues.
Advances in molecular profiling have opened up the possibility to map the expression of genes in cells, tissues, and organs in the human body. Here, we combined single-cell transcriptomics analysis with spatial antibody-based protein profiling to create a high-resolution single-cell type map of human tissues. An open access atlas has been launched to allow researchers to explore the expression of human protein-coding genes in 192 individual cell type clusters. An expression specificity classification was performed to determine the number of genes elevated in each cell type, allowing comparisons with bulk transcriptomics data. The analysis highlights distinct expression clusters corresponding to cell types sharing similar functions, both within the same organs and between organs.
-
Comprehensive bioinformatics analysis of EXOSC family genes in lung adenocarcinoma.
The RNA exosome complex (EXOSC1-10) orchestrates 3'-5' RNA processing and decay, yet its family-wide landscape and clinical relevance in lung adenocarcinoma (LUAD) remain incompletely defined. Here, we conducted an integrative multi-omics analysis of EXOSC family members in LUAD using public transcriptomic and proteomic resources, external validation cohorts, and single-cell data. Across TCGA (59 normal vs. 515 tumors), all EXOSC genes were significantly upregulated in tumors, with concordant increases for most proteins in CPTAC and immunohistochemistry evidence from the Human Protein Atlas. Survival analyses identified EXOSC2, EXOSC3 and EXOSC5 as prognostically informative, with elevated EXOSC2/EXOSC5 also associated with inferior disease-specific survival. Receiver operating characteristic analyses indicated moderate-to-high diagnostic performance for several EXOSC genes, supported by qRT-PCR validation in LUAD cell lines and confirmation in GSE31210. Clinicopathological correlations linked EXOSC1-5 and EXOSC8-10 to advanced stage and metastatic features, whereas EXOSC6 and EXOSC7 showed comparatively limited or context-dependent associations, suggesting functional heterogeneity within the family. Genomic profiling revealed recurrent alterations in 11.83% of patients, with EXOSC4 exhibiting the highest alteration frequency (predominantly amplifications), and network analyses identified core interacting partners centered on RNA surveillance machinery. EXOSC expression was broadly correlated with RNA modification regulators (m1A/m5C/m6A) and displayed heterogeneous relationships with immune checkpoint genes and immune infiltration, while higher EXOSC expression consistently associated with lower ESTIMATE-derived microenvironment scores and an immune profile characterized by Th2/T helper enrichment with reduced cytotoxic and antigen-presenting populations. Gene set enrichment analyses implicated cell-cycle regulation, senescence, chromatin-related programs and extracellular matrix pathways, and EXOSC-high tumors were associated with increased tumor mutational burden and homologous recombination deficiency, together with enrichment of DNA damage response pathways. Single-cell analysis (GSE146100) localized highest EXOSC expression to proliferating monocytes/macrophages and suggested TGF-β-linked communication with endothelial and T-cell compartments. Exploratory translational analyses further indicated an association between EXOSC9 and predicted cisplatin sensitivity. Collectively, these findings position the EXOSC family as a clinically and biologically relevant axis in LUAD, linking RNA surveillance dysregulation to immune contexture and genomic instability, and highlight subunit-specific heterogeneity that warrants mechanistic validation.
-
Effect of aging on rat testicular interstitial compartment: functional losses in endothelial and mesenchymal cells and activation of immune cells.
Human aging is associated with testosterone decline and spermatogenic defects, impacting fertility and health, yet the underlying cellular mechanisms remain poorly understood. This study aimed to establish a regulatory cell atlas of Leydig cells in aging rat testes and characterize intercellular interactions. Using single-cell RNA sequencing and immunohistochemistry, interstitial cells from young (3-month) and aged (21-month) BN rat testes were analyzed. Among 8 identified interstitial cell types, aging was not synchronous, but with remarkable heterogeneity and stochasticity. Mesenchymal cells exhibited reduced expression of genes involved in detoxification and extracellular matrix maintenance, alongside increased immune regulation genes. Endothelial cells, the most communicatively active population, showed decreased angiogenesis and cell adhesion/migration but enhanced immune responses and leukocyte chemotaxis. In immune populations, dendritic cells decreased while lymphocytes increased, with no significant change in macrophages. Transcriptomic shifts indicated a transition from innate to adaptive immunity. The loss of dendritic cells and gain of lymphocytes may be linked to CCL7 and CXCL9-12, as receptors Ccr1/Ccr5 and Cxcr3 were upregulated in lymphocytes but downregulated in dendritic cells. Overall, inflammatory activation and functional losses occurred in both immune and non-immune cells during testicular aging. This innate-to-adaptive immune shift may further compromise non-immune cell functions, accelerating testicular aging.
-
Bioinformatics screened of biomarkers for the prognosis of hepatocellular carcinoma.
BackgroundThis study aimed to identify hub genes linked to hepatocellular carcinoma (LIHC) pathogenesis using bioinformatics analysis.MethodA total of 3865 samples from 12 datasets in the HCCDB database were analyzed to identify prognostic expression genes (PDGs). Enrichment analysis using DAVID and GSCA databases unveiled biological processes and signaling pathways associated with PDGs. Cytohubba app was utilized to identify 6 hub genes from the PDGs. Verification of hub genes was conducted using three GEO datasets and Western blot. Histopathological staining data of hub genes in LIHC patients were retrieved from the Human Protein Atlas database. Comprehensive analyses of hub genes were performed, including immune infiltration, prognosis, survival, methylation, gene mutation, related miRNA, and single-cell type. Potential therapeutic drugs were predicted using GDSC and CTRP databases.ResultA total of 1259 differential genes were screened, yielding 82 PDGs (36 up-regulated and 46 down-regulated genes). Hub genes identified included CDC20, TOP2A, CDK1 (up-regulated), and CAT, TAT, FTCD (down-regulated). These hub genes exhibited strong associations with immune cells and showed promising prognostic value based on AUC analysis. Reduced promoter methylation levels of TOP2A, CDK1, and FTCD in LIHC were observed. Single nucleotide polymorphisms analysis highlighted prevalent variants and miRNA expression associations impacting patient survival. Hub genes were enriched in various cell types. Trametinib, selumetinib, RDEA119, and teniposide were identified as potential drugs for LIHC treatment.ConclusionCDC20, TOP2A, CDK1, CAT, TAT, and FTCD may contribute to LIHC development and serve as novel prognostic biomarkers.
-
A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte.
The functions of epithelial tissues are dictated by the types, abundance and distribution of the differentiated cells they contain. Attempts to restore tissue function after damage require knowledge of how physiological tasks are distributed among cell types, and how cell states vary between homeostasis, injury-repair and disease. In the conducting airway, a heterogeneous basal cell population gives rise to specialized luminal cells that perform mucociliary clearance1. Here we perform single-cell profiling of human bronchial epithelial cells and mouse tracheal epithelial cells to obtain a comprehensive census of cell types in the conducting airway and their behaviour in homeostasis and regeneration. Our analysis reveals cell states that represent known and novel cell populations, delineates their heterogeneity and identifies distinct differentiation trajectories during homeostasis and tissue repair. Finally, we identified a novel, rare cell type that we call the 'pulmonary ionocyte', which co-expresses FOXI1, multiple subunits of the vacuolar-type H+-ATPase (V-ATPase) and CFTR, the gene that is mutated in cystic fibrosis. Using immunofluorescence, modulation of signalling pathways and electrophysiology, we show that Notch signalling is necessary and FOXI1 expression is sufficient to drive the production of the pulmonary ionocyte, and that the pulmonary ionocyte is a major source of CFTR activity in the conducting airway epithelium.
-
Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer.
This study aimed to determine the prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer (HER2+ BC). Transcriptome sequencing and clinicopathological data were downloaded from the Cancer Genome Atlas. The 10X single cell sequencing dataset was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus. Exosomes-Related Genes were extracted from the ExoCarta and Gene Set Enrichment Analysis databases. FGF9, SF3B4, and EPCAM were found and deemed the most accurate predictive signatures. Patients with HER2+ BC were subtyped into three groupings by exosome prognostic gene (EPGs). The expression of SF3B4 was positively linked with the infiltration of macrophages, neutrophils, and CD4+ T cells. The expression characteristics of EPGs were associated with the biological process of "response to xenobiotic stimuli." Interactions were relatively high between malignant epithelial cells and fibroblasts, endothelial cells, monocytes, and macrophages. Malignant epithelial cells interact more with fibroblasts and endothelial cells. The migration inhibitory factor pathway was the primary outgoing signaling pattern, while the C-C motif chemokine ligand pathway was the primary incoming signaling pattern for communication between malignant epithelial cells and macrophages. This study described the role of exosome signatures in the prognosis and microenvironment of HER2+ BC and provided a basis for future research.
-
Single-cell and bulk transcriptome analysis unveils a ligand-receptor-based signature for prognostication and reveals that TREM1 controls the malignant behaviors of hepatocellular carcinoma.
The transcriptional heterogeneity and cellular ecosystem diversity of HCC await further exploration. Single-cell and bulk RNA sequencing data from HCC cells are analyzed to generate a LASSO model for HCC prognostication. CCK-8, scratch assay, flow cytometry, and ROS assays are used to validate how TREM1 may affect HCC cell biological behaviors in vitro. qPCR, western blot analysis, immunohistochemistry, and flow cytometry are applied in a xenograft model to test the effects of TREM1 knockdown on carcinogenesis and the tumor microenvironment. A single-cell atlas of the multicellular ecosystem comprising 13 cell types in HCC is constructed. On the basis of ligand-receptor marker genes specifically extracted from the cell populations, a prognostic model is defined and subsequently validated in additional clinical cohorts. For the first time, a heterogeneous immune microenvironment is observed between low- and high-risk patients, primarily involving macrophages, CD4+ T cells, M1 macrophages, and regulatory T (Treg) cells. Sufficient evidence validates the positive effects of TREM1 on HCC cell proliferation, migration, and apoptosis. Additionally, TREM1 positively modulates the levels of the proinflammatory cytokines IL-1β, TNF-α, and MCP-1. TREM1 downregulation alters the proportions of M1 macrophages and Tregs in the tumor tissue from our HCC xenograft model. Eventually, the Nrf2/Keap1 signaling pathway, which is related to oxidative stress, is shown to be a key pathway downstream of TREM1 downregulation. In summary, we construct a novel prognostic model for HCC on the basis of ligand-receptor marker genes and investigate the role of TREM1 in HCC progression and its impact on the TME.
-
Development and validation of a hypoxia- and mitochondrial dysfunction- related prognostic model based on integrated single-cell and bulk RNA sequencing analyses in gastric cancer.
INTRODUCTION: Gastric cancer (GC) remains a major global health threat ranking as the fifth most prevalent cancer. Hypoxia, a characteristic feature of solid tumors, significantly contributes to the malignant progression of GC. Mitochondria are the major target of hypoxic injury that promotes mitochondrial dysfunction during the development of cancers including GC. However, the gene signature and prognostic model based on hypoxia- and mitochondrial dysfunction-related genes (HMDRGs) in the prediction of GC prognosis have not yet been established. METHODS: The gene expression profile datasets of stomach cancer patients were retrieved from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Prognostic genes were selected using Least Absolute Shrinkage and Selection Operator Cox (LASSO-Cox) regression analysis to construct a prognostic model. Immune infiltration was evaluated through ESTIMATE, CIBERSORT, and ssGSEA analyses. Tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) were utilized to explore implications for immunotherapy. Furthermore, in vitro experiments were conducted to validate the functional roles of HMDRGs in GC cell malignancy. RESULTS: In this study, five HMDRGs (ZFP36, SERPINE1, DUSP1, CAV1, and AKAP12) were identified for developing a prognostic model in GC. This model stratifies GC patients into high- and low-risk groups based on median risk scores. A nomogram predicting overall survival (OS) was constructed and showed consistent results with observed OS. Immune infiltration analysis indicated that individuals in the high-risk group tend to exhibit increased immune cell infiltration. Additionally, analysis of cancer immunotherapy responses revealed that high-risk group patients exhibit poorer responses to cancer immunotherapy compared to the low-risk group. Immunohistochemistry (IHC) staining indicated that the expression levels of HMDRGs were remarkably correlated with GC, of which, SERPINE1 displayed the most pronounced up-regulation, while ZFP36 exhibited the most notable down-regulation in GC patients. Furthermore, in vitro investigation validated that SERPINE1 and ZFP36 contribute to the malignant processes of GC cells correlated with mitochondrial dysfunction. CONCLUSIONS: This study presents a novel and efficient approach to evaluate GC prognosis and immunotherapy efficacy, and also provides insights into understanding the pathogenesis of GC.