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 402 из 495-
SNRPB2 in the pan-cancer landscape: A bioinformatics exploration and validation in hepatocellular carcinoma.
Aberrant splicing is a significant contributor to gene expression abnormalities in cancer. SNRPB2, a component of U2 small nuclear ribonucleoprotein particles (snRNPs), contributes to the assembly of the spliceosome, the molecular machinery responsible for splicing. To date, few studies have investigated the role of SNRPB2 in tumorigenesis. We examined data sourced from various public databases, such as The Cancer Genome Atlas(TCGA), the Clinical Proteomic Tumor Analysis Consortium(CPTAC), and Gene Expression Omnibus(GEO). Our investigation included gene expression, genomic and epigenomic scrutiny, gene set enrichment assessment(GSEA), and immune cell infiltration evaluation. Furthermore, we performed empirical validation to ascertain the impact of SNRPB2 suppression on the proliferation and migration of liver cancer cells. Analysis of gene expression revealed widespread upregulation of SNRPB2 across a spectrum of cancer types, with heightened levels of SNRPB2 expression in numerous tumors linked to unfavorable prognosis. Genomic and epigenomic assessments revealed connections between SNRPB2 expression and variations in SNRPB2 copy number, DNA methylation patterns, and RNA modifications. Through gene set enrichment analysis, the involvement of SNRPB2 in vital biological processes and pathways related to cancer was identified. Furthermore, scrutiny of immune cell infiltration suggested a potential relationship between SNRPB2 and the tumor microenvironment, which was reinforced by multiple single-cell sequencing profiles. Subsequent experimental validation revealed that silencing SNRPB2 effectively impeded the proliferation and migration of liver cancer cells. Taken together, these findings underscore the prospective utility of SNRPB2 as a prognostic biomarker and a promising candidate for immunotherapy in cancer. It is necessary to engage in additional exploration into its underlying mechanisms and clinical treatment potential.
-
Mitochondrial-impaired ductal epithelium fuels TLS formation in Sjögren's disease.
OBJECTIVES: Progressive inflammatory cell infiltration within salivary glands is a defining feature of advanced Sjögren's disease (SjD) and is frequently accompanied by tertiary lymphoid structure (TLS) formation. However, the initial events driving this pathogenic trait in SjD progression are not fully understood. METHODS: We collected 848 labial salivary gland (LSG) biopsies (668 SjD, 180 non-SjD) and profiled bulk transcriptomics, single cell RNA-sequencing (scRNA-seq), spatial transcriptomics, transmission electron microscopy (TEM), and histology. In vivo functional validation was performed in NOD/ShiLtj mice with spontaneous SjD via nicotinamide mononucleotide administration to restore mitochondrial function. RESULTS: Mitochondrial function was impaired in LSG tissues from SjD patients, with functional validation in NOD/ShiLtj mice showing attenuated ductal injury and reduced immune cell infiltration. scRNA-seq analyses revealed that each LSG cellular subset harbours a distinct mitochondrial transcriptional profile, which we identified here as a molecular fingerprint for individual cellular subsets. TEM established an ultrastructural atlas of human minor salivary glands, showing that striated duct (SD) cells are most enriched with mitochondria among all epithelial subtypes. In SjD LSGs, particularly those with TLSs, profound mitochondrial dysfunction and impaired oxidative phosphorylation were observed. A previously unrecognized proinflammatory SD subset, SD-C1 (marked by matrix metalloproteinase 7), was markedly expanded in SjD-TLS+ tissues and exhibited severe mitochondrial impairment. SD-C1 cells showed enhanced crosstalk with T cells, B cells, and macrophages via immune signalling pathways and were spatially colocalized with immune cell aggregates in periductal regions where TLSs formed. CONCLUSIONS: Mitochondrial injury in SD epithelial cells emerges as a trigger of TLS formation and progressive autoimmunity in SjD. Therapies that preserve mitochondrial integrity and functionality in ductal cells may mitigate salivary gland degeneration during SjD progression.
-
Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer.
BACKGROUND: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. METHODS: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2 , CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2/BrafV600E/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2 -/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. RESULTS: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.
-
Single-cell landscape of undifferentiated pleomorphic sarcoma.
Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive malignant soft tissue tumor with a poor prognosis; however, the identity and heterogeneity of tumor populations remain elusive. Here, eight major cell clusters were identified through the RNA sequencing of 79,569 individual cells of UPS. UPS originates from mesenchymal stem cells (MSCs) and features undifferentiated subclusters. UPS subclusters were predicted to exist in two bulk RNA datasets, and had a prognostic value in The Cancer Genome Atlas (TCGA) dataset. The functional heterogeneity of malignant UPS cells and the immune microenvironment were characterized. Additionally, the fused cells were innovatively detected by expressing both monocyte/macrophage markers and other subcluster-associated genes. Based on the ligand-receptor interaction analysis, cellular interactions with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) were abundant. Furthermore, 73% of patients with UPS (48/66) showed positive EGFR expression, which was associated with a poor prognosis. EGFR blockade with cetuximab inhibited tumor growth in a patient-derived xenograft model. Our transcriptomic studies delineate the landscape of UPS intratumor heterogeneity and serve as a foundational resource for further discovery and therapeutic exploration.
-
Pan-cancer multi-omics characterization of calcyphosine and its revealed links to the immune microenvironment and regulatory networks in endometrial carcinoma.
OBJECTIVE: The calcium-dependent activator protein for secretion (CAPS) has emerged as a protein of interest in tumor biology; however, its functional significance in endometrial carcinoma (EC) remains largely unexplored. METHODS: We performed an integrative analysis leveraging bulk RNA sequencing data from The Cancer Genome Atlas, GTEx, and publicly available EC datasets, coupled with gene set enrichment analysis (GSEA) and single-cell transcriptomic profiling. The association between CAPS expression and clinicopathological parameters as well as patient prognosis was systematically assessed. In addition, functional enrichment, intercellular communication, and immune infiltration analyses were conducted to elucidate the molecular and microenvironmental roles of CAPS. In vitro assays were employed to validate the biological effects of CAPS knockdown on EC cell proliferation, migration, and invasion. RESULTS: CAPS was significantly upregulated in early-stage, low-grade, and endometrioid endometrial carcinoma, and its elevated expression was associated with improved patient survival. GSEA indicated that high CAPS expression was correlated with enhanced ribosome biogenesis and oxidative phosphorylation, along with suppression of proliferative signaling, reflecting a metabolically differentiated phenotype. Single-cell transcriptomic analysis revealed that CAPS was specifically enriched in terminally differentiated secretory epithelial cells, promoting epithelial maturation and oxidative metabolism. Furthermore, CAPS-positive cells exhibited extensive crosstalk with immune cells, suggesting a potential role in facilitating anti-tumor immune responses. Functional assays confirmed that CAPS knockdown markedly enhanced EC cell proliferation, migration, and invasion. CONCLUSION: CAPS may act as a tumor suppressor in EC by stabilizing microtubule architecture, reprogramming cellular metabolism, and modulating immune interactions within the tumor microenvironment. These findings highlight CAPS as a promising prognostic biomarker and potential therapeutic target in EC.
-
Brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke.
Cerebral ischemia triggers a powerful inflammatory reaction involving both peripheral leukocytes and brain resident cells. Recent evidence indicates that their differentiation into a variety of functional phenotypes contributes to both tissue injury and repair. However, the temporal dynamics and diversity of post-stroke immune cell subsets remain poorly understood. To address these limitations, we performed a longitudinal single-cell transcriptomic study of both brain and mouse blood to obtain a composite picture of brain-infiltrating leukocytes, circulating leukocytes, microglia and endothelium diversity over the ischemic/reperfusion time. Brain cells and blood leukocytes isolated from mice 2 or 14 days after transient middle cerebral artery occlusion or sham surgery were purified by FACS sorting and processed for droplet-based single-cell transcriptomics. The analysis revealed a strong divergence of post-ischemic microglia, macrophages, and neutrophils over time, while such diversity was less evident in dendritic cells, B, T and NK cells. Conversely, brain endothelial cells and brain associated-macrophages showed altered transcriptomic signatures at 2 days post-stroke, but low divergence from sham at day 14. Pseudotime trajectory inference predicted the in-situ longitudinal progression of monocyte-derived macrophages from their blood precursors into day 2 and day 14 phenotypes, while microglia phenotypes at these two time points were not connected. In contrast to monocyte-derived macrophages, neutrophils were predicted to be continuously de-novo recruited from the blood. Brain single-cell transcriptomics from both female and male aged mice did not show major changes in respect to young mice, but aged and young brains differed in their immune cell composition. Furthermore, blood leukocyte analysis also revealed altered transcriptomes after stroke. However, brain-infiltrating leukocytes displayed higher transcriptomic divergence than their circulating counterparts, indicating that phenotypic diversification into cellular subsets occurs within the brain in the early and the recovery phase of ischemic stroke. In addition, this resource report contains a searchable database https://anratherlab.shinyapps.io/strokevis/ to allow user-friendly access to our data. The StrokeVis tool constitutes a comprehensive gene expression atlas that can be interrogated at the gene and cell type level to explore the transcriptional changes of endothelial and immune cell subsets from mouse brain and blood after stroke.
-
A multi-omic machine learning approach deconstructs the role of amino acid metabolism in the immune microenvironment and prognosis of colon adenocarcinoma.
BACKGROUND: The clinical heterogeneity of colon adenocarcinoma (COAD) complicates patient prognosis and treatment. While metabolic reprogramming is a key driver of tumor progression, the role of histidine metabolism in the COAD immune microenvironment remains unclear. METHODS: Through an integrated analysis of public single-cell and bulk transcriptomic data, we mapped the COAD cellular atlas and assessed histidine metabolism activity. A prognostic Histidine Metabolism-related Model (HRM) was constructed using an ensemble of 101 machine learning algorithms, and its biological underpinnings were explored. The function of the key gene, TRIP6, was validated via in vitro experiments. RESULTS: Single-cell analysis identified epithelial cells as the hub of histidine metabolism, which remodels TME intercellular communication. The machine learning-derived HRM robustly stratified patient prognosis across a primary and two validation cohorts. High HRM scores correlated with an "infiltrated-exhausted" immune phenotype, characterized by high immune infiltration alongside elevated checkpoint expression. The key signature gene TRIP6 was identified as a driver of poor prognosis and an immunosuppressive state, and its silencing suppressed malignant phenotypes in vitro. CONCLUSION: Histidine metabolism is a critical regulator of the COAD immune microenvironment. Our prognostic model, the HRM, provides a clinically relevant tool for risk stratification, while its key mediator, TRIP6, represents a novel therapeutic target linking tumor metabolism to immune evasion.
-
Transcriptome profiling reveals liver metastasis-associated genes in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, the mechanisms underlying the acquisition of the metastatic potential in PDAC has not been well understood. In this study, we identified a total of 154 genes upregulated in primary tissues of PDAC with liver metastasis using the Genome Cancer Atlas (TCGA) and GSE151580 cohorts. The epithelial-mesenchymal transition and glycolysis were enriched by the liver metastasis-related genes, indicating that the liver metastasis-related genes might be functionally relevant to liver metastasis in PDAC. Moreover, we also found that the liver metastasis-related genes were primarily regulated at epigenetic level. Particularly, SFN, a cell cycle checkpoint protein, and KRT19, a marker gene for ductal cells, were predicted to be regulated by multiple methylation sites at the promoter. Clinically, we for the first time defined a liver metastasis score (LMS), which was derived from liver metastasis-related genes, and closely associated with clinical characteristics such as disease type and tumor grade, in PDAC. Furthermore, we also divided the samples into high and low LMS groups using three cohorts with long-term follow-up (TCGA, GSE71729, and E-MTAB-6134), which exhibited significantly different prognostic outcomes across three PDAC cohorts, suggesting that the LMS might be a good indicator for risk stratification in PDAC. Furthermore, we also found that the liver metastasis-related genes were primarily expressed in malignant ductal cells by integrative analysis of the bulk and single-cell gene expression data. Moreover, the malignant ductal cells and M0 macrophages were highly correlated with LMS, indicating that the two cell types might function as tumor-promoting cells in PDAC. In summary, the systematic analysis for the first time defined an LMS score to evaluate the risk of liver metastasis in PDAC and revealed that malignant ductal cells might promote PDAC liver metastasis, which greatly improves our understanding of the liver metastasis-related genes, their underlying mechanisms, and association with prognosis in PDAC.
-
CIAO1 as a crucial signature gene of cuproptosis in gastric cancer.
Gastric cancer is a global health challenge, necessitating the identification of novel biomarkers and therapeutic targets. The present study aimed to assess the role of cuproptosisrelated genes (CRGs) in gastric cancer, with the goal of establishing a predictive model consisting of key regulators with prognostic significance, thereby enabling the identification of key genes. Data from The Cancer Genome Atlas and Gene Expression Omnibus databases were used to analyze CRGs in stomach adenocarcinoma (STAD). Least absolute shrinkage and selection operator regression analysis was applied to create a risk model, and its predictive accuracy was confirmed for several clinical subgroups. Moreover, the prognostic value of essential regulators was evaluated through multiple analyses. A risk model with 15 CRGs was used to effectively predict STAD prognosis, demonstrating areas under the receiver operating characteristic curve values of 0.822, 0.811 and 0.922 for 1-, 3- and 5-year overall survival rates, respectively. The risk scores were associated with survival and tumor site. Among the CRGs, the gene for cytosolic iron-sulfur assembly component 1 (CIAO1) was revealed to be critical and associated with histological type, age and treatment outcome. Moreover, single-cell analysis demonstrated that CIAO1 is highly expressed in numerous types of cancer cells, and a high expression of CIAO1 was associated with upregulated transcription levels of immune checkpoints, increased tumor mutation load and decreased immune scores, highlighting its complex role in the tumor microenvironment. CIAO1 knockdown experiments were performed, and eliminating CIAO1 was associated with a reduction in the levels of iron-sulfur proteins and an increase in heat shock protein 70 expression, thereby inducing copper-dependent cell death. Furthermore, treatment with the drugs dasatinib and AT-9283 were associated with an inhibition of CIAO1 expression in gastric cancer cells, and decreased rates of tumor spread and invasion. Taken together, the findings of the present study suggest that CIAO1 is a promising biomarker both for assessing prognosis and evaluating the tumor immune microenvironment of gastric cancer.
-
Comprehensive analysis of diverse cytokine patterns in the prognosis and tumor microenvironment of lung adenocarcinoma.
BACKGROUND: The aim of this study was to elucidate the comprehensive roles of cytokines in lung adenocarcinoma (LUAD). METHODS: Cytokine-related genes were analyzed in LUAD using sequencing datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Gene Set Variation Analysis (GSVA) was employed to quantify enrichment of four cytokine families—interferons (IFNs), tumor necrosis factors (TNFs), interleukins (ILs), and chemokines (CKs)—across samples. Differential expression and survival analyses assessed the impact of each family on LUAD prognosis. A prognostic model based on TNF family genes was constructed using the least absolute shrinkage and selection operator (LASSO) regression. Functional enrichment of the TNF Score (TNFS) was performed with ClusterProfiler. Finally, the role of the key gene TNFRSF11A was validated by small interfering RNA (siRNA) knockdown, followed by Transwell migration, colony formation, and wound-healing assays. RESULTS: Integrated expression and survival analyses identified the TNF family as a critical regulator in LUAD. TNF scores were significantly elevated in tumor versus normal tissues, whereas CK enrichment predicted improved survival and high TNF enrichment predicted poorer survival. Differential profiling in TCGA and GEO cohorts revealed five overexpressed TNF genes—TNFRSF11A, TNFRSF13B, TNFRSF17, TNFSF13, and TNFSF11—correlated with adverse outcomes. A five-gene LASSO-derived risk model demonstrated strong prognostic performance for overall, disease-free, disease-specific, and progression-free survival. High TNFS was associated with dysregulation of cell-cycle, adhesion, and cytokine signaling pathways, as well as altered infiltration of T cells, B cells, and macrophages. Single-cell analysis further revealed that malignant cells with high TNFRSF11A expression exhibited significantly enhanced intercellular communication with fibroblasts and CD8 + T cells, characterized by the activation of specific signaling pathways. TNFRSF11A emerged as the top contributor, with expression positively correlated with smoking history, advanced TNM stage, and recurrence. Functional assays confirmed that TNFRSF11A knockdown significantly impaired LUAD cell proliferation, migration, and invasion. CONCLUSION: The TNF cytokine family plays a pivotal role in LUAD. TNFRSF11A, previously unstudied in this context, represents a novel key driver of LUAD progression.