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Downregulation of PHB1 due to Loss of VHL Protein Expression Promotes the Malignancy Progression of Kidney Renal Clear Cell Carcinoma.
BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is the most common subtype of renal cell carcinoma, accounting for 75-80% of cases. Although Prohibitin 1 (PHB1) has been implicated in tumorigenesis, its role in KIRC remains unclear. This study aimed to investigate the expression, function, and underlying mechanisms of PHB1 in KIRC. METHODS: PHB1 expression and clinical relevance were analyzed using the Cancer Genome Atlas database (TCGA), Gene Expression Omnibus database (GEO), and TIMER3.0 datasets. Single-cell RNA sequencing (scRNA-seq) data from 19 KIRC patients and normal kidney samples were used to assess cell-type-specific expression. Functional experiments, including CCK-8, EdU incorporation, colony formation, and Transwell assays, were performed to evaluate the effects of PHB1 on cell proliferation, migration, and invasion. A xenograft model was used to evaluate the effects of PHB1 in vivo. Western blotting and correlation analyses were conducted to assess the potential regulatory interplay between VHL, SKP2, PHB1, and p53. RESULTS: PHB1 was significantly downregulated in KIRC tissues. Single-cell analysis showed reduced PHB1 expression in tumor-derived epithelial cells, fibroblasts, endothelial cells, and immune cells. Lower PHB1 levels were associated with poorer overall survival. PHB1 overexpression inhibited proliferation and migration, whereas knockdown promoted these effects. In vivo, PHB1 overexpression reduced tumor growth. Moreover, VHL knockout altered the protein levels of SKP2 and PHB1. Cellular manipulation of PHB1 moderately altered endogenous p53 protein expression. Based on TCGA data analysis, PHB1 expression showed a positive correlation with VHL and a negative correlation with SKP2. CONCLUSIONS: Collectively, PHB1 acts as a potential tumor suppressor in KIRC. Its expression pattern is associated with the VHL-SKP2 signaling axis, and the tumor-suppressive effects of PHB1 may be partially associated with the modulation of p53 expression. These findings suggest that PHB1 has the potential to serve as a reliable biomarker and therapeutic candidate for KIRC treatment.
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Pan-cancer single-cell landscape of tumor-infiltrating T cells.
T cells play a central role in cancer immunotherapy, but we lack systematic comparison of the heterogeneity and dynamics of tumor-infiltrating T cells across cancer types. We built a single-cell RNA-sequencing pan-cancer atlas of T cells for 316 donors across 21 cancer types and revealed distinct T cell composition patterns. We found multiple state-transition paths in the exhaustion of CD8+ T cells and the preference of those paths among different tumor types. Certain T cell populations showed specific correlation with patient properties such as mutation burden, shedding light on the possible determinants of the tumor microenvironment. T cell compositions within tumors alone could classify cancer patients into groups with clinical trait specificity, providing new insights into T cell immunity and precision immunotherapy targeting T cells.
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Distinct subnetworks of the thalamic reticular nucleus.
The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition1-5. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders6-9. However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN-thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits.
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Ligand-receptor interaction atlas within and between tumor cells and T cells in lung adenocarcinoma.
Purpose: Lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths worldwide. Although tumor cell-T cell interactions are known to play a fundamental role in promoting tumor progression, these interactions have not been explored in LUAD. Methods: The 10x genomics single-cell RNA sequencing (scRNA-seq) and gene expression data of LUAD patients were obtained from ArrayExpress, TCGA, and GEO databases. scRNA-seq data were analyzed and infiltrating tumor cells, epithelial cells, and T cells were identified in the tumor microenvironment. Differentially expressed ligand-receptor pairs were identified in tumor cells/normal epithelial cells and tumor T cells/non-tumor T cells based on corresponding scRNA-seq and gene expression data, respectively. These important interactions inside/across cancer cells and T cells in LUAD were systematically analyzed. Furthermore, a valid prognostic machine-learning model based on ligand-receptor interactions was built to predict the prognosis of LUAD patients. Flow cytometry and qRT-PCR were performed to validate the significantly differently expressed ligand-receptor pairs. Results: Overall, 39,692 cells in scRNA-seq data were included in our study after quality filtering. A total of 65 ligand-receptor pairs (17 upregulated and 48 downregulated), including LAMB1-ITGB1, CD70-CD27, and HLA-B-LILRB2, and 96 ligand-receptor pairs (41 upregulated and 55 downregulated), including CCL5-CCR5, SELPLG-ITGB2, and CXCL13-CXCR5, were identified in LUAD cancer cells and T cells, respectively. To explore the crosstalk between cancer cells and T cells, 114 ligand-receptor pairs, including 11 ligand-receptor pair genes that could significantly affect survival outcomes, were identified in our research. A machine-learning model was established to accurately predict the prognosis of LUAD patients and ITGB4, CXCR5, and MET were found to play an important role in prognosis in our model. Flow cytometry and qRT-PCR analyses indicated the reliability of our study. Conclusion: Our study revealed functionally significant interactions within and between cancer cells and T cells. We believe these observations will improve our understanding of potential mechanisms of tumor microenvironment contributions to cancer progression and help identify potential targets for immunotherapy in the future.
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The role of acrylamide exposure in prostate cancer progression: An integrated analysis based on network toxicology and experimental validation.
OBJECTIVE: Acrylamide (AA), a widespread environmental and food-borne pollutant, has been classified as a probable human carcinogen. However, its specific role and underlying mechanisms in the progression of prostate cancer (PCa) remain poorly elucidated. This study aims to comprehensively investigate the effect of AA on PCa progression and its molecular mechanisms. METHODS: Differentially expressed AA-related genes (DEARGs) were identified by intersecting data from the Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed to reveal biological functions of DEARGs. A prognostic signature was constructed using Lasso regression analysis. The expression and cellular localization of the key genes were analyzed using single-cell RNA sequencing (scRNA-seq) data. Additionally, the effects of glycidamide (GA) on PCa cells malignant phenotypes and tumor growth in vivo were experimentally validated. RESULTS: We identified a total of 165 DEARGs significantly associated with PCa. Functional analysis revealed they mainly enriched in PI3K-Akt and cAMP signaling pathway. The prognostic model constructed from the six DEARGs (CYP11A1, TUBB3, ALB, ESPL1, FOXN4, ISYNA1) demonstrated satisfactory predictive accuracy for biochemical recurrence-free survival (BCRFS) in PCa patients. scRNA-seq analysis delineated the specific expression of six target genes within the tumor microenvironment. It was found that expression of CYP11A1 was downregulated, while expressions of TUBB3, ALB, ESPL1, FOXN4 and ISYNA1 were upregulated after treatment with GA. In vitro and in vivo experiments confirmed that GA significantly enhanced proliferation, migration, invasion of PCa cells and tumor growth. RNA‑sequencing and functional rescue assays further revealed that the MAPK pathway may be a key mechanism by which GA promoted proliferation, invasion, and metastasis of PCa cells. CONCLUSION: This study successfully identified and validated an AA-related prognostic model to effectively predict BCRFS of PCa. The oncogenic effects of GA are primarily mediated by the activation of specific MAPK signaling pathways, elucidating a key mechanistic basis for its toxicity in PCa.
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Metabolic reprogramming and M2 macrophage depletion define the microenvironment of adenomyosis.
BACKGROUND: Adenomyosis is a chronic gynecological disorder characterized by the invasion of endometrial tissues into the myometrium of the uterus, with pathophysiology linked to chronic inflammation and metabolic dysregulation. However, the understanding of the molecular mechanisms and underlying pathologies remains limited. This study aims to elucidate the metabolic reprogramming and immune dysregulation within the eutopic endometrium from patients diagnosed with adenomyosis, and identify potential therapeutic targets or diagnostic indicators. METHODS: We analyzed publicly available microarray (GSE78851), bulk RNA-seq (GSE193928) and single-cell RNA-seq (Human Endometrial Cell Atlas) datasets to explore the microenvironment of eutopic endometrium from adenomyosis patients. Transcriptomic differences were assessed in GSE78851 (3 adenomyosis versus 5 controls), followed by immune composition and metabolic flux analysis. Findings on immune infiltration and metabolic changes were further validated in GSE193928 (6 adenomyosis versus 15 controls after quality control). Metabolic flux analysis was further extended to single-cell RNA sequencing data derived from endometrial samples of 63 donors. Key genes involved in keratan sulfate biosynthesis were further validated by RT-qPCR and immunofluorescence staining on endometrial biopsy samples. RESULTS: Our study revealed widespread reprogramming in eutopic adenomyosis endometrium, characterized by enhanced immune-related pathways, reduction of M2 macrophage abundance, and disrupted metabolic processes. Further investigation of scRNA-seq data highlighted the cell type-specific metabolic profiles and immune-metabolic interplay within the endometrial microenvironment. Notably, the dysfunction of keratan sulfate biosynthesis, coupled with reduced M2 macrophage level, emerged as a consistent feature. Importantly, four key genes involved in keratan sulfate biosynthesis, including CHST1, CHST6, B4GALT1, and B3GNT2, were upregulated in eutopic endometrium compared to controls, suggesting their potential role in the pathophysiology of the disease. CONCLUSIONS: This study identifies dysregulation of keratan sulfate biosynthesis as a central feature of adenomyosis and links it to reduced M2 macrophage abundance and immune-metabolic imbalance. Validation of four keratan sulfate related genes strengthens their potential as biomarkers or therapeutic targets, providing novel mechanistic insight into the pathogenesis of adenomyosis.
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A single-cell atlas of large B cell lymphomas reveals distinct malignant archetypes predictive of clinical outcomes.
Large B cell lymphomas (LBCLs) exhibit significant heterogeneity which leads to disparate treatment response, with up to 40% of patients developing refractory disease or relapsing within the first two years. To understand the cellular and molecular basis of this heterogeneity, we performed single-cell RNA-seq, BCR-seq, and TCR-seq on LBCL tumor biopsies, generating an atlas of 63 LBCL cases, mostly classified as diffuse LBCL, not otherwise specified (DLBCL NOS). We identified five conserved transcriptional archetypes of malignant B cells that co-occur within individual tumors, with varying proportions across patients. Notably, high abundance of Archetype 4, characterized by memory B cell features and quiescence markers, correlated with poor event-free survival following standard immunochemotherapy, a finding which was validated in independent cohorts through deconvolution of bulk RNA-seq data. Our study provides a novel framework for patient stratification based on the quantification of malignant cellular states, with implications for precision therapy of LBCLs.
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Role of BTLA in ovarian cancer and its clinical prognostic significance based on multi-omics analysis.
BACKGROUND: Ovarian cancer (OV) is a highly lethal gynecological malignancy with limited effective biomarkers for prognosis and precision immunotherapy. B and T lymphocyte attenuator (BTLA) is an immune checkpoint molecule involved in tumor immune regulation, but its role in OV remains unclear. METHODS: Transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to evaluate BTLA expression and its potential clinical relevance in OV. Exploratory multivariable Cox regression analysis was performed to examine the association between BTLA expression and patient prognosis. Functional characteristics were investigated through gene set enrichment and variation analyses, protein-protein interaction analysis, and regulatory network construction. Single-cell RNA sequencing (ScRNA-seq) was applied to explore cellular heterogeneity and BTLA-related cell-cell communication. Drug sensitivity analyses and molecular docking were conducted to assess therapeutic relevance. Experimental assays were performed to validate BTLA expression. RESULTS: BTLA was significantly upregulated in OV tissues compared with normal controls. Higher BTLA expression was associated with patient prognosis in exploratory Cox regression and Kaplan-Meier (KM) analyses. Functional enrichment revealed associations with immune- and tumor-related pathways including epithelial mesenchymal transition (EMT), interleukin-10 signaling, and interferon responses. Single-cell analysis demonstrated BTLA-related transcriptional heterogeneity across cell populations, with epithelial cells showing the highest activity. Drug sensitivity profiling identified differential responses between BTLA expression groups, and molecular docking suggested moderate binding affinity between BTLA and genistein (Vina score = - 6.3 kcal/mol). Experimental validation confirmed increased BTLA expression at both mRNA and protein levels in OV tissues. CONCLUSION: These findings suggest that BTLA may be involved in the tumor immune microenvironment of OV and may provide preliminary clues as a potential biomarker and therapeutic target.
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Comprehensive Analysis of a Platelet- and Coagulation-Related Prognostic Gene Signature Identifies CYP19A1 as a Key Tumorigenic Driver of Colorectal Cancer.
BACKGROUND: The intricate interplay between the platelet-coagulation system and the progression of malignant tumors has profound therapeutic implications. However, a thorough examination of platelet and coagulation markers specific to colorectal cancer (CRC) is conspicuously absent in the current literature. Consequently, there is an urgent need for further exploration into the mechanistic underpinnings of these markers and their potential clinical applications. METHODS: By integrating RNA-seq data and clinicopathological information from patients with CRC in the cancer genome atlas, we identified genes related to the platelet-coagulation system using weighted gene co-expression networks and univariate Cox analysis. We established a prognostic risk model based on platelet- and coagulation-related genes using Lasso Cox regression analysis and validated the model in two independent CRC cohorts. We explored potential biological functional disparities between high-risk and low-risk groups through comprehensive bioinformatics analysis. RESULTS: Our findings indicate that colorectal cancer patients classified as high-risk generally exhibit poorer prognoses. Moreover, the model's risk scores were associated with the differential composition of the immune tumor microenvironment, suggesting its applicability to infer immunotherapy responsiveness. Cellular functional experiments and animal experiments indicated that CYP19A1 expression in CRC influences malignant phenotype and platelet activation. CONCLUSIONS: In summary, we present a novel platelet- and coagulation-related risk model for prognostic assessment of patients with CRC and confirm the important role of CYP19A1 in promoting malignant progression of CRC.
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Identification of 5-Gene Prognostic Markers and Functional Verification of RRBP1 in 5-Fluorouracil Resistance of Colorectal Cancer by Multi-Omics Analysis and Experimental Verification.
Acquired resistance to 5-fluorouracil (5-FU) is a primary clinical challenge in colorectal cancer (CRC) treatment. Our study aimed to identify key factors predictive of 5-FU resistance and to elucidate their functional mechanisms by combining multi-omics analysis with experimental verification. The prognostic model was constructed based on the gene expression omnibus (GEO, GSE196900, GSE166555) and the cancer genome atlas (TCGA)-Colon Adenocarcinoma (COAD) datasets combined with regression analysis. Kaplan-Meier (K-M), receiver operating characteristic (ROC) curve, and nomogram were used to evaluate the predictive performance of the prognostic model. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) were used for functional enrichment analysis. Single-cell RNA sequencing (scRNA-seq, GSE166555) and qRT-PCR analysis were used to analyze the tumor microenvironment and gene expression. In cell experiments, CCK-8 assay measured IC50 value. Glycolysis metabolism was evaluated by detecting glucose consumption, lactic acid production, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR); cell stemness was evaluated by sphere formation assay. A 5-gene prognostic model was successfully constructed, which could effectively distinguish the high-/low-risk groups of CRC patients and was significantly correlated with overall survival. Ribosome binding protein 1 (RRBP1) is highly expressed in cancer tissues of non-responders to chemotherapy. It is also highly expressed in tumor epithelial cells, and its high expression is closely related to aneuploidy characteristics, up-regulation of oncogenes, and activation of pro-survival pathways. In vitro experiments confirmed that knockdown of RRBP1 significantly enhanced the sensitivity of CRC cells to 5-FU and inhibited cell proliferation. Mechanistically, RRBP1 knockdown effectively reversed the enhanced glycolysis activity and stem cell-like properties of 5-FU-resistant cells. This study established RRBP1 as a key CRC prognostic factor and 5-FU resistance driver, operating through the regulation of cell glycolysis and stemness. RRBP1 emerges as a new biomarker and therapeutic target for predicting the efficacy of 5-FU.