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Establishment of a risk score model for bladder urothelial carcinoma based on energy metabolism-related genes and their relationships with immune infiltration.
Bladder urothelial carcinoma (BLCA) is a common malignant tumor of the human urinary system, and a large proportion of BLCA patients have a poor prognosis. Therefore, there is an urgent need to find more efficient and sensitive biomarkers for the prognosis of BLCA patients in clinical practice. RNA sequencing (RNA-seq) data and clinical information were obtained from The Cancer Genome Atlas, and 584 energy metabolism-related genes (EMRGs) were obtained from the Reactome pathway database. Cox regression analysis and least absolute shrinkage and selection operator analysis were applied to assess prognostic genes and build a risk score model. The estimate and cibersort algorithms were used to explore the immune microenvironment, immune infiltration, and checkpoints in BLCA patients. Furthermore, we used the Human Protein Atlas database and our single-cell RNA-seq datasets of BLCA patients to verify the expression of 13 EMRGs at the protein and single-cell levels. We constructed a risk score model; the area under the curve of the model at 5 years was 0.792. The risk score was significantly correlated with the immune markers M0 macrophages, M2 macrophages, CD8 T cells, follicular helper T cells, regulatory T cells, and dendritic activating cells. Furthermore, eight immune checkpoint genes were significantly upregulated in the high-risk group. The risk score model can accurately predict the prognosis of BLCA patients and has clinical application value. In addition, according to the differences in immune infiltration and checkpoints, BLCA patients with the most significant benefit can be selected for immune checkpoint inhibitor therapy.
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Spatial and functional dissection of cancer-associated fibroblasts-mediated immune modulation in H. pylori-associated gastric cancer.
BACKGROUND: Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment, yet their spatial organization and immunomodulatory functions in H. pylori-associated gastric cancer (GC) remain incompletely understood. METHODS: We profiled formalin-fixed paraffin-embedded (FFPE) tumors from 71 GC patients using spatial transcriptomics and integrated single-cell RNA-seq from three independent cohorts (China, USA, and Singapore). CAF-immune cell colocalization was quantified by neighborhood enrichment and aggregation index score. Ligand-receptor inference and trajectory analysis resolved CAF signaling and state transitions. To delineate post-transcriptional control, ARE-motif scanning and expression correlations were combined with laser-assisted crosslinking and immunoprecipitation sequencing (LACE-seq) to nominate ZFP36 targets. Immune contexture and prognostic associations were evaluated using CIBERSORT-ABS and Kaplan-Meier analyses in The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) cohorts. RESULTS: We first defined the spatial distributions of the four CAF subtypes reported in prior studies and found that their immune associations varied across histologic and infection-defined GC subtypes. In H. pylori-positive tumors, THBS1⁺ CAFs were spatially enriched near regulatory T cells (Tregs) and were associated with local immunosuppression through WNT5-FZD interactions. In parallel, ZFP36 bound AU-rich elements within the FN1 3' untranslated region (3'UTR), destabilizing FN1 mRNA and thereby diminishing FN1⁺ CAF-mediated cytotoxic T lymphocyte (CTL) activation. Together, these axes promoted Treg accumulation and suppression of CTL activation. CONCLUSIONS: These findings reveal infection-associated stromal programs that shape the immune landscape in GC and highlight CAF-directed pathways as potential therapeutic targets in H. pylori-associated GC.
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[Expression regulation of lipid metabolism gene ABHD5 in the mouse of testes].
OBJECTIVE: To explore the expression regulation of lipid metabolism gene ABHD5 in testes. METHODS: Differential gene analysis was performed by integrating databases of TCGA and GTEx to identify the target gene ABHD5. The expression trends of ABHD5 gene in testicular carcinoma tissue were analyzed. Human testis single-cell atlases were obtained from the Human Protein Atlas and Male Health Atlas databases to determine the expression distribution of ABHD5 across different testicular cell types. Additionally, the GTEx database was utilized to visualize the expression pattern of ABHD5 in the testis, thereby enhancing the understanding of its transcriptional profile. The relationship between ABHD5 expression and age was assessed through integrated database analysis. Western blotting and immunofluorescence were performed to detect differential expressions of ABHD5 in testicular tissues of young and aged mice respectively. RESULTS: The TCGA database indicated that the expression of ABHD5 in human testicular carcinoma tissue was significantly lower than that in normal testicular tissue which showed a negative correlation with patient survival. ABHD5 was highly expressed in germ cells of the testis reveaked from Human Protein Atlas and Male Health Atlas databases. The stability of ABHD5 protein was crucial for testicular tissue, and its expression decreased with age. Furthermore, Western blot and immunofluorescence staining demonstrated that ABHD5 expression in the testicular tissue of aged mice was significantly lower than that in young mice. CONCLUSION: ABHD5 plays an important role in testicular tissue, and may be inseparable from testicular tumors and reproductive aging. However, its mechanism of action remains to be further studied.
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Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation.
INTRODUCTION: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss. RESULTS: RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3'-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets' steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression. DISCUSSION: Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.
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Development of a novel prognostic prediction model using mitochondrial-related genes and single-cell sequencing data for colorectal carcinoma.
BACKGROUND: Colorectal carcinoma (CRC) is a prevalent malignancy worldwide. Due to suboptimal screening practices, CRC is frequently diagnosed at an advanced stage. The role of mitochondrial abnormalities in the advancement of CRC is significant, but the prognostic effect of mitochondrial genes remains unclear. Recent research emphasizes mitochondrial dysfunction's key role in oncogenesis and cancer progression. Mitochondria are vital for cellular metabolism, energy production, and regulating processes like apoptosis, redox homeostasis, and signal transduction. Their dysfunction causes metabolic reprogramming, heightened oxidative stress, and cell death resistance. Though mitochondrial abnormalities link to CRC's aggressive phenotypes, the prognostic value of a comprehensive set of mitochondrial genes remains unclear, leaving a critical knowledge gap. The primary objective of this study was to systematically investigate the prognostic potential of mitochondrial genes in CRC and to develop a novel, reliable risk-scoring model. We aimed to identify key mitochondrial genes associated with patient survival, construct a predictive signature, and validate its efficacy in independently prognosticating overall survival (OS). METHODS: This study used single-cell RNA sequencing (scRNA-seq) data of CRC tissues from The Cancer Genome Atlas (TCGA), and a comprehensive set of 1,650 mitochondrial genes from MitoCarta 3.0. A differential gene expression analysis, gene set enrichment analysis (GSEA), pathway analysis, and Cox proportional hazards regression analysis were conducted. RESULTS: The Cox regression analysis identified five mitochondrial genes (i.e., CPT2, ACSL6, MOCS1, TERT, and PTRH1). These five genes were used to establish a reliable risk-scoring system. Patients with elevated risk scores had more severe clinical manifestations and worse survival outcomes. These results were corroborated in an external validation set (GSE17536 cohort). A predictive model was developed based on these genes that had robust predictive capabilities with areas under the curve (AUCs) of 0.75, 0.77, and 0.78 in the prediction of the 1-, 3-, and 5-year OS of CRC patients, respectively. Additionally, the correlation between the risk score and immune microenvironment characteristics (e.g., immune infiltration patterns, stromal/immune scores) further substantiated the predictive power of the model. CONCLUSIONS: This study established a novel prognostic model for CRC based on mitochondrial genes, thereby extending the understanding of the disease's progression. Subsequent studies should seek to validate these findings within a broader cohort of patients and explore the potential therapeutic roles of the identified mitochondrial genes in the management of CRC.
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Mechanisms of synergistic regulation of the tumor microenvironment by fibroblasts and keratinocytes in esophageal squamous cell carcinoma.
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly invasive malignant tumor, and its tumor microenvironment (TME) plays a pivotal role in disease progression and treatment resistance. As key components of the TME, fibroblasts and keratinocytes are hypothesized to synergistically regulate tumor biological behavior. METHODS: This study integrated single-cell transcriptomic data with bulk RNA-seq data from ESCC to investigate the interaction mechanisms between fibroblasts and keratinocytes within the tumor microenvironment. Rigorous quality control, standardization, and clustering analyses were performed on the single-cell data, identifying ten distinct cell subpopulations, including fibroblasts and keratinocytes. The proportions and expression profile differences of these two cell types were compared between experimental and control groups. Cell-cell communication analysis deciphered ligand-receptor pairs and associated signaling pathways governing intercellular interactions. Molecular subtyping of The Cancer Genome Atlas (TCGA) cohort samples was subsequently performed using non-negative matrix factorization (NMF) based on interaction-specific genes. A multi-gene prognostic model was constructed via least absolute shrinkage and selection operator (LASSO) regression, and its predictive efficacy was evaluated. Finally, functional enrichment, immune microenvironment assessment, and differential expression analyses revealed differences in biological functions and immune infiltration patterns across distinct risk subtypes. RESULTS: By integrating the gene expression profiles of these two cell types, a novel molecular classification system was successfully established, enabling the stratification of ESCC patients into C1(high-risk) and C2(low-risk) subtypes with marked differences in survival outcomes. Patients classified as subtype C2 had a median survival of 3.8 months, significantly longer than the 1.8 months observed in the high-risk subtype C1, highlighting the substantial clinical relevance of this classification. Further analysis revealed that the high-risk cohort exhibited significant enrichment in metabolism-related pathways, such as endocytosis and glyceride metabolism, whereas the low-risk cohort was predominantly associated with pathways involved in cell junctions and structural maintenance. Mechanistically, the interaction between these two cell types jointly promotes the reprogramming of the tumor immune microenvironment by regulating immune cell infiltration, HLA molecule expression, and immune checkpoint activity. Furthermore, the study identified key genes, including SLIT2 and SFRP1, which display cell-type-specific expression patterns in ESCC and hold potential as prognostic biomarkers or therapeutic targets. This research provides novel insights into the regulatory mechanisms of the ESCC tumor microenvironment, laying a theoretical foundation for the development of precision therapeutic strategies targeting the tumor microenvironment. CONCLUSION: This study elucidates the synergistic regulatory mechanisms between fibroblasts and keratinocytes within the tumor microenvironment of ESCC. These findings offer a novel theoretical foundation for molecular classification, prognosis prediction, and precision treatment of ESCC.
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A single-cell genomic atlas for the effects of chronic ethanol exposure in the mouse dorsal striatum.
Alcohol use disorder (AUD) is characterized by compulsive drinking, which is thought to be mediated by effects of chronic intermittent ethanol exposure on the dorsal striatum, the input nucleus of the basal ganglia. Despite significant efforts to understand the impact of ethanol on the dorsal striatum, the rich diversity of striatal cell types and multitude of ethanol targets expressed by them necessitates an unbiased, discovery-based approach. In this study, we used single-nuclei RNA-sequencing (snRNA-seq; n = 86,715 cells) to examine the impact of chronic intermittent ethanol exposure on the dorsal striatum in C57BL/6 male and female mice. We detected 462 differentially expressed genes at FDR < 0.05, the majority of which were mapped to spiny projection neurons (SPNs), the most prominent cell type in the striatum. Gene co-expression network analysis and functional annotation of differentially expressed genes revealed down-regulation of postsynaptic intracellular signaling cascades in SPNs. Inflammation-related genes were down-regulated across many neuronal and non-neuronal cell types. Gene set enrichment analyses also pointed to altered states of rare cell types, including the induction of angiogenesis-related genes in vascular cells. A gene module down-regulated specifically in canonical SPNs was enriched for calcium-signaling genes and components of glutamatergic synapses, as well as for genes associated with genetic risk for AUD. Genetic perturbations of six of this module's hub genes - Foxp1, Bcl11b, Pde10a, Rarb, Rgs9, and Itgr1 - had causal effects on its expression in the mouse striatum and/or on the broader set of differentially expressed genes in alcohol-exposed mice. These data provide important clues as to the impact of ethanol on striatal biology and provide a key resource for future investigation.
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Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development.
Medulloblastoma is currently subclassified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA sequencing (RNA-seq) in large, well-annotated cohorts of medulloblastoma, we show that transcriptionally group 3 and group 4 medulloblastomas exist as intermediates on a bipolar continuum between archetypal group 3 and group 4 entities. Continuum position is prognostic, reflecting a propensity for specific DNA copy-number changes, and specific switches in isoform/enhancer usage and RNA editing. Examining single-cell RNA-seq (scRNA-seq) profiles, we show that intratumoral transcriptional heterogeneity along the continuum is limited in a subtype-dependent manner. By integrating with a human scRNA-seq reference atlas, we show that this continuum is mirrored by an equivalent continuum of transcriptional cell types in early fetal cerebellar development. We identify distinct developmental niches for all four major subgroups and link each to a common developmental antecedent. Our findings show a transcriptional continuum arising from oncogenic disruption of highly specific fetal cerebellar cell types, linked to almost every aspect of group 3/group 4 molecular biology and clinico-pathology.
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Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis.
The female mammary epithelium undergoes reorganization during development, pregnancy, and menopause, linking higher risk with breast cancer development. To characterize these periods of complex remodeling, here we report integrated 50 K mouse and 24 K human mammary epithelial cell atlases obtained by single-cell RNA sequencing, which covers most lifetime stages. Our results indicate a putative trajectory that originates from embryonic mammary stem cells which differentiates into three epithelial lineages (basal, luminal hormone-sensing, and luminal alveolar), presumably arising from unipotent progenitors in postnatal glands. The lineage-specific genes infer cells of origin of breast cancer using The Cancer Genome Atlas data and single-cell RNA sequencing of human breast cancer, as well as the association of gland reorganization to different breast cancer subtypes. This comprehensive mammary cell gene expression atlas ( https://mouse-mammary-epithelium-integrated.cells.ucsc.edu ) presents insights into the impact of the internal and external stimuli on the mammary epithelium at an advanced resolution.
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Intercellular communication atlas reveals Oprm1 as a neuroprotective factor for retinal ganglion cells.
The progressive death of mature neurons often results in neurodegenerative diseases. While the previous studies have mostly focused on identifying intrinsic mechanisms controlling neuronal survival, the extracellular environment also plays a critical role in regulating cell viability. Here we explore how intercellular communication contributes to the survival of retinal ganglion cells (RGCs) following the optic nerve crush (ONC). Although the direct effect of the ONC is restricted to the RGCs, we observed transcriptomic responses in other retinal cells to the injury based on the single-cell RNA-seq, with astrocytes and Müller glia having the most interactions with RGCs. By comparing the RGC subclasses with distinct resilience to ONC-induced cell death, we found that the high-survival RGCs tend to have more ligand-receptor interactions with other retinal cells, suggesting that these RGCs are intrinsically programmed to foster more communication with their surroundings. Furthermore, we identified the top 47 interactions that are stronger in the high-survival RGCs, likely representing neuroprotective interactions. We performed functional assays on one of the receptors, μ-opioid receptor (Oprm1), a receptor known to play roles in regulating pain, reward, and addictive behavior. Although Oprm1 is preferentially expressed in intrinsically photosensitive retinal ganglion cells (ipRGC), its neuroprotective effect could be transferred to multiple RGC subclasses by selectively overexpressing Oprm1 in pan-RGCs in ONC, excitotoxicity, and glaucoma models. Lastly, manipulating Oprm1 activity improved visual functions or altered pupillary light response in mice. Our study provides an atlas of cell-cell interactions in intact and post-ONC retina, and a strategy to predict molecular mechanisms controlling neuroprotection, underlying the principal role played by extracellular environment in supporting neuron survival.