Your browser does not allow saving data (e.g. private mode): bookmarks will be lost when the tab closes.
Search PubMed
Keywords, author, journal, years — results from PubMed, abstracts with Russian translation, bookmarks in your browser.
Found: 4 942
Page 485 of 495-
Gap junction protein beta 5 interacts with Gαi3 to promote Akt activation and cervical cancer cell growth.
Identifying novel therapeutic targets for cervical cancer is crucial for improving patient outcomes and reducing the global burden of this disease. Gap junction protein beta 5 (GJB5) is a member of the connexin family of proteins involved in cell-to-cell communication. This study investigated GJB5's expression and functional significance in cervical cancer. Analysis of The Cancer Genome Atlas (TCGA) data demonstrated significantly increased GJB5 mRNA expression in cervical cancer tissues compared to normal cervical epithelium. Moreover, high GJB5 expression correlated with reduced overall survival and other adverse clinical outcomes. Single-cell RNA sequencing corroborated GJB5 overexpression within the malignant tumor cell population. The downregulation of GJB5 through shRNA or CRISPR/Cas9 gene knockout techniques significantly impaired the viability, proliferation, and migratory capacity of cervical cancer cells, while concurrently inducing apoptotic processes. Conversely, the forced overexpression of GJB5 resulted in enhanced malignant behaviors. Investigations into the underlying mechanisms revealed that GJB5 is integral to the activation of the Akt-mTOR (mammalian target of rapamycin) signaling pathway. GJB5 knockdown or knockout led to diminished phosphorylation of Akt and S6 kinase, whereas GJB5 overexpression correlated with increased Akt-mTOR signaling in primary human cervical cancer cells. Additionally, we identified a novel interaction between GJB5 and the Gαi3 (G alpha inhibitory protein 3), underscoring the crucial role of GJB5 in mediating Akt activation via Gαi3. In vivo studies utilizing xenograft models provided further evidence for the oncogenic function of GJB5. The knockdown of GJB5 resulted in a marked reduction in the growth of cervical cancer xenografts. Observations of proliferation arrest, inactivation of the Akt-mTOR pathway, and the induction of apoptosis were noted in GJB5-depleted cervical cancer xenograft tissues. Collectively, these findings underscore GJB5 as a key oncogenic driver in cervical cancer and indicate that targeting GJB5 could be a promising therapeutic approach for this disease.
-
TCL1A-expressing B cells are critical for tertiary lymphoid structure formation and the prognosis of oral squamous cell carcinoma.
BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant tumor with a poor prognosis. Traditional treatments have limited effectiveness. Regulation of the immune response represents a promising new approach for OSCC treatment. B cells are among the most abundant immune cells in OSCC. However, the role of B cells in OSCC treatment has not been fully elucidated. METHODS: Single-cell RNA sequencing analysis of 13 tissues and 8 adjacent normal tissues from OSCC patients was performed to explore differences in B-cell gene expression between OSCC tissues and normal tissues. We further investigated the relationship between differentially expressed genes and the immune response to OSCC. We utilized tissue microarray data for 146 OSCC clinical samples and RNA sequencing data of 359 OSCC samples from The Cancer Genome Atlas (TCGA) to investigate the role of T-cell leukemia 1 A (TCL1A) in OSCC prognosis. Multiplex immunohistochemistry (mIHC) was employed to investigate the spatial distribution of TCL1A in OSCC tissues. We then investigated the effect of TCL1A on B-cell proliferation and trogocytosis. Finally, lentiviral transduction was performed to induce TCL1A overexpression in B lymphoblastoid cell lines (BLCLs) to verify the function of TCL1A. RESULTS: Our findings revealed that TCL1A was predominantly expressed in B cells and was associated with a better prognosis in OSCC patients. Additionally, we found that TCL1A-expressing B cells are located at the periphery of lymphatic follicles and are associated with tertiary lymphoid structures (TLS) formation in OSCC. Mechanistically, upregulation of TCL1A promoted the trogocytosis of B cells on dendritic cells by mediating the upregulation of CR2, thereby improving antigen-presenting ability. Moreover, the upregulation of TCL1A expression promoted the proliferation of B cells. CONCLUSION: This study revealed the role of B-cell TCL1A expression in TLS formation and its effect on OSCC prognosis. These findings highlight TCL1A as a novel target for OSCC immunotherapy.
-
Machine learning and multi-omic empowered risk stratification and therapeutic framework targeting nucleotide metabolism and mast cell for stomach adenocarcinoma patients.
BACKGROUND: Mast cell and nucleotide metabolism(NM) encodes the Stomach adenocarcinoma (STAD) progression and tumor immune microenvironment(TME) heterogeneity. Research targeting deciphering NM-mast cell axis in STAD can pave the way for the deeper understanding of STAD pathogenesis. METHODS: STAD stomach tissue bulk profiles(GSE26899 and GSE10326) were utilized for identification of Mast cell and nucleotide metabolism(MNM)-associated shared differentially expressed genes(DEGs) via integrative bioinformatic analysis, including Limma, ssGSEA and WGCNA. Next, Lasso-cox regression was cross-employed for elaboration of predictive model and MNM-associated hub gene identification in TCGA-STAD and GSE84437 bulk profiles for STAD patients. Besides, deep learning algorithm(SOM) was utilized for risk stratification for STAD patients in TCGA-STAD dataset. Indeed, we also elucidated the molecular and immune heterogeneity of hub gene at bulk(TCGA-STAD cohort) and single-cell transcriptomic(GSE158937) levels of STAD patients, especially in virtual malignant cells at spatial and temporal manners. Besides, GSCA database with ridge regression were cross-performed for identification of optimal therapeutic framework for STAD patient treatment and then validated by molecular docking. Finally, in vitro study examined the relationship between hub gene and STAD cancer cell proliferation, growth and metastasis. RESULTS: MNM can guide the STAD patient prognostic forecasting and risk stratification. Particularly, UCK2 can be considered as MNM-associated hub gene involved in STAD pathogenesis proved by in silico and in vitro studies. Indeed, HG-5-113-01 should be considered as drug reproposing framework targeting UCK2 for the treatment of STAD. CONCLUSION: Our study first discovered the integration of MNM mechanisms and predictive roles for STAD patients by combining artificial intelligence(AI) and multi-omic studies.
-
Metal ion transporter SLC39A14-mediated ferroptosis and glycosylation modulate the tumor immune microenvironment: pan-cancer multi-omics exploration of therapeutic potential.
BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal mechanism in cancer progression and therapeutic resistance. Concurrently, glycosylation, as a key post-translational modification, plays a critical role in regulating cell signaling, immune evasion, and metastasis. Although both processes are independently implicated in tumor biology, the intersection between ferroptosis and glycosylation remains largely unexplored. METHODS: We performed a comprehensive pan-cancer multi-omics analysis, integrating bulk transcriptomics, epigenomics, and single-cell RNA sequencing datasets. Ferroptosis and glycosylation-related genes were curated from The Molecular Signatures Database (MSigDB), leading to the identification of the metal ion transporter, SLC39A14 (solute carrier family 39 member 14), as a key intersecting gene. A ferroptosis-related gene signature was constructed using machine learning and Cox regression models, followed by survival analyses, immune microenvironment profiling, and a pathway enrichment analysis across The Cancer Genome Atlas (TCGA) cohort. RESULTS: SLC39A14 was found to be significantly upregulated across multiple tumor types and associated with a poor prognosis, immune-stromal infiltration, and ferroptosis resistance. Among all cancer types analyzed, glioblastoma multiforme (GBM) and kidney renal cell carcinoma (KIRC) exhibited the significantly prognostic associations and the most pronounced differential expression of SLC39A14. Single-cell analysis revealed that SLC39A14 expression was enriched between stromal and immune populations, hypoxic perivascular niches, confirming its microenvironment-specific functions. These findings were corroborated by DNA methylation data showing promoter hypomethylation of SLC39A14 in tumors compared to normal tissues. Functionally, SLC39A14 was highly enriched in pathways related to angiogenesis, the epithelial-to-mesenchymal transition, cytokine signaling, and oxidative stress adaptation including vascular endothelial growth factor (VEGF) and cell metabolism-related signaling. A nomogram integrating SLC39A14 expression with clinical parameters improved overall survival predictions. CONCLUSIONS: In this study, we identified SLC39A14 as a dual regulator at the interface of ferroptosis and glycosylation, with significant impacts on tumor microenvironmental remodeling and therapeutic resistance. By leveraging multi-omics and single-cell transcriptomic data, we establish SLC39A14 as a promising prognostic biomarker and therapeutic target, particularly in brain and kidney cancers where ferroptosis modulation could offer novel clinical strategies.
-
Spatial transcriptomics and single-nucleus RNA sequencing reveal a transcriptomic atlas of adult human spinal cord.
Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics. Moreover, we compared the human findings with previously published single-nucleus data of the adult mouse spinal cord, which revealed an overall similarity in the neuronal composition of the spinal cord between the two species while simultaneously highlighting some degree of heterogeneity. Additionally, we examined the sex differences in the spinal neuronal subclusters. Several genes, such as SCN10A and HCN1, showed sex differences in motor neurons. Finally, we classified human dorsal root ganglia (DRG) neurons using spatial transcriptomics and explored the putative interactions between DRG and spinal cord neuronal subclusters. In summary, these results illustrate the complexity and diversity of spinal neurons in humans and provide an important resource for future research to explore the molecular mechanisms underlying spinal cord physiology and diseases.
-
Immunological and pathological characteristics of brain parenchymal and leptomeningeal metastases from non-small cell lung cancer.
Brain parenchymal metastases (BM) and leptomeningeal metastases (LM) represent distinct subtypes of central nervous system metastases (CNSm) from lung cancer, posing significant clinical challenges. The local immune landscape of LM remains elusive. Herein, we utilized single-cell RNA sequencing to build a cell atlas of LM, and systematically examine the immune profiling and cell heterogeneity between BM and LM. Our analysis reveals that BM has more CXCL9+ macrophages, CXCL13+CD4+ T cells and B cells than LM, exhibiting the presence of tertiary lymphoid (TLS) structures, which is associated with a favorable response to tyrosine kinase inhibitors (TKI). Conversely, a remarkably immunosuppressive tumor microenvironment (TME) is detected in LM, characterized by lymphocyte depletion and a concurrent enrichment of SPP1+ macrophages, compared to BM. Furthermore, we identified significant blood-brain barrier (BBB) cell discrepancies between BM and LM, and substantial phenotypic reprogramming of BBB cells in CNSm. This reprogramming encompassed alterations in transporter gene expression, extracellular matrix production and dysregulated cell-cell interactions, potentially contributing to the metastatic process. In summary, this study highlights the divergent cellular and molecular landscapes of BM vs LM, offering critical insights into potential therapeutic targets and informing the development of improved treatment strategies for non-small cell lung cancer patients with CSNm.
-
Spatial and cell type transcriptional landscape of human cerebellar development.
The human neonatal cerebellum is one-fourth of its adult size yet contains the blueprint required to integrate environmental cues with developing motor, cognitive and emotional skills into adulthood. Although mature cerebellar neuroanatomy is well studied, understanding of its developmental origins is limited. In this study, we systematically mapped the molecular, cellular and spatial composition of human fetal cerebellum by combining laser capture microscopy and SPLiT-seq single-nucleus transcriptomics. We profiled functionally distinct regions and gene expression dynamics within cell types and across development. The resulting cell atlas demonstrates that the molecular organization of the cerebellar anlage recapitulates cytoarchitecturally distinct regions and developmentally transient cell types that are distinct from the mouse cerebellum. By mapping genes dominant for pediatric and adult neurological disorders onto our dataset, we identify relevant cell types underlying disease mechanisms. These data provide a resource for probing the cellular basis of human cerebellar development and disease.
-
Using Gjd3-CreEGFP mice to examine atrioventricular node morphology and composition.
The atrioventricular node (AVN) coordinates the timing of atrial and ventricular contraction to optimize cardiac performance. To study this critical function using mouse genetics, however, new reagents are needed that allow AVN-specific manipulation. Here we describe a novel Gjd3-CreEGFP mouse line that successfully recombines floxed alleles within the AVN beginning at E12.5. These mice have been engineered to express CreEGFP under the control of endogenous Gjd3 regulatory elements without perturbing native protein expression. Detailed histological analysis of Gjd3-CreEGFP mice reveals specific labeling of AVN cardiomyocytes and a subset of cardiac endothelial cells. Importantly, we show that Gjd3-CreEGFP mice have preserved cardiac mechanical and electrical function. In one application of our newly described mouse line, we provide a three-dimensional (3D) view of the AVN using tissue clearing combined with confocal microscopy. With this 3D model as a reference, we identify specific AVN sub-structures based on marker staining characteristics. In addition, we use our Gjd3-CreEGFP mice to guide microdissection of the AVN and construction of a single-cell atlas. Thus, our results establish a new transgenic tool for AVN-specific recombination, provide an updated model of AVN morphology, and describe a roadmap for exploring AVN cellular heterogeneity.
-
E2F1 Promotes the Occurrence of Head and Neck Squamous Cell Carcinoma and Serves as a Prognostic Biomarker.
Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumor occurring in various sites such as the oral cavity, pharynx, larynx, and nasal cavity. This study aimed to explore the biological functions and prognostic value of E2F transcription factor 1 (E2F1) in HNSCC. Transcriptome and single-cell sequencing (scRNA-seq) data of HNSCC patients were analyzed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). All samples were divided into high and low expression groups based on the expression levels of E2F1. A risk model was constructed based on Lasso-Cox regression, and the differences between the two groups in terms of prognosis were explored. The scRNA-seq data of HNSCC samples were analyzed using the Seurat package to identify cell types. AUCell was used to score different types of cells, and subsequently, the interaction pathways between the high-scoring cell population and other cell populations were explored using the CellChat package. The expression level of E2F1 in tumor tissues was higher than that in normal tissues, which was confirmed by in vitro experiments. Analysis of transcriptome data from TCGA revealed significant differences in overall survival (OS) between the high and low expression groups. Prognostic genes were selected based on DEGs between the two groups, and a risk model was constructed. Subsequently, a nomogram model was constructed based on clinical factors and risk scores, which exhibited good predictive performance. The expression landscape of prognostic genes in different cell types was explored using scRNA-seq data of HNSCC samples. Dendritic cell populations were identified as high-scoring cell populations, and the pathways of interaction between this cell population and other cell populations were explored. We identified E2F1 as an independent prognostic factor closely associated with the prognosis and immune response of HNSCC.
-
Integrative bioinformatics and experimental validation of the prognostic and functional relevance of XDH and ITPA in non-small cell lung cancer.
Purine metabolism has been implicated in tumor biology and immune regulation, but the clinical and biological relevance of purine metabolism-related genes in non-small cell lung cancer (NSCLC) remains incompletely defined. Transcriptomic data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project, together with TCGA clinical data, were analyzed to identify differentially expressed purine metabolism-related genes and assess their prognostic associations. Immune infiltration was evaluated using single-sample gene set enrichment analysis (ssGSEA), and single-cell transcriptomic datasets were analyzed to characterize the cellular context of candidate genes. Stemness features and drug sensitivity were assessed using transcriptome-based computational models. XDH and ITPA protein expression was examined by Western blotting and immunohistochemistry (IHC) in an independent NSCLC cohort and in cell models. Stable knockdown of XDH or ITPA was performed in H1299 cells, with key functional findings further evaluated in A549 cells. Cisplatin sensitivity was assessed using cell-viability dose-response assays in H1299 and A549 cells. Several purine metabolism-related genes were upregulated in NSCLC and associated with overall survival (OS). XDH and ITPA showed higher protein expression in tumor tissues and were associated with adverse clinicopathological features and poorer survival. Higher expression of these genes was also associated with altered immune infiltration patterns. The messenger RNA-based stemness index (mRNAsi) was associated with ITPA and XDH expression in different directions, whereas higher XDH expression was associated with higher predicted half-maximal inhibitory concentration (IC50) values for cisplatin. Knockdown of XDH or ITPA attenuated proliferative, clonogenic, migratory, and invasive phenotypes in H1299 cells, with key findings reproduced in A549 cells. XDH knockdown also reduced the experimentally determined cisplatin IC50 in both H1299 and A549 cells. XDH and ITPA may represent candidate prognostic and functionally relevant purine metabolism-related genes in NSCLC. The integrated clinical, computational, and cellular findings support their association with NSCLC progression-related phenotypes, while the underlying molecular mechanisms and broader clinical applicability require further investigation.