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: 4 945
Page 473 of 495-
Development and validation of a lipid metabolism-related prognostic model for gastric adenocarcinoma.
BACKGROUND: Lipid metabolism plays a critical role in the development, progression, and immune regulation of gastric adenocarcinoma (GA). However, its prognostic significance and relationship with the tumor microenvironment (TME) remain unclear. This study aimed to construct a GA lipid metabolism-related prognostic model and evaluate its clinical relevance in GA. METHODS: Lipid metabolism-related differentially expressed genes (DEGs) were identified from The Cancer Genome Atlas (TCGA) database. A prognostic lipid metabolism-related signature for GA (GA-LMRS) was developed via least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. The model's predictive performance was validated in multiple cohorts. Functional enrichment, tumor mutation burden (TMB), and immune correlation analyses were performed. Drug sensitivity analysis was conducted to assess the immunotherapy response. RESULTS: A 14-gene GA-LMRS was established, effectively stratifying patients into high- and low-risk groups. High-risk patients exhibited significantly poorer survival (P<0.001), and the model demonstrated robust predictive ability [area under the curve (AUC) >0.71]. Functional analysis revealed enrichment of the high-risk genes in extracellular matrix remodeling, immune evasion, and cancer-related pathways, whereas low-risk genes were associated with DNA repair and metabolic processes. High-risk patients had higher TMB, upregulated immune checkpoint expression, and lower sensitivity to CTLA4 inhibitors, suggesting immunotherapy resistance. In contrast, low-risk and C2 subtype patients were more likely to benefit from immune checkpoint inhibitors (ICIs). CONCLUSIONS: GA-LMRS serves as a reliable prognostic tool and reflects the immune status of patients with GA. Targeting lipid metabolism may improve immunotherapy efficacy. Future studies should integrate single-cell sequencing and multicenter clinical data to enhance model applicability and therapeutic strategies.
-
The MYC/TXNIP axis mediates NCL-Suppressed CD8+T cell immune response in lung adenocarcinoma.
BACKGROUND: Lung adenocarcinoma is a deadly malignancy with immune evasion playing a key role in tumor progression. Glucose metabolism is crucial for T cell function, and the nucleolar protein NCL may influence T cell glucose metabolism. This study aims to investigate NCL's role in T cell glucose metabolism and immune evasion by lung adenocarcinoma cells. METHODS: Utilizing single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we analyzed cell clustering, annotation, and prognosis. In vitro experiments involved manipulating NCL expression in CD8+ T cells to study immune function and glucose metabolism. In vivo studies using an orthotopic transplant mouse model monitored NCL's impact on CD8+ T cell glucose metabolism and anti-tumor immune function. RESULTS: NCL was associated with T cell dysfunction and glucose metabolism. NCL silencing enhanced CD8+ T cell glucose metabolism, cytotoxicity, and infiltration, while NCL overexpression had the opposite effect. NCL overexpression relieved MYC-mediated transcriptional repression of TXNIP, reducing CD8+ T cell glucose metabolism. In vivo, NCL inhibited CD8+ T cell glucose metabolism through the MYC/TXNIP axis, hindering anti-tumor immune function. CONCLUSIONS: NCL overexpression suppresses CD8+ T cell glucose metabolism and anti-tumor immune function, promoting lung adenocarcinoma progression via the MYC/TXNIP axis.
-
Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring.
High-risk neuroblastoma, a leading cause of pediatric cancer mortality, exhibits substantial intratumoral heterogeneity, contributing to therapeutic resistance. To understand tumor microenvironment evolution during therapy, we longitudinally profiled 22 patients with high-risk neuroblastoma before and after induction chemotherapy using single-nucleus RNA and ATAC sequencing and whole-genome sequencing. This revealed profound shifts in tumor and immune cell subpopulations after therapy and identified enhancer-driven transcriptional regulators of neuroblastoma neoplastic states. Poor outcome correlated with proliferative and metabolically active neoplastic states, whereas more differentiated neuronal-like states predicted better prognosis. Proportions of mesenchymal neoplastic cells increased after therapy and a high proportion correlated with a poorer chemotherapy response. Macrophages significantly expanded towards pro-angiogenic, immunosuppressive and metabolic phenotypes. We identified paracrine signaling networks and validated the HB-EGF-ERBB4 axis between macrophage and neoplastic subsets, which promoted tumor growth through the induction of ERK signaling. These findings collectively reveal intrinsic and extrinsic regulators of therapy response in high-risk neuroblastoma.
-
Single-cell analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells.
INTRODUCTION: The ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral immune signaling in the airway contributes to the severity of coronavirus disease 2019 (COVID-19). Additionally, COVID-19 is influenced by age and has more severe presentations in older individuals. Hence we investigate the role of innate immune signaling as a function of lung development and age. METHOD: We investigated the transcriptome of the airway epithelium using pediatric and adult lung tissue samples from the LungMAP Human Tissue Core Biorepository. Specifically, lung lobes were digested and cultured into a biomimetic model of the airway epithelium on an air-liquid interface. Cells were then infected with SARS-CoV-2 and subjected to single-cell RNA sequencing. The data was analyzed using Seurat, scType, Monacle and tools to infer cell-cell communication. RESULTS: The clustering analysis identified following six cell populations: club cells, proliferating epithelial cells, multiciliated precursor cells, ionocytes, and two biologically distinct clusters of ciliated cells (FOXJ1high and FOXJ1low). Interestingly, the two ciliated cell clusters showed different infection rates and enrichment of processes involved in ciliary biogenesis and function; we observed a cell-type-specific suppression of innate immunity in infected cells from the FOXJ1low subset. We also identified a significant number of genes that were differentially expressed in lung cells derived from children as compared to adults, suggesting the differential pathogenesis of SARS-CoV-2 infection in children versus adults. CONCLUSION: This work reveals age dependent differences in the lung epithelial cell response to SARS-CoV-2 infection. The results can be used to identify drug targets to modulate molecular signaling cascades that mediate an innate immune response.
-
Construction of a radiogenomic signature based on endoplasmic reticulum stress for predicting prognosis and systemic combination therapy response in hepatocellular carcinoma.
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. Various factors in the tumor environment (TME) can lead to the activation of endoplasmic reticulum stress (ERS), thereby affecting the occurrence and development of tumors. The objective of our study was to develop and validate a radiogenomic signature based on ERS to predict prognosis and systemic combination therapy response. METHODS: Using data from The Cancer Genome Atlas Program (TCGA) as a training cohort and data from International cancer genome consortium (ICGC) as a testing cohort. Univariate Cox regression and multivariate Cox regression analysis were used to identify prognostic-related genes and construct a model. HCC single-cell data obtained from Gene Expression Omnibus (GEO) were used to map gene signatures and explore inter-cellular signaling communications. Finally, a radiogenomic signature was used to predict the objective response rate (ORR) and overall survival (OS). RESULTS: A total of four gene signatures related to ERS, including Stanniocalcin-2 (STC2), Melanoma-Associated Antigen 3 (MAGEA3), BR Serine/Threonine-Protein Kinase 2 (BRSK2), DEAD/H-Box Helicase 11 (DDX11) were identified. Macrophages were significantly different between high-risk and low-risk groups. The high-risk group showed higher targeting programmed cell death-1 (PD-1) and mutated tumor protein p53 (TP53) scores. Drug sensitivity analysis found that most sensitive drugs target the phosphatidylinositol 3-kinase/ mechanistic target of rapamycin (PI3K/mTOR) signaling pathway. Further research revealed the expression of STC2 in the endothelial cells (ECs), particularly plasmalemma vesicle associated protein (PLVAP) + ECs, and may regulate the reprogramming and function of macrophages. Furthermore, we identified nine radiomic features and established a radiogenomic signature based on ERS that can predict prognosis and response to systemic combination therapy. This signature can guide systemic combination therapy for patients with unresectable HCC. CONCLUSIONS: We established an ERS prognostic model that can predict patient prognosis. We also found that ERS is closely related to the TME and is mainly manifested in the interaction between tumor-associated endothelial cells (TAEs) and tumor-associated macrophages (TAMs). Moreover, we constructed a radiogenomic signature based on the ERS. This signature can guide subsequent combination therapy for patients with unresectable HCC.
-
[Mechanism of betulinic acid against colorectal cancer based on bioinformatics and experimental validation].
This study explored the therapeutic potential and underlying mechanisms of betulinic acid(BA) in the treatment of colorectal cancer(CRC) through integrated bioinformatics analysis and in vitro experimental validation. Potential targets of BA against CRC were identified by mining multiple public databases, including BATMAN-TCM, PharmMapper, DrugBank, and GeneCards. A total of 100 overlapping targets were identified. Protein-protein interaction(PPI) network was constructed to screen for core targets. Differentially expressed genes(DEGs) in CRC patients were obtained from the cancer genome atlas(TCGA), and single-cell RNA sequencing analysis was employed to identify the specific cell clusters potentially affected by BA. Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed on the common targets to clarify the potential signaling pathways and biological processes. Core targets were further validated through molecular docking with BA. A methyltransferase-like 3(METTL3) knockdown model was established using HCT116 colorectal cancer cells. The cells were treated with varying concentrations of BA(9.375, 18.75, 37.5, 75, and 150 μmol·L~(-1)). Cell viability was assessed using CCK-8 assay. Additionally, wound healing assays were used to assess cell migration ability, while Transwell assays were conducted to evaluate both migration and invasion ability. Western blot analysis was performed to measure the expression levels of METTL3, as well as peroxisome proliferator-activated receptors(PPAR)γ and PPARα. Network pharmacology analysis revealed that the therapeutic effects of BA on CRC were primarily associated with 100 therapeutic targets and 26 signaling pathways, with PPAR signaling pathway identified as a key pathway. Molecular docking demonstrated that BA exhibited a strong binding affinity to the core targets. In vitro experiments confirmed that BA significantly inhibited the proliferation, migration, and invasion of HCT116 cells. Western blot indicated that BA treatment downregulated METTL3 expression and reduced the expression of PPARγ and PPARα compared to the control group. These findings suggest that BA may inhibit the proliferation, migration, and invasion of CRC cells by down-regulating METTL3 expression, thereby reducing the m~6A methylation level of PPARγ and PPARα mRNA, leading to decreased mRNA stability and translational efficiency, and ultimately modulating the PPAR signaling pathway.
-
Regional and aging-specific cellular architecture of non-human primate brains.
BACKGROUND: Deciphering the functionality and dynamics of brain networks across different regions and age groups in non-human primates (NHPs) is crucial for understanding the evolution of human cognition as well as the processes underlying brain pathogenesis. However, systemic delineation of the cellular composition and molecular connections among multiple brain regions and their alterations induced by aging in NHPs remain largely unresolved. METHODS: In this study, we performed single-nucleus RNA sequencing on 39 samples collected from 10 brain regions of two young and two aged rhesus macaques using the DNBelab C4 system. Validation of protein expression of signatures specific to particular cell types, brain regions, and aging was conducted through a series of immunofluorescence and immunohistochemistry staining experiments. Loss-of-function experiments mediated by short hairpin RNA (shRNA) targeting two age-related genes (i.e., VSNL1 and HPCAL4) were performed in U251 glioma cells to verify their aging effects. Senescence-associated beta-galactosidase (SA-β-gal) staining and quantitative PCR (qPCR) of senescence marker genes were employed to assess cellular senescence in U251 cells. RESULTS: We have established a large-scale cell atlas encompassing over 330,000 cells for the rhesus macaque brain. Our analysis identified numerous gene expression signatures that were specific to particular cell types, subtypes, brain regions, and aging. These datasets greatly expand our knowledge of primate brain organization and highlight the potential involvement of specific molecular and cellular components in both the regionalization and functional integrity of the brain. Our analysis also disclosed extensive transcriptional alterations and cell-cell connections across brain regions in the aging macaques. Finally, by examining the heritability enrichment of human complex traits and diseases, we determined that neurological traits were significantly enriched in neuronal cells and multiple regions with aging-relevant gene expression signatures, while immune-related traits exhibited pronounced enrichment in microglia. CONCLUSIONS: Taken together, our study presents a valuable resource for investigating the cellular and molecular architecture of the primate nervous system, thereby expanding our understanding of the mechanisms underlying brain function, aging, and disease.
-
PLXNB2 promotes breast cancer progression and lung metastasis through the AMPK signaling pathway.
Breast cancer is one of the most common malignancies among women worldwide, and metastasis remains the leading cause of breast cancer-related mortality. Although PLXNB2 regulates cell migration and intracellular signaling, its expression pattern and mechanistic role in breast cancer progression and lung metastasis remain unclear. This study investigated PLXNB2 expression in breast cancer (BRCA) and examined its contribution to tumor progression and pulmonary metastasis. PLXNB2 expression in tumor and adjacent normal tissues was analyzed using The Cancer Genome Atlas (TCGA) data. Weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, single-cell transcriptomics, and spatial transcriptomics were used to identify PLXNB2-associated pathways and cellular contexts. Associations with tumor grade and survival were evaluated in clinical cohorts, and the effects of lentiviral PLXNB2 knockdown on proliferation, migration, and invasion were assessed in breast cancer cell lines. Tumorigenicity and metastasis were further examined in vivo. PLXNB2 was significantly upregulated in breast cancer and was enriched predominantly in malignant epithelial cells. High PLXNB2 expression independently predicted poor overall survival in the GSE20711 cohort (HR = 1.610; 95% CI, 1.100-2.357; P = 0.013) and was positively associated with tumor grade (P < 0.05). WGCNA and transcriptomic analyses identified AMPK signaling as a key downstream pathway. PLXNB2 knockdown reduced p-AMPK and p-ACC1 levels without altering total AMPK or ACC1 expression, and reciprocal endogenous co-immunoprecipitation detected AMPK in PLXNB2 immunoprecipitates and PLXNB2 in AMPK immunoprecipitates, supporting an association between the two proteins. In vivo, PLXNB2 depletion reduced tumor growth, lung metastasis, and p-AMPK and p-ACC1 expression. These findings indicate that PLXNB2 promotes breast cancer progression and lung metastasis by activating AMPK signaling and may serve as a diagnostic, prognostic, and therapeutic biomarker.
-
Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer.
The use of immune adjuvants such as toll-like receptor (TLR) agonists reflects a novel strategy in prostate cancer (PCa) therapy. However, interleukin-1 receptor associated kinase 1 (IRAK1), a central effector of TLR signaling, has been shown to be responsible for resistance to radiation-induced tumor cell death. In order to better understand the function and epigenetic regulation of IRAK1 in PCa, we performed in vitro cell culture experiments together with integrative bioinformatic studies using the latest single-cell RNA-sequencing data of human PCa and normal prostate (NOR), and data from The Cancer Genome Atlas. We focused on key effectors of TLR signaling, the Myddosome-complex components IRAK1, IRAK4 and MYD88 (myeloid differentiation primary response 88), and TRAF6 (tumor-necrosis-factor receptor associated factor 6). In PCa, IRAK1-mRNA was specifically enriched in luminal epithelial cells, representing 57% of all cells, whereas IRAK4 and MYD88 were predominantly expressed in leukocytes, and TRAF6, in endothelial cells. Compared to NOR, only IRAK1 was significantly overexpressed in PCa (Benjamini-Hochberg adjusted p<2x10-8), whereas the expression of IRAK4, MYD88, and TRAF6 was unchanged in PCa, and IRAK1-expression was inversely correlated with a specific differentially methylated region (IRAK1-DMR) within a predicted promoter region enriched for H3K27ac (Spearman correlation r<-0.36; Fisher's test, p<10-10). Transcription factors with high binding affinities in IRAK1-DMR were significantly enriched for canonical pathways associated with viral infection and carcinogenic transformation in the Kyoto Encyclopedia of Gene and Genomes analysis. DU145 cells, exhibiting hypermethylated IRAK1-DMR and low IRAK1-expression, reacted with 4-fold increased IRAK1-expression upon combined treatment with 5-aza-2-deoxycytidine and trichostatin A, and were unresponsive to infection with the uropathogenic Escherichia coli strain UTI89. In contrast, PC3 and LNCaP cells, exhibiting hypomethylated IRAK1-DMR and high endogenous IRAK1-mRNA levels, responded with strong activation of IRAK1-expression to UTI89 infection. In summary, exclusive overexpression of IRAK1 was observed in luminal epithelial cells in PCa, suggesting it has a role in addition to Myddosome-dependent TLR signaling. Our data show that the endogenous epigenetic status of PCa cells within IRAK1-DMR is decisive for IRAK1 expression and should be considered as a predictive marker when selective IRAK1-targeting therapies are considered.
-
CCT6B as a candidate chaperonin-related molecule in hepatocellular carcinoma: Bioinformatic analysis and preliminary experimental validation.
PURPOSE: Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited therapeutic options and poor prognosis, highlighting the need for prognostic biomarkers and novel molecular candidates. This study aimed to identify chaperonin-related genes associated with HCC prognosis and to preliminarily explore the biological relevance of CCT6B. METHODS: The Cancer Genome Atlas (TCGA) database and R were used to identify molecular chaperonin-related genes associated with HCC prognosis. A prognostic model was constructed using least absolute shrinkage and selection operator (LASSO)-Cox regression, and the association between CCT6B expression and survival was evaluated. Western blotting (WB) was performed to compare CCT6B protein levels in paired HCC tumor and adjacent nontumor tissues. shRNA-mediated CCT6B knockdown was conducted in SNU-182 cells, and migration, proliferation, and apoptosis were assessed using wound-healing, MTT, and flow cytometry assays, respectively. Apoptosis-related proteins (BAX, Bcl-2, Cyt-c, Caspase-9, Caspase-3, and P53) were measured by WB. RESULTS: Bioinformatics analysis identified nine chaperonin-related genes associated with HCC prognosis in the TCGA-LIHC cohort. CCT6B was selected for exploratory validation due to its transcriptomic pattern and limited prior characterization in HCC. Although CCT6B mRNA was downregulated in public transcriptomic datasets, Western blot analysis of three paired clinical samples suggested a possible increase in CCT6B protein abundance in tumor tissues; however, this observation should be interpreted as preliminary because of the very small sample size. In SNU-182 cells, shRNA-mediated CCT6B knockdown was associated with reduced proliferation and migration and increased apoptosis, accompanied by changes in intrinsic apoptosis-related proteins. Because these functional data were generated in a single cell line using one knockdown strategy, they should be regarded as preliminary and hypothesis-generating. CONCLUSION: This study identified a TCGA-derived chaperonin-related prognostic signature in HCC and prioritized CCT6B as a biologically distinctive candidate for preliminary validation. CCT6B showed transcriptomic downregulation in public datasets, while limited protein-level observations suggested a possible discordant trend that requires confirmation. CCT6B knockdown in one HCC cell line was associated with altered proliferation, migration, apoptosis, and apoptosis-related protein expression. However, because of the limited clinical sample size, single-cell-line validation, lack of rescue and gain-of-function experiments, absence of in vivo data, and unresolved mRNA-protein discordance, CCT6B should currently be regarded as a candidate chaperonin-related molecule of biological interest rather than a validated prognostic biomarker or therapeutic target in HCC.