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 471 of 495-
Development of stemness-related signature to optimize prognosis prediction and identify XMD8-85 as a novel therapeutic compound for glioma.
Glioma is a highly invasive and aggressive type of brain cancer with poor treatment response. Stemness-related transcription factors form a regulatory network that sustains the malignant phenotype of gliomas. We conducted an integrated analysis of stemness-related transcription factors using The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets, established the characteristics of stemness-related transcription factors, including Octamer-Binding Protein 4 (OCT4), Meis Homeobox 1 (MEIS1), E2F Transcription Factor 1 (E2F1), Transcription Factor CP2 Like 1 (TFCP2L1), and RUNX Family Transcription Factor 1 (RUNX1). The characteristic of stemness-related transcription factors was identified as an independent prognostic factor for glioma patients. Patients in the high-risk group have a worse prognosis than those in the low-risk group. The glioma microenvironment in the high-risk group exhibited a more active immune status. Single-cell level analysis revealed that stem cell-like cells exhibited stronger intercellular communication than glioma cells. Meanwhile, patients in different risk stratification exhibited varying sensitivities to immunotherapy and small molecule drug therapy. XMD8-85 was more effective in the high-risk group, and its antitumor effects were validated both in vivo and in vitro. Our results indicate that this prognostic feature will assist clinicians in predicting the prognosis of glioma patients, guiding immunotherapy and personalized treatment, as well as the potential clinical application of XMD8-85 in glioma treatment, and helping to develop effective treatment strategies.
-
The role of CD47 in immune escape of colon cancer and its correlation with heterogeneity of tumor immune microenvironment.
BACKGROUND: Cluster of differentiation 47 (CD47), a transmembrane protein, plays a critical role in regulating cellular functions and maintaining immune homeostasis. Its expression has been shown to influence cancer prognosis. In this study, we investigated the role of CD47 in tumor progression in colon adenocarcinoma (COAD) and evaluated its potential as a target for immunotherapy. MATERIALS AND METHODS: We analyzed surgical samples from 96 COAD patients. Immunohistochemical analysis was performed on 90 samples, while the remaining 6 were subjected to multiplex immunofluorescence. To explore the association between CD47 expression and clinicopathological characteristics, we integrated transcriptome data from The Cancer Genome Atlas and the Gene Expression Omnibus using R software. The Tumor Immune Estimation Resource and Kaplan-Meier plotter were utilized to assess the relationship between CD47 expression, patient prognosis, and immune infiltration. Furthermore, the single-cell Tumor Immune System Interaction Database was used to examine the correlation between CD47 expression and the tumor microenvironment (TME). All included patients gave oral and written informed consent. The study was approved by the Ethics Committee of 3201 Hospital (full name: Medical Ethics Committee of 3201 Hospital). RESULTS: CD47 was found to be overexpressed in various tumors, including COAD. Higher CD47 expression was significantly associated with more advanced tumor stages, including TNM staging, T staging, and N staging (P < 0.05). A robust correlation was observed between CD47 expression and immune cell infiltration in COAD. Patients with elevated CD47 expression tended to have longer disease-free intervals, although this benefit was diminished in cases with high infiltration of M1 macrophages. The immunosuppressive function of CD47 primarily acted through the CD47/SIRPα pathway. Additionally, distinct cellular compositions and distributions were identified between primary and metastatic COAD, underscoring the heterogeneity of the TME. CD47 also influenced the TME by modulating cytokine and cytokine receptor interactions. CONCLUSION: CD47 represents a promising prognostic biomarker and a potential target for immunotherapy in COAD. These findings provide new insights into therapeutic strategies aimed at modulating the TME and improving patient outcomes.
-
Comprehensive profiling of migratory primordial germ cells reveals niche-specific differences in non-canonical Wnt and Nodal-Lefty signaling in anterior vs posterior migrants.
Mammalian primordial germ cells (PGCs) migrate asynchronously through the embryonic hindgut and dorsal mesentery to reach the gonads. We previously found that interaction with different somatic niches regulates mouse PGC proliferation along the migration route. To characterize transcriptional heterogeneity of migrating PGCs and their niches, we performed single-cell RNA sequencing of 13,262 mouse PGCs and 7868 surrounding somatic cells during migration (E9.5, E10.5, E11.5) and in anterior vs posterior locations to enrich for leading and lagging migrants. Analysis of PGCs by position revealed dynamic gene expression changes between faster or earlier migrants in the anterior and slower or later migrants in the posterior at E9.5; these differences include migration-associated actin polymerization machinery and epigenetic reprogramming-associated genes. We furthermore identified changes in signaling with various somatic niches, notably strengthened interactions with hindgut epithelium via non-canonical WNT (ncWNT) in posterior PGCs compared to anterior. Reanalysis of a previously published dataset suggests that ncWNT signaling from the hindgut epithelium to early migratory PGCs is conserved in humans. Trajectory inference methods identified putative differentiation trajectories linking cell states across timepoints and from posterior to anterior in our mouse dataset. At E9.5, we mainly observed differences in cell adhesion and actin cytoskeletal dynamics between E9.5 posterior and anterior migrants. At E10.5, we observed divergent gene expression patterns between putative differentiation trajectories from posterior to anterior, including Nodal signaling response genes Lefty1, Lefty2, and Pycr2 and reprogramming factors Dnmt1, Prc1, and Tet1. At E10.5, we experimentally validated anterior migrant-specific Lefty1/2 upregulation via whole-mount immunofluorescence staining for LEFTY1/2 and phosphorylated SMAD2/3, suggesting that elevated autocrine Nodal signaling in migrating PGCs occurs as they near the gonadal ridges. Together, this positional and temporal atlas of mouse PGCs supports the idea that niche interactions along the migratory route elicit changes in proliferation, actin dynamics, pluripotency, and epigenetic reprogramming.
-
CEBPB as a candidate mediator of DEGDB-induced tumor-associated phenotypes in colorectal cancer cells.
OBJECTIVE: To investigate the effects of exposure to diethylene glycol dibenzoate (DEGDB) on malignant progression in colorectal cancer (CRC) cells and to identify a prioritized candidate gene. METHODS: PubChem, SwissADME, ADMETlab 3.0, and ProTox 3.0 were used to characterize the chemical structure and predict the physicochemical and toxicological properties of DEGDB. DEGDB-related targets were retrieved from the Comparative Toxicogenomics Database, STITCH, and SwissTargetPrediction and integrated with differentially expressed genes identified in the GSE39582 and GSE44076 datasets. Functional enrichment analysis and reverse transcription quantitative polymerase chain reaction were used to prioritize CEBPB. Using the GSE132465 single-cell ribonucleic acid (RNA) sequencing dataset, we characterized the cell type-specific expression of CEBPB, intercellular communication, pseudotemporal dynamics, and associated regulatory networks. In silico perturbation analysis was performed to predict transcriptional changes after CEBPB knockout. In HCT116 and SW620 cells, cell proliferation, colony formation, Transwell migration, and wound-healing assays were used to evaluate the effects of DEGDB exposure and CEBPB knockdown. The prognostic relevance of CEBPB was assessed in patients with stage I-II colon adenocarcinoma from The Cancer Genome Atlas (TCGA), and molecular docking was used to predict potential interactions between DEGDB and candidate proteins. RESULTS: A total of 35 DEGDB-related genes and 908 CRC-associated differentially expressed genes were identified, yielding five overlapping candidate genes: CEBPB, SCD, DGAT2, IGF2, and PPARG. DEGDB treatment consistently increased CEBPB messenger RNA expression in both cell lines, with a comparatively large magnitude of change; therefore, CEBPB was selected as the prioritized candidate gene. Single-cell analysis showed that CEBPB expression was higher in tumor-derived epithelial cells than in normal-derived epithelial cells and increased progressively along the pseudotime trajectory. In silico knockout analysis suggested that CEBPB deletion could substantially alter transcriptional regulatory networks in CRC-associated cells. DEGDB treatment upregulated CEBPB and enhanced CRC cell proliferation, colony formation, migration, and wound closure; these effects were attenuated by CEBPB-targeting small interfering RNA. In the early-stage colon adenocarcinoma cohort, high CEBPB expression was associated with worse overall survival. Molecular docking predicted potential interactions between DEGDB and the candidate proteins. CONCLUSIONS: Under the in vitro exposure conditions used in this study, DEGDB significantly promoted malignant phenotypes in CRC cells, whereas CEBPB knockdown effectively attenuated these effects. Collectively, these findings indicate that CEBPB may partially mediate DEGDB-induced malignant behavior in CRC cells and may serve as a candidate regulator for subsequent mechanistic studies and population-based exposure and risk assessment.
-
Zonal endothelial cell heterogeneity underlies murine renal vascular development.
The renal vasculature consists of highly specialized blood vessels with distinct physiological functions. Defining their transcriptional signatures and tracing their developmental ontogeny has thus far been challenging due to a lack of regionally specific endothelial biomarkers. Here, we performed single nuclear RNA sequencing (snucRNA-Seq) to interrogate the transcriptional heterogeneity of embryonic renal endothelial cells (ECs). We identified ten endothelial subtypes, and validated regionally restricted expression of novel marker genes of glomeruli, arteries, vasa recta, and immature capillary subtypes using multiplex RNAscope. We also define previously uncharacterized and heterogeneous molecular signatures of the immature renal vasculature, including putative endothelial progenitors. We interrogate biological characteristics of immature EC types using a variety of in vivo tools. Lineage tracing of Esm1-expressing cells reveals the previously unrecognized multi-origin and multi-clonal endothelial tip cell contribution to the glomerular vasculature. Together, this study provides a validated, tool-focused developmental atlas of the murine renal vasculature and elucidates novel cellular mechanisms of nephron vascularization.
-
APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.
APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.
-
Effect of Sortilin1 on promoting angiogenesis and systemic metastasis in hepatocellular carcinoma via the Notch signaling pathway and CD133.
Hepatocellular carcinoma (HCC) is known to be lethal disease. However, its prognosis remains poor, primarily because the precise oncogenic mechanisms underlying HCC progression remain elusive, thus hampering effective treatment. Here, we aimed to identify the potential oncogenes in HCC and elucidate the underlying mechanisms of their action. To identify potential candidate genes, an integrative analysis of eight publicly available genomic datasets was performed, and the functional implications of the identified genes were assessed in vitro and in vivo. Sortilin 1 (SORT1) was identified as a potential candidate oncogene in HCC, and its overexpression in HCC cells was confirmed by analyzing spatial transcriptomic and single-cell data. Silencing SORT1 in Huh-7 and Hep3B cells significantly reduced HCC progression in vitro and in vivo. Functional analyses of oncogenic pathways revealed that SORT1 expression regulated the Notch signaling pathway activation and CD133 expression. Furthermore, analysis of epigenetic regulation of the candidate gene and its clinical implications using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) and our HCC cohort (AJOU_HCC cohort) data demonstrated an inverse correlation between the methylation status of the SORT1 promoter region, specifically at the cg16988986 site, and SORT1 mRNA expression, indicating the epigenetic regulation of SORT1 in HCC. In addition, the distinct methylation status of cg16988986 was significantly associated with patient survival. In conclusion, SORT1 plays a pivotal role in HCC by activating the Notch signaling pathway and increasing CD133 expression. These findings suggest SORT1 as a promising therapeutic target for HCC.
-
Identification and validation of Kif15 as a potential diagnostic and prognostic biomarker in colon cancer.
OBJECTIVE: This study aimed to systematically identify and validate KIF15 as a potential diagnostic and prognostic biomarker in colon cancer (CC) using integrated bioinformatics analyses. We further explored its role in the tumor immune microenvironment and its potential value in immunotherapy, and validated its expression and clinical significance through immunohistochemical analysis. METHODS: Gene expression profiles of CC were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). A protein–protein interaction (PPI) network was constructed, and key genes were identified using the MCODE plugin in Cytoscape. External validation of candidate gene expression was performed using The Cancer Genome Atlas (TCGA) cohort. Kaplan–Meier survival analysis was conducted to evaluate prognostic significance. Receiver operating characteristic (ROC) and time-dependent ROC analyses were applied to assess diagnostic and prognostic performance. A nomogram model was established based on multivariate Cox regression, and its predictive accuracy and stability were evaluated using calibration curves and decision curve analysis (DCA). To investigate the role of KIF15 in the tumor microenvironment, single-cell RNA sequencing data from the TISCH database were analyzed to determine its expression distribution across immune cell subsets. Functional enrichment and immune correlation analyses were performed to elucidate the potential molecular mechanisms of KIF15 in CC progression and to identify downstream hub genes. Finally, immunohistochemistry (IHC) was conducted to validate the tissue expression pattern and clinical relevance of KIF15. RESULTS: A total of 611 DEGs were identified by integrating three GEO datasets (GSE24550, GSE21815, and GSE44076). Based on PPI network construction and MCODE analysis, 13 key genes, including KIF15, were identified. Combined univariate Cox regression and pan-cancer analysis ultimately determined KIF15 as the core gene of interest. TCGA analysis demonstrated that KIF15 was significantly upregulated in CC tissues (P < 0.0001), with a diagnostic ROC AUC of 0.874. Kaplan–Meier analysis showed that high KIF15 expression was significantly associated with poor prognosis (P = 0.004). Multivariate Cox regression confirmed that KIF15 was an independent prognostic factor. The nomogram model constructed based on KIF15 yielded a C-index of 0.783. Time-dependent ROCanalysis showed AUC values of 0.788, 0.777, and 0.712 for 1-, 3-, and 5-year survival, respectively. Calibrationcurves and DCA indicated good predictive consistency and clinical net benefit. Single-cell analysis revealedthat KIF15 was highly expressed in proliferating T cells (Tprolif). Functional enrichment analysis indicatedthat KIF15 was primarily involved in the cell cycle, DNA replication, mitosis, and the p53 signaling pathway.Immune correlation analysis showed significant associations between KIF15 expression and multipleimmune-infiltrating cells as well as immune checkpoint genes. Four downstream hub genes (TTK, CDK1,CHEK1, and KIF2C) were further identified and were all significantly upregulated in CC. IHC results confirmedthat KIF15 was highly expressed in CC tissues (P < 0.001) and was significantly associated with poorprognosis. Pearson correlation analysis demonstrated that KIF15 expression was positively correlated withimmune markers, including PD-1 and PD-L1. CONCLUSION: KIF15 is significantly overexpressed in CC tissues and is strongly associated with unfavorable prognosis, suggesting its potential clinical value in the diagnosis and prognostic assessment of CC. Notably, KIF15 expression is closely correlated with immune cell infiltration and multiple immune checkpoint molecules, indicating a potential role in regulating the tumor immune microenvironment. Therefore, KIF15 may serve as a promising biomarker and potential therapeutic target for immunotherapy, as well as a candidate marker for diagnosis, prognosis evaluation, and individualized treatment in CC.
-
Identification and quantification of immune infiltration landscape on therapy and prognosis in left- and right-sided colon cancer.
BACKGROUND: The left-sided and right-sided colon cancer (LCCs and RCCs, respectively) have unique molecular features and clinical heterogeneity. This study aimed to identify the characteristics of immune cell infiltration (ICI) subtypes for evaluating prognosis and therapeutic benefits. METHODS: The independent gene datasets, corresponding somatic mutation and clinical information were collected from The Cancer Genome Atlas and Gene Expression Omnibus. The ICI contents were evaluated by "ESTIMATE" and "CIBERSORT." We performed two computational algorithms to identify the ICI landscape related to prognosis and found the unique infiltration characteristics. Next, principal component analysis was conducted to construct ICI score based on three ICI patterns. We analyzed the correlation between ICI score and tumor mutation burden (TMB), and stratified patients into prognostic-related high- and low- ICI score groups (HSG and LSG, respectively). The role of ICI scores in the prediction of therapeutic benefits was investigated by "pRRophetic" and verified by Immunophenoscores (IPS) (TCIA database) and an independent immunotherapy cohort (IMvigor210). The key genes were preliminary screened by weighted gene co-expression network analysis based on ICI scores. And they were further identified at various levels, including single cell, protein and immunotherapy response. The predictive ability of ICI score for prognosis was also verified in IMvigor210 cohort. RESULTS: The ICI features with a better prognosis were marked by high plasma cells, dendritic cells and mast cells, low memory CD4+ T cells, M0 macrophages, M1 macrophages, as well as M2 macrophages. A high ICI score was characterized by an increased TMB and genomic instability related signaling pathways. The prognosis, sensitivities of targeted inhibitors and immunotherapy, IPS and expression of immune checkpoints were significantly different in HSG and LSG. The genes identified by ICI scores and various levels included CA2 and TSPAN1. CONCLUSION: The identification of ICI subtypes and ICI scores will help gain insights into the heterogeneity in LCC and RCC, and identify patients probably benefiting from treatments. ICI scores and the key genes could serve as an effective biomarker to predict prognosis and the sensitivity of immunotherapy.
-
LncRNA SNHG6 plays an oncogenic role in colorectal cancer and can be used as a prognostic biomarker for solid tumors.
Small nucleolar RNA host gene 6 (SNHG6) has been recognized as an oncogene in numerous cancers and overexpression of SNHG6 was found to promote colorectal cancer (CRC). Hence, we performed a meta-analysis to examine the clinical importance of the long noncoding RNA (lncRNA) SNHG6. Moreover, comprehensive identification of RNA-binding proteins-mass spectrometry (ChIRP-MS) was conducted to explore the carcinogenic mechanism of lncRNA SNHG6 in CRC. Fourteen studies conducted on 1,139 patients were included in this meta-analysis. We also constructed the protein-protein interactive (PPI) network in string based on the ChIRP-MS results and cytoscape was used to identify core modules in the PPI network, which were then analyzed using the bioinformatics websites, cancer single-cell state atlas (CancerSEA) and G:profilter. The clinical outcomes of the meta-analysis indicated that higher expression of SNHG6 was related with a poorer survival outcome (overall survival: hazard ratio (HR) = 1.92; 95% confidence interval [Cl]: 1.48, 2.49; p < .0001; disease-free survival: HR = 1.84; 95% Cl: 1.02, 3.34; p = .044), higher tumor stage (odds ratio [OR] = 3.35; 95% Cl: 2.57, 4.37; p < .0001), distant metastasis (OR = 1.83; 95% Cl: 1.11, 2.99; p = .017) and lymph node metastasis (OR = 1.33; 95% Cl: 0.93, 1.89; p = .119). The ChIRP-MS results showed that core Module 1 of the PPI was significant in ribosomes and core Module 2 was mainly related to spliceosomes and messenger RNA processing. In conclusion, a higher expression of SNHG6 was found to be associated with a poorer survival outcome, high tumor stage, and distant metastasis in various solid tumors. SNHG6 was also found to be able to affect the processes of transcription and translation to promote CRC.