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PubMed2026

Dysregulated Sheddase Signalling as a Molecular Driver of Plaque Instability Revealed by Integrative Transcriptomics.

Atherosclerosis is a major cause of mortality due to chronic and progressive low-grade inflammation and fibroproliferative remodelling of the intima of arteries. Comprehensive understanding of the interplay between plaque biology and the mechanisms underlying plaque vulnerability and rupture is essential. Here, we aimed to investigate the transcriptomic profiles of stable and unstable atherosclerotic plaques using RNA sequencing data from human carotid atherosclerotic plaque samples based on next-generation knowledge discovery (NGKD) methods. High-throughput RNA-seq data from plaques dissected in stable and unstable regions of four patients were obtained from the Gene Expression Omnibus (GEO) database. GEO RNA-seq Experiments Interactive Navigator (GREIN) software was used to obtain raw gene-level counts and filtered metadata for this dataset. The data were further filtered and normalized using Express analyst to derive differentially expressed genes (DEGs) in unstable plaques compared to stable plaques. The DEGs were further analysed using WebGestalt, STRING DB, preranked gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) software. We identified 4792 DEGs in unstable plaques based on a p-value cutoff of < 0.05. NGKD analysis revealed that the sheddase pathway, collagen degradation, activation of matrix metalloproteinases (MMPs), and extracellular matrix (ECM) degradation ranked among the top five upregulated pathways, whereas the inhibition of MMPs and smooth muscle contraction pathways were identified as the most prominent downregulated pathways in unstable plaques. We found that the sheddase pathway was one of the most significantly upregulated canonical pathways in unstable plaques and this finding opens new avenues for potential therapeutic interventions in patients with atherosclerosis.

Humans↗

PubMed2026

Decreased expression of Krüppel-like factor 4 is associated with colorectal cancer progression.

Krüppel-like factor 4 (KLF4), a key transcription factor,plays an important role in cell proliferation, differentiation, and apoptosis. Here, we explored the prognostic value of KLF4 and its role in colorectal cancer (CRC) progression. We analyzed transcriptomic data and clinical information related to CRC from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. database. Immunohistochemistry was performed to evaluate KLF4 expression in CRC tissue samples. Additionally, we examined the relationship between clinicopathological factors and patient prognosis using Cox proportional hazards model analysis. Lentiviral transfection was used to create KLF4 knockdown HCT-116 cells. Analysis of the TCGA database and two GEO datasets (GSE21510 and GSE117606) revealed that KLF4 was expressed at low levels in CRC. Furthermore, reduced KLF4 levels correlated with lymph node metastasis, distant metastasis, and advanced TNM staging. ROC curve analysis indicated that KLF4 can effectively differentiate cancerous tissue from normal tissue. Functional enrichment analysis identified KLF4 as significantly linked to the glycoprotein metabolic pathway. Our detection of KLF4 expression in CRC tissue samples confirmed its decreased levels and their association with poorer patient survival. However, KLF4 was not identified as an independent prognostic factor. In vitro, KLF4 knockdown promoted HCT-116 cell migration and invasion and downregulated the mRNA expression of glycoprotein synthesis- and glycosylation-related genes. Conversely, KLF4 re-expression markedly reversed these effects. Our findings suggested that low KLF4 expression served as a predictor factor for disease progression in CRC patients. Furthermore, reduced KLF4 levels enhance the migration and invasion of CRC cells, which may be related to impaired glycoprotein metabolism.

Colorectal cancer↗

PubMed2024

Polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA) are associated with the PI3K-AKT pathway activation.

AIMS: We aimed to elucidate the mechanism leading to polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA). BACKGROUND: PCOS is an endocrine disorder. Patients with RSA also have a high incidence rate of PCOS, implying that PCOS and RSA may share the same pathological mechanism. OBJECTIVE: The single-cell RNA-seq datasets of PCOS (GSE168404 and GSE193123) and RSA GSE113790 and GSE178535) were downloaded from the Gene Expression Omnibus (GEO) database. METHODS: Datasets of PSCO and RSA patients were retrieved from the Gene Expression Omnibus (GEO) database. The "WGCNA" package was used to determine the module eigengenes associated with the PCOS and RSA phenotypes and the gene functions were analyzed using the "DAVID" database. The GSEA analysis was performed in "clusterProfiler" package, and key genes in the activated pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Real-time quantitative PCR (RT-qPCR) was conducted to determine the mRNA level. Cell viability and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry, respectively. RESULTS: The modules related to PCOS and RSA were sectioned by weighted gene co-expression network analysis (WGCNA) and positive correlation modules of PCOS and RSA were all enriched in angiogenesis and Wnt pathways. The GSEA further revealed that these biological processes of angiogenesis, Wnt and regulation of cell cycle were significantly positively correlated with the PCOS and RSA phenotypes. The intersection of the positive correlation modules of PCOS and RSA contained 80 key genes, which were mainly enriched in kinase-related signal pathways and were significant high-expressed in the disease samples. Subsequently, visualization of these genes including PDGFC, GHR, PRLR and ITGA3 showed that these genes were associated with the PI3K-AKT signal pathway. Moreover, the experimental results showed that PRLR had a higher expression in KGN cells, and that knocking PRLR down suppressed cell viability and promoted apoptosis of KGN cells. CONCLUSION: This study revealed the common pathological mechanisms between PCOS and RSA and explored the role of the PI3K-AKT signaling pathway in the two diseases, providing a new direction for the clinical treatment of PCOS and RSA.

Humans↗

PubMed2024

Deciphering the molecular nexus of BTG2 in periodontitis and diabetic kidney disease.

OBJECTIVE: To investigate the role of BTG2 in periodontitis and diabetic kidney disease (DKD) and its potential underlying mechanism. METHODS: Gene expression data for periodontitis and DKD were acquired from the Gene Expression Omnibus (GEO) database. Differential expression analysis identified co-expressed genes between these conditions. The Nephroseq V5 online nephropathy database validated the role of these genes in DKD. Pearson correlation analysis identified genes associated with our target gene. We employed Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) networks to elucidate potential mechanisms. Expression levels of BTG2 mRNA were examined using quantitative polymerase Chain Reaction (qPCR) and immunofluorescence assays. Western blotting quantified proteins involved in epithelial-to-mesenchymal transition (EMT), apoptosis, mTORC1 signaling, and autophagy. Additionally, wound healing and flow cytometric apoptosis assays evaluated podocyte migration and apoptosis, respectively. RESULTS: Analysis of GEO database data revealed BTG2 as a commonly differentially expressed gene in both DKD and periodontitis. BTG2 expression was reduced in DKD compared to normal conditions and correlated with proteinuria. GSEA indicated enrichment of BTG2 in the EMT and mTORC1 signaling pathways. The PPI network highlighted BTG2's relevance to S100A9, S100A12, and FPR1. Immunofluorescence assays demonstrated significantly lower BTG2 expression in podocytes under high glucose (HG) conditions. Reduced BTG2 expression in HG-treated podocytes led to increased levels of EMT markers (α-SMA, vimentin) and the apoptotic protein Bim, alongside a decrease in nephrin. Lower BTG2 levels were associated with increased podocyte mobility and apoptosis, as well as elevated RPS6KB1 and mTOR levels, but reduced autophagy marker LC3. CONCLUSION: Our findings suggest that BTG2 is a crucial intermediary gene linking DKD and periodontitis. Modulating autophagy via inhibition of the mTORC1 signaling pathway, and consequently suppressing EMT, may be pivotal in the interplay between periodontitis and DKD.

Periodontitis↗

PubMed2025

Genetic predisposition and mediating pathways in ischemic stroke-induced cardiac arrhythmias: a genome-wide analysis.

INTRODUCTION: The clinical presentation of stroke-heart syndrome (SHS) underscores the interplay between the central nervous system and the cardiovascular system. While cardiac arrhythmia is the prevalent form of cardiac injury in SHS patients, the causal link between ischemic stroke and cardiac arrhythmia is still unclear. METHODS: Mendelian randomization analyses and genome-wide association studies data were used to investigate the causal role of ischemic stroke on cardiac complications. Mediation and colocalization analyses were used to identify potential pathways and shared genetic variants. Single nucleotide polymorphisms (SNPs) associated with arrhythmias and ischemic stroke were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Gene expression omnibus (GEO) database from atrial fibrillation patients were used for validation. RESULTS: Mendelian randomization analyses showed a strong correlation between arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, with ischemic stroke. Diabetic microvascular (nephropathy, retinopathy) and macrovascular (cardiomyopathy, peripheral arterial disease) complications significantly mediated the effect of ischemic stroke on cardiac arrhythmias and atrial fibrillation, explaining 28.69 % and 20.48 % of the indirect effect, respectively. Colocalization analyses identified a shared causal variant in the Phosphodiesterase 3A (PDE3A) gene (rs11045239), providing genetic evidence for a shared pathogenic pathway between ischemic stroke and cardiac arrhythmias. Moreover, KEGG pathway enrichment analyses identified a role of the cyclic adenosine monophosphate (cAMP) signaling pathway in both ischemic stroke and arrhythmias. Validation using the GEO database confirmed a significant upregulation of the PDE3A gene expression in atrial fibrillation patients. CONCLUSION: This study demonstrated a causal link between ischemic stroke and cardiac arrhythmias, with diabetic complications as one mediating factor. The identification of a shared causal variant in the PDE3A gene and the role of the cAMP signaling pathway have the potential to improve prediction and management of SHS patients.

Humans↗

PubMed2026

Screening and identification of key genes related to the immune microenvironment of rectal cancer influenced by radiotherapy based on bioinformatics methods.

OBJECTIVE: Radiotherapy (RT) plays a crucial role in the comprehensive treatment of rectal cancer. However, the impact of radiotherapy on the tumor microenvironment (TME), especially its effect on immune cell infiltration and immune-related gene expression, has not been fully studied. This study aims to screen and analyze key genes related to the immune microenvironment of rectal cancer influenced by radiotherapy based on bioinformatics methods for the purpose of identifying potential biomarkers and providing new insights for the personalized therapy of rectal cancer. METHODS: Using data from the Public Gene Expression Database (GEO) and the Cancer Genomics Database (TCGA), the impact of radiotherapy on the immune microenvironment of rectal cancer was explored using bioinformatics tools. Through screening differentially expressed genes (DEGs), correlation analysis, TIMER database analysis, immune infiltration score, and correlation analysis between key genes and prognosis, the effects of radiotherapy on the immune microenvironment of rectal cancer were investigated. RESULTS: Totally 7 upregulated and 4 downregulated differentially expressed genes were identified, among which MASP1, LTK, SLC9A3R2 were negatively correlated with myeloid suppressor cell infiltration (MDSCs), while ZP2 was positively correlated. The expression of MASP1 and SLC9A3R2 was closely related to the level of immune cell infiltration and played significant roles in the immune microenvironment. High expression of MASP1 was significantly correlated with survival benefits from immune checkpoint inhibitor therapy, while SLC9A3R2 was closely related to the efficacy of PD-L1 inhibitors and CTLA4 inhibitors. CONCLUSIONS: MASP1 and SLC9A3R2, as two key genes that may be related to the immune microenvironment of rectal cancer radiotherapy, deserve further exploration of their roles in the mechanism. The combination of radiotherapy and immunotherapy holds promising prospects in the treatment of rectal cancer, and exploration of related mechanisms will provide new strategies and targets for the treatment of various tumors and rectal cancer.

Bioinformatics↗

PubMed2026

Expression of PIEZO1 in lung adenocarcinoma correlates with PD-L1 expression, cell migration, and poor prognosis: an exploratory study.

BACKGROUND AND AIMS: Lung adenocarcinoma (LUAD) treatment is challenging process. and the function of PIEZO1, a mechanically sensitive ion channel has not been systematically determined. In this study we aimed to explore the expression, potential associations, and clinical significance of PIEZO1 in LUAD. METHODS AND AIMS: A comprehensive bioinformatics analysis was performed using data from the Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus (GEO) database and other databases. Experimental validation was performed to confirm the expression patterns and preliminarily examine the associations of PIEZO1 in LUAD cell lines. RESULTS: PIEZO1 expression was significantly lower in LUAD tissues than in normal lung tissues (P < 0.05). Its expression was correlated with advanced pathological stage, lymph node involvement, and distant metastasis. High PIEZO1 expression was associated with a distinct immune-related tumor microenvironment, characterized by correlations with the expression levels of multiple immune checkpoint molecules, and was identified as an independent factor associated with poor overall survival (HR = 1.49; 95% CI 1.11-2; P < 0.007). In vitro experiments confirmed the downregulated PIEZO1 expression in LUAD cell lines, and functional knockdown experiments revealed its association with cell migration and PD-L1 expression. CONCLUSION: This exploratory study revealed that PIEZO1 expression in LUAD cell lines correlated with the expression of immune-related features and EMT-related genes, as well as poor prognosis. In vitro, PIEZO1 knockdown is associated with reduced cell migration and decreased PD-L1 expression. These findings provide a basis for future investigations into the potential role of PIEZO1 in LUAD.

Gene expression↗

PubMed2024

ZEB family is a prognostic biomarker and correlates with anoikis and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. METHODS: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. RESULTS: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. CONCLUSIONS: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.

Humans↗

PubMed2026

Identification of NR4A2 as a Potential Predictive Biomarker for Atherosclerosis.

INTRODUCTION/OBJECTIVE: Atherosclerosis, a leading cause of death globally, is characterized by the buildup of immune cells and lipids in medium to large-sized arteries. However, its precise mechanism remains unclear. The purpose of this study is to explore innovative and reliable biomarkers as a viable approach for the identification and management of atherosclerosis. METHODS: The atherosclerosis-related datasets GSE100927 and GSE66360 were retrieved from the Gene Expression Omnibus (GEO) database. The Limma package in the R programming language was utilized, applying the criteria of |logFC| > 1 and P < 0.05. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the 127 identified DEGs using R. Machine learning techniques were then applied to these data to explore and pinpoint potential biomarkers. The diagnostic potential of these markers was assessed via Receiver Operating Characteristic (ROC) curve analysis. Finally, western blot, real-time quantitative PCR (qRT-PCR), and immunohistochemistry (IHC) were employed to confirm the key biomarkers. RESULTS: Our research indicated that a total of 127 DEGs linked to atherosclerosis were successfully identified. Through the application of machine learning methods, eight critical genes were highlighted. Among these, Nuclear Receptor Subfamily 4 Group A Member-2 (NR4A2) emerged as the most promising marker for further investigation. CIBERSORT analysis revealed that NR4A2 expression levels were significantly correlated with multiple immune cell types, including B cells, plasma cells, and macrophages. Additional validation experiments confirmed that NR4A2 expression was indeed elevated in atherosclerotic plaques, supporting its potential as a biomarker for atherosclerosis. CONCLUSION: Our study identified NR4A2 as a potential immune-related biomarker for the diagnosis and treatment of atherosclerosis.

Atherosclerosis↗

PubMed2026

Multi-omics Approaches to CCAAT/Enhancer-Binding Protein Beta in Oral Squamous Cell Carcinoma: Crosstalk Between Tumor Cells and Tumor-Associated Macrophages Driving Disease Progression.

BACKGROUND: CCAAT/Enhancer-Binding Protein Beta (CEBPB) is an important transcription factor that regulates tumor progression. However, the mechanism by which CEBPB regulates the progression of Oral Squamous Cell Carcinoma (OSCC) remains incompletely understood. Tumor progression depends on complex intercellular interactions within the tumor microenvironment. The purpose of this study was to investigate the role and epigenetic regulatory mechanisms of CEBPB in interactions between OSCC cells and tumor-infiltrating immune cells. METHODS: Bulk RNA-seq, ChIP-seq, and scRNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. The HOMER algorithm was employed to identify enhancers and predict the CEBPB-binding motif. Cell cluster analysis, functional enrichment, and intercellular interaction analysis were performed using the "Seurat" R package. H3K27ac enrichment at GAS6 enhancers was validated by ChIP-qPCR. Metastatic OSCC cells with CEBPB knockdown or GAS6 overexpression were established and co-cultured with THP-1 cells. IL-10 and IL-6 secretion from co-cultured THP-1 cells was detected via ELISA. Chemotaxis of OSCC cells toward THP-1 cells was assessed through a Transwell assay. RESULTS: CEBPB was upregulated in OSCC and correlated with poor prognosis. By integrating H3K27ac ChIP-seq and bulk RNA-seq data, 131 CEBPB-regulated enhancer-controlled genes were identified in lymph node metastatic OSCC cells. scRNA-seq analysis revealed eight major cell clusters in primary foci and lymph node metastases, including T/NK cells, malignant epithelial cells, B/plasma cells, macrophages, fibroblasts, dendritic cells, endothelial cells, and mast cells, with the malignant epithelial cells stratified into distinct sub-clusters. CEBPB expression was elevated in malignant epithelial cells of lymph node metastases compared to primary foci. Furthermore, 15 pairs of enhanced ligand-receptor interactions were identified in lymph node metastases relative to primary foci. GAS6 was a CEBPB-regulated enhancer-controlled gene, primarily mediating interactions between malignant cells and macrophages. CEBPB knockdown in metastatic OSCC cells significantly impaired their chemotaxis toward cocultured THP-1 cells, and downregulated IL-10/IL-6 secretion and CD206 expression in cocultured THP-1 cells. Conversely, GAS6 overexpression reversed these inhibitory effects. CONCLUSION: CEBPB activated GAS6 transcription in metastatic OSCC cells. The CEBPB/ GAS6 axis in metastatic OSCC cells enhanced their chemotaxis toward macrophages and promoted the M2 polarization of macrophages, thereby facilitating the establishment of an immunosuppressive microenvironment.

Humans↗

PubMed2025

Discovery of novel diagnostic biomarkers of hepatocellular carcinoma associated with immune infiltration.

OBJECTIVE: Diagnosis of hepatocellular carcinoma (HCC) remains challenging for clinicians. Machine learning approaches and big data analyses are viable strategies for identifying HCC diagnostic markers. MATERIALS AND METHODS: In this study, we downloaded mRNA expression profiles of HCC from the GEO database and used random forest and machine learning algorithms, such as least absolute shrinkage and selection operator, to screen for reliable diagnostic genes. Disease Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis enrichment analyses were performed to explore differential gene functions and disease pathways. CIBERSORT was performed to calculate the immune cell infiltration of HCC and the correlation between diagnostic genes and immune cells. Cell experiments were performed to evaluate the function of R-spondin 3 (RSPO3) in HCC cells. Immunohistochemical staining was used to evaluate the protein expression of CD138, CD206 and iNOS. RESULTS: The results indicated that extracellular matrix protein 1 (ECM1), Niemann-Pick C1-Like 1 (NPC1L1) and RSPO3 were down-regulated in HCC compared with the normal group (p < 0.05), which was validated in clinical tissue samples. Moreover, ECM1, NPC1L1 and RSPO3 had high diagnostic values (AUC > 0.75) for HCC in both training and test groups. Immuno-infiltration analysis revealed that ECM1 and RSPO3 were highly positively correlated with neutrophil and macrophage M2 levels, whereas they were negatively correlated with Tregs. RSPO3-si affected cell proliferation and apoptosis in HCC. Furthermore, RSPO3 exhibited a positive correlation with tumour progression, the proportion of plasma cells and M2 macrophages in mice, while showing a negative association with M1 macrophages. CONCLUSION: The present study identified ECM1, NPC1L1 and RSPO3 as new diagnostic biomarkers for HCC based on normal and diseased samples from HCC, meanwhile the pro-oncogenic function of RSPO3 and its regulation on immune infiltration have been confirmed.

Carcinoma, Hepatocellular↗

PubMed2025

Role of HLA-DRA-CREB3L4 regulatory axis in the pathogenesis of ovarian endometriosis: Inhibition of CREB3L4 expression by HLA-DRA increases the risk of disease.

BACKGROUND: Ovarian endometriosis is a common gynecological condition characterized by the abnormal growth of endometrial-like tissue in locations outside the uterus, and its development remains poorly understood. This study aims to investigate potential protein regulatory networks and assess their impact on disease risk using both protein quantitative trait locus (pQTL) analysis and Mendelian randomization (MR) techniques. METHODS: This study systematically integrates two major genome-wide pQTL databases, UKB-PPP and deCODE, to identify pQTL signals associated with ovarian endometriosis. Additionally, we utilized the GEO database to validate differences in protein expression. We conducted a Mendelian randomization analysis to further explore the regulatory relationships between proteins and their roles in disease development. RESULTS: After the Bonferroni correction, we identified 33 pQTL signals from UKB-PPP and 19 pQTL signals from deCODE. Among these, 8 signals from UKB-PPP and 3 signals from deCODE were validated based on expression differences. The mediation analysis results indicate that HLA-DRA significantly increases the risk of developing ovarian endometriosis by inhibiting the expression of CREB3L4 (with a mediation proportion of 13.99 %), and the direction of the mediation effect is consistent with the total effect. CONCLUSION: This study provides new insights that HLA-DRA downregulates the expression of CREB3L4, which may affect the risk of developing endometriosis. The results provide new evidence for understanding the genetic and molecular basis of ovarian endometriosis and establish a theoretical foundation for the development of future diagnostic markers and targeted treatment strategies.

Humans↗

PubMed2025

miR-9-5p/HMMR regulates the tumorigenesis and progression of clear cell renal cell carcinoma through EMT and JAK1/STAT1 signaling pathway.

BACKGROUND: The most common malignant type of kidney cancer is clear cell renal cell carcinoma (ccRCC). The expression levels of hyaluronan-mediated motility receptor (HMMR) in many tumor types are significantly elevated. HMMR is closely associated with tumor-related progression, treatment resistance, and poor prognosis, and has yet to be fully investigated in terms of its expression patterns and molecular mechanisms of action in ccRCC. Further research is imperative to elucidate these aspects. METHODS: We used The Cancer Genome Atlas (TCGA) database to preliminarily investigate HMMR expression and function in ccRCC and the data for 19 samples from the NCBI GEO database (GSE207493) for single-cell analysis. We assessed the differential expression level of HMMR between ccRCC cancerous tissues and their matched non-tumor tissues. Subsequently, a series of in vivo and in vitro experiments were designed to elucidate the biological function of HMMR in ccRCC, including Transwell assays, CCK-8 assays, clone formation assays and subcutaneous xenograft experiments in nude mice. Through bioinformatics analysis, we identified potential microRNAs (miRNAs) that may regulate HMMR, as well as the possible signaling pathways involved. Finally, we conducted a series of cellular functional experiments to validate our hypotheses regarding the HMMR axis. RESULTS: HMMR expression was significantly up-regulated in tumor tissues of ccRCC patients, and elevated HMMR expression level showed a strong correlation with ccRCC progression and adverse prognoses of patients. Knocking down HMMR inhibited the proliferative and migratory abilities of ccRCC cells, while its overexpression amplified these oncogenic properties. In nude mice model, reduced HMMR expression inhibited ccRCC tumor proliferation in vivo. Furthermore, overexpression of an upstream transcriptional regulator, miR-9-5p, effectively downregulated HMMR expression and thus impeded ccRCC cells proliferation and migration. HMMR might influence ccRCC growth via the Epithelial-Mesenchymal Transition (EMT) pathway and the Janus Kinase 1/Signal Transducer and Activator of Transcription 1 (JAK1/STAT1) pathway. CONCLUSIONS: HMMR is overexpressed in ccRCC, and there is a significant link between high HMMR expression and tumor progression, as well as poor patient prognosis. Specifically, HMMR could be targeted and inhibited by miR-9-5p and might modulate the tumorigenesis and progression of ccRCC through both EMT and JAK1/STAT1 signaling pathway.

Carcinoma, Renal Cell↗

PubMed2026

Key hub genes and pathways associated with HCV-related hepatocellular carcinoma as potential diagnostic biomarkers.

BACKGROUND: Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) remains a major global health challenge, with high morbidity and mortality despite recent therapeutic advances. Early detection and identification of reliable molecular biomarkers are essential to improve patient outcomes. Therefore, the present study aimed to investigate key hub genes and pathways associated with HCV-related HCC as potential diagnostic biomarkers. METHODS: The datasets GSE69715 and GSE62232 were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were recognized according to an adjusted p-value and a log fold change (logFC). The GEO2R tool facilitated the identification of common DEGs across the two datasets. Pathways were explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. Furthermore, protein-protein interactions (PPIs) were assessed through Cytoscape. The target genes were confirmed through a GEPIA analysis. RESULTS: A total of 421 common DEGs were identified, and 80 hub genes were subsequently determined through GEO and PPI network analyses, respectively. The GO and KEGG pathways analysis presented DEGs were enhanced in metabolic pathways, cellular components, extracellular exosome, detoxification of copper ion and monooxygenase activity. The GEPIA analysis indicated a notable variation in the expression levels of four specific genes -CDKN2A, CDK1, CCNB1, and TOP2A-when comparing normal samples to tumor samples. CONCLUSION: The present study discovered novel genes by expression variation in HCV-related hepatocellular carcinoma development. These findings suggest that CDKN2A, CDK1, CCNB1, and TOP2A are promising candidates for diagnostic biomarkers and present a valuable opportunity for the early identification of HCV-HCC, which could lead to improved treatment outcomes.

Bioinformatics↗

PubMed2026

Elucidating the Mechanism of Xiaoqinglong Decoction in Chronic Urticaria Treatment: An Integrated Approach of Network Pharmacology, Bioinformatics Analysis, Molecular Docking, and Molecular Dynamics Simulations.

INTRODUCTION: Xiaoqinglong Decoction (XQLD) is a traditional Chinese medicinal formula commonly used to treat chronic urticaria (CU). However, its underlying therapeutic mechanisms remain incompletely characterized. This study employed an integrated approach combining network pharmacology, bioinformatics, molecular docking, and molecular dynamics simulations to identify the active components, potential targets, and related signaling pathways involved in XQLD's therapeutic action against CU, thereby providing a mechanistic foundation for its clinical application. METHODS: The active components of XQLD and their corresponding targets were identified using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. CU-related targets were retrieved from the OMIM and GeneCards databases. Subsequently, core components and targets were determined via protein-protein interaction (PPI) network analysis and component-target-pathway network construction. Topological analyses were performed using Cytoscape software to prioritize core nodes within these networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database to identify enriched biological processes and signaling pathways. Molecular docking was performed to evaluate binding interactions between key components and core targets, while molecular dynamics (MD) simulations were employed to assess the stability of the component-target complexes with the lowest binding energy. Finally, CU-related targets of XQLD were validated using datasets from the Gene Expression Omnibus (GEO) database. RESULTS: A total of 135 active components and 249 potential targets of XQLD were identified, alongside 1,711 CU-related targets. Core components, such as quercetin, kaempferol, beta-sitosterol, naringenin, stigmasterol, and luteolin, exhibited high degree values in the constructed networks. The core targets identified included AKT1, TNF, IL6, TP53, PTGS2, CASP3, BCL2, ESR1, PPARG, and MAPK3. GO and KEGG pathway enrichment analyses revealed the PI3K-Akt signaling pathway as a central regulatory mechanism. Molecular docking studies demonstrated strong binding affinities between active components and core targets, with the stigmasterol-AKT1 complex exhibiting the lowest binding energy (-11.4 kcal/mol) and high stability in MD simulations. Validation using GEO datasets identified 12 core genes shared between CU-related targets and XQLD-associated targets, including PTGS2 and IL6, which were also prioritized as core targets in the network pharmacology analyses. DISCUSSION: This study comprehensively integrates multidisciplinary approaches to clarify the potential molecular mechanisms of XQLD in treating CU, highlighting its multitarget and multipathway synergistic effects. Molecular docking and dynamics simulations confirm the stable interaction between stigmasterol and the core target AKT1. Additionally, GEO dataset analysis verifies the pathogenic relevance of targets such as PTGS2 and IL6, significantly enhancing the credibility of our findings. These results provide a modern scientific basis for the traditional therapeutic effects of XQLD on CU and have important implications for developing multitarget treatments for this condition. However, this study mainly relies on database mining and computational simulations. Further in vitro and in vivo experimental validations are needed to confirm the predicted component-target-pathway interactions. CONCLUSION: This study identifies the active components, potential targets, and pathways through which XQLD exerts therapeutic effects on CU. These findings provide a theoretical foundation for further mechanistic studies and support their clinical application in the treatment of CU.

Molecular Docking Simulation↗

PubMed2025

A multifaceted investigation into the impact of m6A methylation-related genes on pancreatic cancer, integrating insights from various databases and foundational experimental research.

BACKGROUND: Despite advances in surgical techniques, immunotherapy, the mortality rate associated with pancreatic cancer (PC) has been on the rise in recent years. Understanding the importance of RNA N6-methyladenosine (m6A) in PC is critical for prognosis, tumor microenvironment, and immunotherapy efficacy. The study aims to identify m6A methylation regulators that play an important role in the development and progression of PC by mining databases. The effect of insulin-like growth factor-binding protein 3 (IGFBP3) on pancreatic tumors was explored, and the related mechanisms were explored. METHODS: We analyzed the expression of m6A regulators in PC by digging deeper into the datasets of The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, and analyzed its relationship with the prognosis of patients with PC, looking for m6A methylation regulators that play an important role in the development and progression of PC. Reuse the ConsensusClusterPlus package, Cox analysis, and unsupervised clustering to delineate three distinct m6A clusters - designated as m6A cluster A, m6A cluster B, and m6A cluster C single-sample gene set enrichment analysis, gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses evaluated the different pathway roles of these clusters in the development and progression of PC. Finally, the cell lines with IGFBP3 overexpression and knockdown were constructed by lentivirus transfection, the transfection effect was identified by WB, and the effects of IGFBP3 overexpression/knockdown on the survival and growth of PC cell lines were verified by cell cloning experiments and cell counting kit-8 experiments, and the possible related pathways were explored by KEGG. RESULTS: Most m6A regulatory factors are highly expressed in PC, and their high expression is negatively correlated with the prognosis of patients with PC. Furthermore, m6A regulatory factors may influence the occurrence and development of PC through metabolic pathways, stroma activation pathways, immune regulatory processes, and the immune microenvironment. Finally, the overexpression of IGFBP3 promoted the growth of PC cells, and vice versa. CONCLUSIONS: Most m6A regulatory factors are differentially expressed in PC and are associated with the prognosis of patients with PC, potentially influencing the occurrence and development of PC through pathways such as the immune microenvironment. The overexpression of IGFBP3 can promote the growth of PC cells and vice versa.

IGFBP3↗

PubMed2026

Bioinformatics Analysis and Experimental Validation of Key Genes Associated With Hypoxia and Ischemia in Myocardial Infarction.

BACKGROUND: This study aimed to screen and identify core hypoxia-ischemia-related genes associated with myocardial infarction (MI). METHOD: Two transcriptomic datasets, GSE97320 and GSE48060, were retrieved from the Gene Expression Omnibus (GEO) database. After data integration and batch effect elimination, differential expression analysis was performed to screen differentially expressed genes (DEGs), and the corresponding visualization analysis was conducted. Hypoxia-ischemia-related genes were acquired from the GeneCards database; hypoxia-ischemia related genes (HIRGs) were subsequently identified by intersecting the retrieved genes with screened DEGs. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were implemented to explore the biological functions and underlying signaling pathways of HIRGs. A combination of protein-protein interaction (PPI) network analysis and random forest (RF) algorithm was applied to screen hub genes from HIRGs. The external GEO dataset GSE66360 was utilized to validate the expression patterns of candidate hub genes. Furthermore, an acute myocardial infarction (AMI) mouse model was established, and quantitative real-time polymerase chain reaction (qPCR) was performed to detect the mRNA expression levels of hub genes in myocardial tissues for in vivo validation. RESULTS: A total of 633 DEGs and 308 hypoxia-ischemia-related genes were screened in the present study, among which 21 overlapping HIRGs were obtained. PLAUR and IL1B were finally identified as two hub genes from HIRGs based on PPI network and random forest algorithm. The qPCR results revealed that the expression levels of PLAUR and IL1B were significantly upregulated in the AMI group compared with the sham operation group (p < 0.05). CONCLUSION: The present findings demonstrated that PLAUR and IL1B serve as pivotal genes involved in the pathological hypoxia-ischemia process of AMI. These two genes may act as novel biomarkers and promising therapeutic targets for the recognition and clinical intervention of hypoxia-ischemia injury following AMI.

Myocardial Infarction↗

PubMed2024

Identification and analysis of key genes related to efferocytosis in colorectal cancer.

UNLABELLED: The impact of efferocytosis-related genes (ERGs) on the diagnosis of colorectal cancer (CRC) remains unclear. In this study, efferocytosis-associated biomarkers for the diagnosis of CRC were identified by integrating data from transcriptome sequencing and public databases. Finally, the expression of biomarkers was validated by real-time quantitative polymerase chain reaction (RT-qPCR). Our study may provide a reference for CRC diagnosis. BACKGROUND: It has been shown that some efferocytosis related genes (ERGs) are associated with the development of cancer. However, it is still uncertain how ERGs may influence the diagnosis of colorectal cancer (CRC). METHODS: In our study, the CRC cohorts were gained from transcriptome sequencing and the gene expression omnibus (GEO) database (GSE71187). Efferocytosis related biomarkers with diagnostic utility for CRC were identified through combining differentially expressed analysis, machine learning algorithms, and receiver operating characteristic (ROC) analysis. Then, infiltration abundance of immune cells between CRC and control was evaluated. The regulatory networks (including mRNA-miRNA-lncRNA and miRNA/transcription factors (TF)-mRNA networks) were created. Finally, the expression of biomarkers was validated via real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: There were 3 biomarkers (ELMO3, P2RY12, and PDK4) related diagnosis for CRC patients gained. ELMO3 was highly expressed in CRC group, while P2RY12 and PDK4 was lowly expressed. Besides, the infiltrating abundance of 3 immune cells between CRC and control groups was significantly differential, namely activated CD4 memory T cells, macrophages M0, and resting mast cells. We then constructed a mRNA-miRNA-lncRNA network containing 3 mRNAs, 33 miRNAs, and 22 lncRNAs, and a miRNA/TF-mRNA network including 3 mRNAs, 33 miRNAs, and 7 TFs. Additionally, RT-qPCR results revealed that the expression trends of all biomarkers were consistent with the transcriptome sequencing data and GSE71187. CONCLUSION: Taken together, this study provides three efferocytosis related biomarkers (ELMO3, P2RY12, and PDK4) for diagnosis of CRC, providing a scientific reference for further studies of CRC.

Humans↗