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Epithelial-mesenchymal transition (EMT) plays a critical role in tumor progression; however, the underlying molecular mechanisms of EMT in papillary thyroid carcinoma (PTC) remain incompletely understood. This study aimed to investigate EMT-related mechanisms in PTC using an integrative approach combining single-cell RNA sequencing and machine learning. Differentially expressed genes (DEGs) between PTC and normal thyroid tissues were identified, and EMT-related candidate genes were obtained by intersecting DEGs with EMT-related genes (EMT-RGs). Prognostic genes were screened using univariate Cox regression, and a risk model was constructed based on 101 machine learning algorithm combinations. Patients were stratified into high- and low-risk groups (HRG and LRG) according to risk scores, and the model was validated in an internal cohort. Additional analyses included nomogram construction, immune infiltration profiling, tumor mutational burden (TMB) assessment, drug sensitivity prediction, and molecular regulatory network analysis. Prognostic gene expression was further validated in vitro. Eight EMT-related prognostic genes (TYRO3, E2F1, TNFSF15, TGFBR3, PTX3, FHL2, SNAI1, and WT1) were identified. Patients in the HRG exhibited significantly poorer overall survival than those in the LRG. The nomogram showed good predictive accuracy for survival estimation. Immune infiltration analysis revealed significant differences between risk groups across six immune-related features. Splice site-related mutations were predominantly observed in the LRG but were absent in the HRG. Drug sensitivity analysis indicated higher sensitivity to BIRB.0796 in the LRG, whereas ABT-263, AG-014699, BX-795, and DMOG were more effective in the HRG. Single-cell analysis identified fibroblasts as key cell populations, with FHL2, PTX3, and TGFBR3 showing increased activity during critical differentiation stages. In vitro experiments confirmed expression patterns consistent with bioinformatics findings. This study identifies eight EMT-related prognostic genes in PTC and highlights their potential value as biomarkers for prognostic evaluation and therapeutic stratification. Show less

Copyright: © 2026 Adeyika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aberrant DNA methylation changes lead to abnormal gene expression that contributes to the development and progression of prostate cancer (PCa). Inquiry of genome-wide DNA methylation dataset, we identified the homeodomain pancreatic and duodenal homeobox 1 (PDX1) gene as differentially hypermethylated in PCa compared to normal prostate tissues. Immunohistochemical analysis of matched PCa and normal prostate tissues using tissue microarray showed a significant 2.33-fold (p = 0.0001) higher PDX1 protein expression in the PCa compared to the normal prostate tissues. In PCa cell lines (PC-3 and LNCaP) engineered to stably overexpress or knockdown PDX1, the ectopic PDX1 expression significantly enhanced cell proliferation and migration, whereas PDX1 knockdown suppressed these phenotypic processes. Quantitative RT-PCR and Western blot analysis demonstrated that PDX1 overexpression was associated with increased expression of key metabolic regulators; INSR, IGF1R, CXCR4, CDH2, TWIST1, and SNAI1, whereas there is decreased expression of ESR2, and TNFα. Conversely, PDX1 knockdown led to the opposite effect in expression profiles of these metabolites. Notably, these effects were more pronounced under high-glucose conditions compared to low-glucose environments. Overall, our findings suggest that PDX1 plays a tumor-promoting role in human PCa cells by influencing expression of metabolites in insulin, inflammatory, and epithelial-mesenchymal transition (EMT) signaling pathways. Given its potential role in metabolic regulation, full insights into the function of PDX1 in PCa could contribute to improved treatment and prevention strategies, particularly for men with PCa and comorbidities such as obesity and diabetes. Show less

Prostate cancer is the second most commonly diagnosed cancer worldwide. Although androgen deprivation therapy initially demonstrates clinical benefit, disease relapse with more aggressive phenotypes frequently occurs. The acidic tumor microenvironment in solid tumors may alter drug responsiveness. This study investigates how extracellular pH influences the cytotoxic effects of bicalutamide in human prostate cancer cell lines. PC3 and LNCaP cells were exposed to bicalutamide at varying concentrations at pH 7.4 and pH 6.8. IC50 values were determined using the MTT assay. Cell migration, apoptosis, and cell cycle distribution were evaluated by wound-healing assay, annexin V/PI staining, and DNA content analysis, respectively. The expression of Bicalutamide (140 μg/mL) reduced PC3 cell viability to 39.62% at pH 7.4 compared with 51.36% at pH 6.8. In LNCaP cells, viability declined to 33.64% at pH 7.4% and 56.09% at pH 6.8. Treated PC3 cells exhibited significantly greater migration at pH 6.8 ( The efficacy of bicalutamide in prostate cancer cells is significantly influenced by extracellular pH. The drug exerts stronger cytotoxic, antimigratory, and proapoptotic effects at physiological pH (7.4) compared with acidic conditions (6.8). Show less

Colorectal cancer (CRC) is a highly aggressive malignancy prone to liver metastasis, which significantly worsens prognosis of patients. Autophagy supports tumor cell survival by meeting metabolic demands and evading programmed cell death. This study aimed to develop a prognostic risk signature for CRC patients by integrating autophagy- and metastasis-related genes and to investigate its association with the tumor immune microenvironment and implications for immunotherapy. Weighted gene co-expression network analysis (WGCNA) identified candidate genes related to autophagy and liver metastasis. Univariate Cox and LASSO regression analyses were employed to develop a risk signature in the TCGA cohort, which was subsequently validated using an independent GEO cohort. Functional enrichment, immune infiltration, the heterogeneity and dynamics of macrophages and A prognostic risk signature incorporating six biomarkers ( In our study, we developed and validated a novel autophagy- and liver metastasis-associated prognostic signature for CRC. The risk signature effectively predicts alterations in the tumor immune microenvironment, immunotherapy, chemotherapy sensitivity and intercellular communication across different risk groups. Importantly, our findings reveal that autophagy and liver metastasis synergistically foster an immunosuppressive microenvironment, highlighting a potential target for therapeutic intervention. Show less

Schizophrenia (SCZ) is a complex psychiatric disorder, and its pathogenic mechanisms are not yet fully understood. The identification of reliable blood biomarkers and molecular subtypes for early diagnosis and effective therapy remains a significant challenge. To address this issue, we utilized a combination of bioinformatics and machine learning (ML) to identify potential biomarkers for SCZ. Our approach involved the integration of 12 different ML algorithms to develop a diagnostic signature based on data from several datasets, including GSE18312, GSE27383, GSE38485, GSE54913, and GSE165604. A nomogram was constructed using these datasets for potential clinical applications. In addition, clustering analysis was performed on SCZ patients using consensus clustering and non-negative matrix factorization (NMF) algorithms. We further evaluated subtype differences in biological functions and immune cells through various methods, such as gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), Proteomaps, and IOBR analyses. Our results identified a diagnostic signature composed of 16 genes (APBB2, CLCN1, SYDE1, PAX5, SNAI1, DAZL, UNC93B1, PLAGL2, HS3ST1, ITPKB, PILRA, BTLA, SWAP70, AZI2, ADM, and AVPR2), which demonstrated robust performance in diagnosing SCZ across eight different datasets. A nomogram based on these genes was created, providing clinical benefits for SCZ patients. Among the identified genes, AZI2 was found to be the most critical, influencing inflammation and immunity. We also identified potential chemical compounds that could target these 16 genes. Unsupervised clustering and NMF algorithms revealed two distinct subtypes of SCZ, each associated with unique immune cell profiles, biological functions, and protein expression levels. In conclusion, this study not only developed a diagnostic signature and a novel nomogram for SCZ but also provided new insights into the subtypes of SCZ. These findings may pave the way for personalized diagnosis and treatment strategies for SCZ patients. Show less

Primary Sjögren's disease (pSjD) is a chronic autoimmune disease. Clinically, sialography and lip gland biopsy in patients with pSjD show characteristic ductal dilations. However, the roles of the immune responses in ductal dilation remain unknown. We show that Th2 cells and their core cytokine IL-4 promote salivary duct dilatation in human and experimental SjD. Specifically, striated duct dilation is accompanied by periductal lymphocyte infiltration, which is correlated with increased IL-4 levels. In vivo, IL-4 neutralization reduced ductal dilation. Mechanistically, IL-4 induces the formation of cyst-like structures in cultured embryonic submandibular glands of mice. At the molecular level, IL-4 activates SHH signaling pathway in striated duct epithelial cells, upregulating SNAI1 and suppressing Cadherin 1 expression. This process disrupts interepithelial adhesion, leading to ductal dilation. Thus, IL-4 drives salivary gland ductal dilation that interferes with salivary gland function in SjD. Our findings should have implications for a potential therapeutic target in clinical pSjD. Show less

Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of endothelial-to-mesenchymal transition (EndoMT), a key cell-fate process in vascular development and disease, in TAD remains poorly defined. Furthermore, the functional role of PDK4 (pyruvate dehydrogenase kinase 4) as a driver of this pathological cell-fate transition has not been elucidated. To delineate the mechanistic contribution of EndoMT to TAD, we integrated transcriptomic profiling and immunofluorescence analysis in human aortic specimens and a β-aminopropionitrile-induced murine model. Following the identification of PDK4 as a critical downstream effector of EndoMT signaling via RNA-sequencing and chromatin immunoprecipitation assays, its functional role was validated using conditional EC-specific knockout mice and adeno-associated virus-mediated endothelial gene modulation. Serum samples were collected, and ELISA was used to measure levels of endothelial injury markers for assessing EC-dysfunction. In addition, therapeutic potential was assessed using dichloroacetate, a small-molecule PDK4 inhibitor. A robust activation of the EndoMT gene program was observed in both human TAD specimens and murine aortic tissues, characterized by the loss of endothelial identity and acquisition of mesenchymal traits. Transcriptomic screening pinpointed PDK4 as a critical mediator upregulated during EndoMT. Mechanistically, we demonstrated that the transcription factor Our findings demonstrate that the pathological EndoMT program is activated in ECs by PDK4, which aggravates TAD development in β-aminopropionitrile-induced mouse models, highlighting PDK4 as a promising therapeutic target for TAD. Show less

Prostate cancer (PCa) is the most general cancer in men and is often linked with distant metastasis in its later stages. The caffeic acid (CA) derivative, N-(4-methoxyphenyl)methylcaffeamide (MPMCA), demonstrates superior liver-protective effects compared to CA. Nevertheless, the functions of MPMCA on prostate cancer metastasis remain unclear. Here, we demonstrate that MPMCA blocks migration and invasion in prostate cancer cells without affecting cell viability. By suppressing the production of mesenchymal markers Vimentin, N-cadherin and β-catenin and upregulating the production of the epithelial marker Zonula Occludens-1 (ZO-1), MPMCA also controls Epithelial-Mesenchymal Transition (EMT). The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility. Transfection with Snail and Slug cDNA reverses MPMCA's suppression of EMT, migration, and invasion in prostate cancer cells. Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer. Show less

Preeclampsia (PE), a severe hypertensive disorder of pregnancy, is associated with circadian rhythm disruption, but the underlying placental molecular networks remain poorly understood. This study aimed to identify key hub genes, regulatory pathways, and novel biomarkers at the intersection of Early-Onset PE (EOPE) and the placental circadian clock. The placental transcriptomic dataset GSE114691 (20 EOPE vs. 20 gestational age-matched preterm controls) was analyzed to identify differentially expressed circadian genes (DECGs). Hub genes were prioritized via protein-protein interaction (PPI) networks. Hub gene expression was validated using effect size (Cohen's d) analysis, and diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) curve analysis. An upstream TF-miRNA co-regulatory network and drug-gene interactions were also analyzed. This pipeline identified 33 DECGs and 10 central hub genes (TGFB1, SPP1, ENG, CD63, SNAI1, GPT2, APLN, EZR, NTRK2, and GLUD1), all significantly dysregulated in EOPE. Crucially, analysis of the core clock machinery revealed a specific uncoupling of the regulatory feedback loop. ROC analysis revealed exceptional diagnostic potential. Notably, NTRK2 emerged as a novel, near-perfect classifier (Area Under the Curve [AUC] = 0.99), outperforming the established marker ENG (AUC = 0.97). Upstream analysis identified key transcription factors (FOXC1, GATA2), and drug-gene analysis revealed clinically relevant interactions between TGFB1 and the chronotherapeutic agents melatonin and aspirin. This study provides a systems-level map of the disrupted placental circadian network in EOPE. Our findings suggest that circadian misalignment is a central feature of placental pathology, offering a molecular rationale for developing novel chronotherapeutic strategies. Show less

Growth Factor Receptor-Binding Protein 10 (GRB10) is an adaptor protein implicated in tyrosine kinase signaling, yet its pan-cancer role and clinical impact remain incompletely characterized. This study aims to define the pan-cancer landscape of GRB10 dysregulation and its clinical implications for prognosis and immunotherapy response. Multi-omics analysis of 33 TCGA cancers and validation in GEO cohorts assessed GRB10 expression, prognostic impact (Cox regression, Kaplan-Meier), functional enrichment (Gene Set Enrichment Analysis, Gene Set Variation Analysis), immune correlates (Spearman with immune genes, ESTIMATE/CIBERSORT/EPIC/TIMER/xCell infiltration), tumor mutational burden (TMB), and immunotherapy predictive power. In the TCGA pan-cancer cohort, GRB10 was significantly elevated in 11 cancer types (CHOL, COAD, ESCA, HNSC, KIRC, KIRP, LIHC, LUAD, LUSC, STAD, THCA) and downregulated in 4 (BLCA, BRCA, CESC, UCEC). Aberrant GRB10 expression was strongly associated with adverse prognosis in LGG, CESC, COAD, and LUAD for OS, DSS, and PFI, a finding validated externally in GEO colon cancer cohorts. Conversely, it served as a protective factor in KIRC. Functionally, GRB10 was implicated in epithelial-mesenchymal transition (EMT), evidenced by positive correlations with EMT pathway scores and key regulators (ZEB1, ZEB2, SNAI1, SNAI2). GRB10 expression robustly correlated with an immunosuppressive tumor microenvironment (TME), evidenced by negative enrichment of immune response pathways (e.g., IFN-α/γ) and complex associations with immune-related genes. Immune infiltration analysis revealed consistent positive correlations with CD4⁺ memory-resting T cells and negative correlations with CD4⁺ effector memory T cells across most cancers. Critically, high GRB10 expression predicted significantly shorter survival and poorer response rates in multiple immunotherapy-treated cohorts (urothelial carcinoma, melanoma, gastric cancer). GRB10 also showed significant associations with TMB in several cancers, and its protein interaction network was enriched in PI3K-Akt, FoxO, and Rap1 signaling pathways. Our pan-cancer analysis establishes GRB10 as a key facilitator of tumor progression, linked to EMT and an immunosuppressive microenvironment, and nominates it as a novel biomarker for adverse prognosis and resistance to immune checkpoint blockade therapy. The online version contains supplementary material available at 10.1007/s12672-025-04333-x. Show less

G-patch domain-containing protein 2 (GPATCH2), a member of the G-patch domain-containing family, has been implicated in tumor cell growth, but the link between GPATCH2 and hepatocellular carcinoma (HCC) remains uncertain. In the current study, comprehensive bioinformatics analysis revealed that GPATCH2 was markedly upregulated in HCC and positively correlated with aggressive clinicopathological features, including histologic grade, AFP, albumin level, and adjacent hepatic tissue inflammation, as well as miserable outcomes in HCC. GPATCH2 also has certain diagnostic value for HCC, histologic grade, and 1-, 3-, and 5-year survival outcomes. Functionally, loss-of-function experiments disclosed that silencing GPATCH2 suppressed HCC cell proliferation, migration, invasion, and xenograft tumor growth in the subcutaneous mouse model. Silencing GPATCH2 also resulted in an increase in the expression level of CDH1, while causing a decrease in the expression levels of FN1, TWIST1, SNAI1, and SNAI2. Rescue experiments further confirmed SNAI2 as a critical downstream effector mediating GPATCH2-driven oncogenic activity in HCC. Mechanistically, GPATCH2 was uncovered to be transcriptionally activated by the transcription factor Yin Yang 1 (YY1), and can mediate the role of YY1 in promoting HCC progression and elevating SNAI2 expression. Taken together, GPATCH2 is a YY1-regulated oncogenic driver that promotes HCC advancement through SNAI2, highlighting its potential as a diagnostic, prognostic, and therapeutic target for HCC. Show less

The accumulation of advanced glycation end products (AGEs) is a hallmark of prolonged high glucose levels in diabetes mellitus. We have previously reported that hypoxia and AGEs cause epigenetic modification of the repressive mark H3K27me3 in podocytes by downregulation of enhancer of zeste homolog 2 (EZH2) and nuclear inhibitor of protein phosphatase 1 (NIPP1). However, their impact on proximal tubular cells remains unclear. The aim of this study was to investigate the role of AGEs and diabetes on the epigenetic modifications of EZH2 and H3K27me3 in proximal tubular cells and in diabetic ( Show less

The coordination between epithelial progenitors and their mesenchymal niche is critical for organogenesis and repair, yet the mechanisms governing their competitive interactions remain unclear. Here, we reveal a paradigm of tissue-scale fitness sensing in the lung, where mesenchymal Yap levels antagonize epithelial Yap levels to dictate epithelial stem cell fate. We show that reduced fitness in alveolar fibroblasts (AF1s) via Yap/Taz or Myc deletion leads to their apoptotic elimination and a collapse of the alveolar stem cell niche. This niche collapse triggers a pathological competitive response from the epithelium, which undergoes aberrant bronchiolization that phenocopies human pulmonary fibrosis. Mechanistically, we uncovered a molecular switch that controls mesenchymal fate. During development and fibrosis resolution, Snail1/2 sequesters Yap/Taz to drive an adipogenic program, generating niche-supportive AF1s. Conversely, Yap/Taz-TEAD-Myc binding instructs a myogenic, pro-fibrotic program. Our findings demonstrate that inter-tissue cell competition, governed by a Snail/Yap rheostat, orchestrates lung architecture and provides a framework for targeting the mesenchymal niche to treat fibrotic disease. Show less

This study explores the interaction between immune and cancer cells in the tumor microenvironment (TME) of cervical carcinoma (CC), with emphasis on tumor-associated macrophages (M2-TAMs) and the STAT3-NF-κB signaling pathway. It investigates how Treg cell polymorphisms and TAM infiltration through these pathways influence overall survival (OS) in CC patients. This prospective study follows 100 CC patients from 2018 to 2023 using qRT-PCR and immunohistochemistry on tumor samples, and flow cytometry on blood samples to evaluate immunosuppressive cytokines and Treg cell polymorphisms. High stromal CD163+204+ TAM density, mediated by STAT3/NF-κB, correlates with biomarkers such as Ki-67, VEGFα, and FOXP3 (p < 0.001). XPO5 expression is associated with increased STAT3, SNAIL, and HPV 16/18 levels. FOXP3 T allele deletion and HLA-G polymorphism in the blood of patients correlate with higher STAT3 tumor expression and elevated IL-4 and IL-17 blood cytokines. The CXCL12-CXCR4 axis shows a strong association with STAT3, SNAIL in TME and blood cytokines, including IL-6 and IL-12. Elevated CXCL12, CXCR4, and SNAIL expression in TME significantly increases mortality risk. These findings underscore the role of M2TAM infiltration and immune modulation in tumor progression and clinical outcomes in CC. Show less

A crucial aspect of the association involving inflammation and the development of cancer is the ability of cancer cells to undergo a transition into mesenchymal cells. The process is referred to as epithelial-mesenchymal transition (EMT). Cytokines and chemokines, which are inflammatory agents found in the carcinoma microenvironment, induce epithelial-mesenchymal transition (EMT) changes in malignant cells. Evaluating the role of cytokines in EMT in breast carcinoma and investigating their potential therapeutic implications is the objective of this comprehensive research report. The following search criteria were applied to the Cochrane, Embase, PubMed, and Web of Science databases: "cytokines," "the cytokines," "chemokines," "EMT," "epithelial-mesenchymal transition or transformation," "breast tumor," "breast carcinoma," and "breast cancer." A body of research comprising 54 articles has demonstrated that a number of cytokines, including TNF-α, TGF-β, and IL-6, contribute to the promotion of EMT alterations in breast tumors. The epithelial markers E-cadherin and β-catenin were downregulated as a consequence of morphological changes induced by EMT; conversely, the mesenchymal markers N-cadherin, vimentin, and fibronectin were upregulated. The EMT transforming factors (EMT-TF) TWIST/ZEB/SNAI1/SNAI2 were upregulated. Pharmaceuticals with the capacity to specifically target cytokines or their epithelial-mesenchymal transition (EMT) signalling pathways have the potential to significantly reduce treatment resistance, impede the progression of cancer, and prevent the recurrence of breast cancer. Epithelial-mesenchymal transition (EMT) induced by cytokines is a factor in breast cancer progression and metastasis. Show less

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, and ferroptosis has been associated with its pathogenesis. TRIM16 belongs to the TRIM protein family and possesses various biological function. However, the role of TRIM16 in RA has not been reported. Our results showed that TRIM16 was upregulated in collagen-induced arthritis (CIA) mice, and TRIM16 overexpression alleviated joint inflammation. Notably, the level of 4-HNE was decreased in CIA mice, whereas TRIM16 overexpression restored it. The expression of GPX4 and SLC7A11 was upregulated in CIA mice, whereas TRIM16 overexpression significantly suppressed their levels, suggesting that TRIM16 promotes ferroptosis. We then detected TRIM16 expression in TNF-α-induced fibroblast-like synoviocytes (FLS), and found that TNF-α stimulation reduced TRIM16 expression. Overexpression of TRIM16 increased the lipid ROS, Fe Show less

Triple-negative breast cancer (TNBC) presents significant therapeutic challenges. This study investigates the combination effects of Trifolium pratense L. (red clover) and doxorubicin (DOX) on the Wnt/β-catenin signaling pathway, epithelial-mesenchymal transition (EMT) and apoptosis in 4T1 tumor-bearing BALB/c mice. Female BALB/c mice were divided into six (n=10) groups: control, DOX (5 mg/kg), and three treatment groups receiving 100, 200, or 400 mg/kg Co-treatment of Show less

Breast cancer (BC) is the most prevalent malignancy among women worldwide. Growing evidence highlights the crucial role of circular RNAs (circRNAs) in BC carcinogenesis; however, their underlying mechanisms remain largely unknown. In this study, we identify circCLASP1, which is significantly upregulated in BC tissues (n = 65) and serum samples (n = 61). Its expression correlates with lymph node metastasis, ki67 expression, and tumor size. Receiver operation characteristic (ROC) curve analysis reveals area under the curve (AUC) values of 0.8196 (BC tissues) and 0.8902 (BC serum), respectively. Functionally, circCLASP1 knockdown significantly suppresses BC cell proliferation, migration, and invasion. Mechanistically, circCLASP1 prevents the ubiquitin-mediated degradation of GLI1 protein by facilitating its interaction with CCT2, thereby stabilizing GLI1. Moreover, circCLASP1 enhances the nuclear accumulation of GLI1, leading to increased SNAIL expression and thereby upregulating the expression of CCL2 and CCL5, which in turn promotes macrophage M2 polarization, ultimately resulting in BC progression and subsequent lung metastasis. Further analysis reveals that U2AF2 regulates circCLASP1 biogenesis. Collectively, these findings demonstrate that circCLASP1 promotes BC progression and an immunosuppressive microenvironment via the CCT2/GLI1/SNAIL axis, highlighting its potential as a prognostic biomarker and therapeutic target for BC. Show less

The Kruppel-like factor 15(KLF15) gene functions as a crucial transcriptional modulator involved in numerous cellular processes such as differentiation, proliferation, growth, and programmed cell death. The epithelial-to-mesenchymal transition (EMT) provides malignant cells with the adaptability and movement necessary for tumor advancement and spread, with zinc finger E-box binding homeobox 1(ZEB1) playing a pivotal role as a transcriptional factor in EMT. This investigation initially examined the association between the KLF15 protein and EMT associated transcription factors such as ZEB1, Slug, and Snail, along with marker proteins like E-cadherin and β-catenin in bladder cancer. Furthermore, we explored their connections with clinicopathological attributes and conducted prognostic analyses. Immunohistochemical techniques were utilized to ascertain the presence of KLF15 protein and EMT-associated transcription factor proteins, along with their marker proteins in 110 specimens of bladder cancer tissues. Concurrently, clinicopathological data and postoperative survival statistics were amassed. The rates of KLF15 and Slug protein expression were linked with pathological differentiation, lymphatic involvement, and pTNM staging. The protein expression rates of ZEB1, Slug, Snail, E-cadherin, and β-catenin also showed associations with lymphatic metastasis and pTNM stages. Notably, the expression of KLF15, the coexpression of KLF15 and ZEB1, and lymphatic metastasis emerged as independent prognostic indicators for the overall survival rates in bladder cancer cases. EMT enhances the risk of tumor recurrence and reduces overall survival durations in bladder cancer cases. Furthermore, KLF15 is a significant contributor to the EMT pathway in bladder cancer, primarily through its interaction with the transcription factor ZEB1. KLF15 and ZEB1 might serve as key biomarkers for metastasis and prognosis, offering potential new targets for therapeutic intervention in bladder cancer. Show less

To investigate the role and mechanism of the SREBP1/SNAI1 signalling pathway in the effect of brexpiprazole on the EMT and metastasis of CRC. The effects of different concentrations of brexpiprazole on cell migration, cell invasion and protein expression Brexpiprazole significantly inhibited the migration and invasion of CRC cells; downregulated the expression of SREBP1(m), SNAI1 and MMP9; upregulated the expression of E-Cad and ZO1; and decreased the levels of secreted ICAM-1 and VEGF in the supernatant of CRC cells. Western blotting and dual-luciferase assays revealed that SREBP1 could directly regulate the expression of SANI1. On the other hand, Brexpiprazole inhibits the migration, invasion and metastasis of CRC cells by inhibiting the SREBP1/SNAI1 signalling pathway and downregulating the expression of EMT-related factors. Show less

The majority of pregnancy loss in ruminants occurs during the first two months of gestation, and a failure in placenta development is a major cause of pregnancy loss in cattle after day 20. Gaining a cell-type level understanding of normal placental development is essential for uncovering how this critical organ, responsible for nutrient exchange, gas transfer, and waste removal, fails during pregnancy loss. This study integrated single-cell RNA sequencing (scRNA-seq) from sheep and cattle during early placental development. Nineteen distinct cell populations were identified across species, with mesenchymal, epithelial, and trophoblast cells showing largely conserved expression profiles. Interestingly, two trophoblast clusters were unique to cattle, with one expressing IFNT2 (uninucleate) and another expressing CSH2 and PAG17 (binucleate). Genes associated with epithelial-to-mesenchymal transition (EMT), such as SNAI1, SNAI2, ZEB1, VIM, CDH1, and CLDN4, showed dynamic and prominent expression patterns in trophoblasts. Pseudotime and cell-cell signaling analyses supported the occurrence of EMT in uninucleate trophoblasts. Gene ontology comparisons revealed similarities between ruminant and human extravillous trophoblasts, suggesting conserved EMT across placental types. Collectively, these findings highlight EMT as a potentially critical process in early ruminant placentation. Show less

Despite extensive research, the pathogenesis and predispositions underlying long COVID (long-term coronavirus disease 2019) remain poorly understood. To address this, we analyzed the immunological landscapes of 44 patients with long COVID and 44 matched convalescents using single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) and validated the findings with plasma cytokine measurements via Luminex technology. While the immune cell compositions showed minimal quantitative differences only among natural killer (NK) cells, the transcriptome analyses identified distinct gene expression patterns, particularly in classical monocytes: patients with long COVID exhibited downregulation of the inflammation-associated genes, including These findings show that monocytes might be dysregulated and/or exhausted in patients with long COVID. Show less

Melanoma cells evade drug treatment by changing their phenotype from proliferative to migrative cells and vice versa in a process known as phenotype switching. The Microphthalmia-associated transcription factor (MITF) is a key regulator of phenotype switching in melanoma. Previous studies have shown that loss of MITF affects the expression of epithelial-to-mesenchymal transition marker genes such as E-cadherin (CDH1) and N-cadherin (CDH2). However, the specific roles of CDH1 and CDH2 in phenotype switching as well as their direct correlation with MITF remain unclear. This study aimed to investigate how MITF regulates CDH1 expression in melanoma. The results showed that a 1 kb intronic CDH1 fragment (CDH1-B) leads to MITF-dependent activation of CDH1 expression through specific binding sites. Although MITF represses the expression of the epithelial-to-mesenchymal transition transcription factors SNAIL, ZEB1, and TWIST1, knockdown of SNAI1 and TWIST1 did not affect CDH1 expression or expression from the CDH1-B element. In addition, ZEB1 did not affect expression from the CDH1-B element, suggesting that MITF activates CDH1 directly through this regulatory element. Our results show the direct role of MITF in regulating CDH1 expression in melanoma, highlighting an important step in the phenotype switching process. Show less

The development of an immunosuppressive microenvironment is a critical factor in stomach carcinogenesis. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) serve a pivotal function in mediating immune suppression. However, the precise mechanisms underlying PMN-MDSCs infiltration into the tumor immune microenvironment (TIME) and their immunosuppressive functions remain poorly understood. In this investigation, we observed that PMN-MDSCs were up-regulated during stomach carcinogenesis, with gastric cancer (GC) cells secreting CCL26 to promote the infiltration of PMN-MDSCs into the TIME via the CX3CR1 receptor. The infiltrating CX3CR1 Show less

Glioma is a highly aggressive malignancy with no effective treatment. This study investigates the role of protein tyrosine phosphatase receptor type N (PTPRN) in glioma progression. The U87 human glioma cell line was used to monitor proliferation, invasion, and migration during PTPRN knockdown. The viability, migration, and invasion were analyzed using the Cell Counting Kit-8 assay, transwell migration, and invasion assays. Additionally, the expression of proteins associated with the cell cycle was examined using western blotting. The knockdown of PTPRN resulted in a reduction in glioma cell proliferation, migration, and invasion, as well as the expression of cell cycle markers like Show less

Embryonic stem cells can be instructed to form gastruloids, an efficient four-dimensional model for studying some aspects of post-implantation embryonic patterning, which undergo gastrulation-like processes, illustrating their robust self-organizing capacity to form embryo-like patterns. Here, we study the molecular and cellular mechanisms underlying this remarkable property and report that self-organization competence is associated with a cell-specific coordination of a cadherin switch. E-cadherin repression by Snai1 is indeed critical for this process, with Snai1 triggering the cell-specific pace of pluripotency exit, thus allowing a coordinated transition from E- to N-cadherin to occur. In contrast, we find that N-cadherin inactivation unleashes gastruloids' morphogenetic competence, for it leads to the formation of embryo-like structures with proper rostro-caudal somite patterning without requiring any addition of extracellular matrix. Altogether, this work establishes a molecular mechanism that integrates the exit from pluripotency and the pace of cell differentiation, leading to the self-organizing potential of gastruloids. Show less

Endothelial-to-mesenchymal transition (EndMT) is a biological process through which lung vascular endothelial cells (ECs) transdifferentiate into mesenchymal-like cells. EndMT has recently been implicated in the development and progression of pulmonary vascular remodeling in pulmonary hypertension (PH); however, its underlying regulatory mechanisms remain incompletely understood. MicroRNAs (miRNAs) are key post-transcriptional regulators of EC gene expression and cellular responses to various stimuli. Notably, microRNA-153 (miR-153) has been shown to directly target SNAI1 to modulate epithelial-to-mesenchymal transition (EMT), a process closely related to EndMT and extensively studied in cancer. Whether miR-153 also participates in EndMT regulation, however, remains unknown. In this study, we demonstrate that 72-hour hypoxic exposure induces SNAI1-mediated EndMT in human lung vascular ECs. Hypoxia also increased cell proliferation and disrupted intercellular junctions, leading to enhanced endothelial permeability. Reduced miR-153 expression was observed in both hypoxia- and TGF-β1-induced EndMT, as well as in ECs isolated from PH patients exhibiting an EndMT phenotype. Similar to hypoxia, TGF-β1 promoted EC permeability. Loss of miR-153 enhanced SNAI1-mediated EndMT, endothelial survival, and permeability under normoxic conditions, whereas miR-153 overexpression attenuated EndMT induced by hypoxia or TGF-β1. However, miR-153 restoration did not completely recover endothelial barrier integrity disrupted by these stimuli. In conclusion, miR-153 serves as a critical regulator of EndMT, maintaining endothelial identity and barrier function. Therapeutic delivery of miR-153 may therefore represent a novel strategy to inhibit EndMT and attenuate pulmonary vascular remodeling in PH. Show less

Cervical Cancer is the second most common gynecological malignancy affecting a large group of women worldwide. The molecular mechanism of cervical cancer progression is still not very clear. As a result, diagnosis of cervical cancer occurs at a very advanced stage when the disease has spread to its malignant stage, causing death in the majority of women. EMT is a major culprit associated with the malignant transformation of tumor cells during cancer progression and metastasis. Hence, identification of new biomarkers to detect cervical cancer at an early stage is essential to minimize incidence and mortality. The present study aims to identify Common Differentially Expressed Genes (DEGs) and early biomarkers associated with EMT in cervical cancer. The Datasets were downloaded from the Gene Expression Omnibus (GEO) database, with Accession numbers GSE26511, GSE67522, and GSE9750. Then, the Gene Ontology (GO), KEGG pathway enrichment analysis, and protein-protein interactions (PPI) were done. Further hub genes were identified by molecular interaction networks using Cytoscape from the constructed network of DEGs. Afterwards, survival analysis was performed to assess the prognostic significance of eight hub genes associated with EMT in cervical cancer. A total of 11,339 overlapping DEGs were identified from all three datasets, among all the total 61 DEGS, and 8 hub genes were linked to the EMT pathway. Our study suggests that these eight hub genes, CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2, may be critically associated with EMT progression. Among the eight identified EMT hub genes, CDH2 (N-cadherin) demonstrated a significant association with overall survival, while FN1 (fibronectin) was notably linked to disease-free survival, underscoring their prognostic value in cervical cancer. Based on these findings, our study suggests that CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2 hold potential diagnostic and prognostic significance in the progression of cervical cancer. Show less