The ion channel gene GJB2 emerges as a therapeutic target for LUAD with significant prognostic value. Herein, the potential mechanisms of GJB2 were investigated. GJB2 expression was analyzed by bioinformatics, RT-qPCR and western blotting. In vitro functional assays and A549 xenografts detected the role of GJB2. The upstream mechanism of GJB2 was explored. GJB2 was up-regulated and associated with the poor overall survival of LUAD patients. GJB2 knockdown inhibited cell malignancy and impaired mitochondrial homeostasis. HSF4 enhanced GJB2 transcription. GJB2 knockdown lowered PI3K/AKT activity. SC79 reversed the in vitro impacts of GJB2 inadequacy and promoted tumor growth when HSF4 was up-regulated and GJB2 was down-regulated simultaneously. GJB2, transcriptionally activated by HSF4, activates PI3K/AKT pathway to support LUAD tumorigenesis and development.
Glioblastomas (GBs) are the most frequent and aggressive central nervous system tumors, whose progression is influenced by sex hormones. 17β-estradiol (E2), promotes an epithelial-to-mesenchymal transition (EMT)-like process and enhances proliferative, migratory, and invasive capacities in GB through intracellular estrogen receptors. However, the role of G protein-coupled estrogen receptor (GPER) in GB remains poorly understood. We evaluated the effects of E2, the GPER-agonist G-1, and the GPER-antagonist G-15 on EMT-related processes, migration, and invasion in U251 and U87 GB-derived cells. GPER activation by E2 and G-1 increased migration and invasion, whereas G-15, alone or combined, reduced these effects. GPER activation also induced a mesenchymal-like phenotype. These findings suggest that GPER-associated signaling contributes to EMT-like phenotypic changes, migration, and invasion in GB.
This cross-sectional study investigated galectin-1, -3, and -9 in adenomyosis. Analysis of hysterectomy tissues from premenopausal women via western blot, qPCR, immunohistochemistry, and Masson's staining revealed significantly elevated galectin levels compared to controls. Galectin expression positively correlated with fibrosis severity (r = 0.476, 0.925, 0.563, all p < .05), which in turn moderately correlated with dysmenorrhea (VAS score) and uterine enlargement. Findings indicate that galectins are implicated in adenomyosis-related fibrosis and pain, suggesting their potential as therapeutic targets.
Endometrial cancer(EC) is increasing worldwide, but its molecular mechanisms remain unclear. This study explored whether RBM15B-mediated m6A modification of FOXM1 promotes EC progression through the AURKA/TPX2 axis and epithelial-mesenchymal transition(EMT). Bioinformatics analyses assessed FOXM1 expression and prognosis in EC. RNA pull-down, MeRIP-PCR, dot blot, and RNA stability assays examined m6A regulation. Colony formation, Transwell, wound healing, and tumor sphere assays evaluated malignant behaviors. FOXM1 was significantly upregulated in EC and associated with unfavorable prognosis. Functional assays showed that FOXM1 enhanced proliferation, migration, invasion, and stemness of EC cells. Mechanistically, RBM15B increased m6A modification of FOXM1 mRNA and promoted expression. RBM15B knockdown inhibited malignant phenotypes and reduced activation of the downstream AURKA/TPX2 pathway. RBM15B-mediated m6A methylation stabilizes FOXM1 expression, activates the AURKA/TPX2 axis, and promotes EMT and EC progression. Targeting the RBM15B/FOXM1/AURKA/TPX2 pathway may offer therapeutic potential.
Epithelial dynamics require rapid remodeling of cell adhesion during extrusion, division, and migration. We identify a matriptase-dependent mechanism regulating the Ca2+- independent adhesion molecules EpCAM and Trop-2. Matriptase activation cleaves these CAMs into two-chain forms, promoting internalization and degradation, followed by replenishment through new synthesis. This turnover enables rapid adaptation of adhesion to environmental cues. Loss of matriptase disrupts this cycle, impairing epithelial integrity, extrusion, mitosis, and collective migration. Matriptase activity is tightly controlled by zymogen activation and inhibition by HAI-1, restricting CAM cleavage. Environmental factors, including pH, redox state, and chloride levels, modulate activation, linking external stimuli to adhesion remodeling. This protease-driven pathway provides a rapid, adaptable system for epithelial adhesion control.
The secretion of chemokines by cancer-associated fibroblasts (CAFs) is a critical driver of cancer progression. Nevertheless, the precise contribution of CAFs in the nasopharyngeal carcinoma (NPC) tumor microenvironment to disease progression is yet to be fully understood. In this study, C-X-C motif chemokine ligand 11 (CXCL11) was identified to be upregulated in tumor tissues of NPC patients and NPC cells compared to counterpart normal tissues and cell lines. The CAFs-secreted CXCL11 was found to enhance the proliferative, invasive, and migratory capacities of NPC cells. CAFs-derived CXCL11 upregulates CXCR3 expression to facilitate NPC cell proliferation, migration, and invasion. Through mechanism investigation, we confirmed that CXCL11/CXCR3 axis upregulated PD-L1 expression through p65-mediated transcription activation. Finally, in vivo experiments further validated the tumor-promoting role of CAFs-secreted CXCL11 in NPC. In conclusion, our findings reveal a novel mechanism wherein CAFs-secreted CXCL11 promotes NPC malignant progression by activating the CXCR3/PD-L1 signaling axis.
Meox1 is aberrantly expressed in several malignancies, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the effects of Meox1 on HCC cells and explore the underlying molecular mechanisms. Cell proliferation, colony formation, migration, invasion, and cell cycle distribution were assessed by CCK-8, clonogenic, Transwell, and flow cytometry assays, respectively. Protein expression was examined by Western blotting. Meox1 silencing significantly inhibited proliferation, clonogenic capacity, migration and invasion of HCC cells. Cell cycle analysis showed a reduction in G1-phase cells with a marked accumulation in the G2 phase following Meox1 knockdown. Western blot analysis revealed that suppression of Meox1 reduced p21CIP1/WAF1 expression. Meox1 contributest to HCC progression and may represent a potential therapeutic target.
E-cadherin is a key component of adherens junctions which maintains epithelial integrity. In keratinocytes, wound healing requires dynamic modulation of adhesion and cytoskeletal organization. Using a wound healing assay combined with stimulated emission depletion/atomic force microscopy (STED/AFM), we analysed E-cadherin binding during murine keratinocyte migration. Wound closure occurred within 6 h and was accompanied by E-cadherin accumulation at the leading edge. Transient expression of E-Cadherin-SNAP enabled investigation of E-cadherin interactions. Inhibition of actin polymerization abolished E-cadherin binding and reduced cellular stiffness. Imaging of SiR-actin-labeled cells enabled simultaneous visualization of migration and measurement of binding and mechanical properties. E-cadherin retained functional binding properties during migration. These findings establish STED/AFM as a powerful method to investigate single-molecule binding properties in migrating cells.
Tensins are a family of adhesion proteins that play a role in constructing the cytoskeleton, as well as in intracellular and extracellular communication. Their expression was evaluated in 22 pancreatic cancer patients using the immunohistochemistry method. TNS1 expression occurred more frequently among patients with tumor diameter ≥ 2 cm, which may suggest an association with the development of pancreatic cancer. Intraductal TNS1 was observed less often with presence of necrosis and hemorrhages in tumor. The fact that cancer cells secrete TNS1 suggests that it could be investigated as a potential target for liquid biopsies. TNS4 expression occurred more frequently among females and was observed when necrosis in tumor was strong. TNS2 and TNS3 are not involved in the development of ductal pancreatic adenocarcinoma.
Neuraminidase 1 (NEU1) regulation of atrial fibrillation (AF) progression via fibrosis remains unknown. Mice receiving AAV9-mediated NEU1 knockdown were infused with Ang II and subjected to programmed electrical stimulation to induce AF. Left atrial dilation and fibrosis were evaluated by echocardiography, histology, and fibrosis markers. Primary mouse atrial fibroblasts treated with Ang II were assessed for proliferation and migration by EdU staining and Transwell. The N6-methyladenosine (m6A) modification of NEU1 by methyltransferase-like 3 (METTL3) was confirmed through m6A quantification, RNA immunoprecipitation, MeRIP-qPCR and actinomycin D experiments. NEU1 knockdown attenuated atrial dilation, fibrosis, and AF susceptibility. Mechanistically, METTL3 stabilized NEU1 via m6A modification, promoting Ang II‑induced atrial fibroblast activation. Thus, NEU1, stabilized by METTL3 via m6A, exacerbates Ang II‑induced AF susceptibility.
Preeclampsia (PE) is a severe pregnancy complication with unclear molecular mechanisms. Our research investigated the effect of UNC5C-AS1 on human umbilical vein endothelial cell (HUVEC) function in PE. UNC5C-AS1 was downregulated in PE placentas. Upregulating UNC5C-AS1 promoted HUVEC migration, invasion, tube formation, and the expression of vascular permeability factors, while UNC5C-AS1 silencing exhibited an opposite effect. UNC5C-AS1 directly targeted the miR148a3p/EMP1 axis. MiR-148a-3p was up-regulated and EMP1 was downregulated in PE. The regulatory effects of UNC5C-AS1 overexpression on HUVEC functions were reversed by miR-148a-3p mimics, and this reversal was subsequently rescued by EMP1 upregulation. UNC5C-AS1 overexpression ameliorated tissue damage in the PE mouse model. UNC5C-AS1 alleviated the PE-associated injury and modulated HUVEC function by targeting miR-148a-3p/EMP1 axis.
EPB41L1-5 is known to maintain cell morphology and signal transduction, with evidence suggesting it can inhibit tumor progression. However, its role in kidney renal clear cell carcinoma (KIRC) is not fully understood. This study evaluated EPB41L1-5’s prognostic value in KIRC using bioinformatics methods and validation through qPCR, immunohistochemistry, and cell functional experiments. The results demonstrated a decreased expression of EPB41L in KIRC tissue compared to normal renal tissue, correlating with lower survival rates. Low EPB41L expression was also associated with overall survival in KIRC. Additionally, EPB41L was found to be involved in extracellular matrix regulation, G protein-coupled receptor ligand binding, and multiple immune cell infiltrations. In addition, their elevated methylation levels are associated with poor prognosis in KIRC patients. Overall, EPB41L family is a potential molecular marker for predicting KIRC prognosis, offering insights for therapeutic development.
In the tumor microenvironment, tissue-resident macrophages (TRMs) promote malignant tumor progression, yet their tissue-specific heterogeneity and complex functions bring research challenges. This study analyzes the research status and trends of TRMs in oncology. Via VOSviewer, CiteSpace, R software and WoSCC, a visual bibliometric network was built for quantitative analysis, with future research directions explored in depth. The US leads in publications and academic influence, and the University of Washington tops in paper output. Research focuses on TRMs’ origin, classification and tumor microenvironment functions; microglia and Kupffer cells are the most studied subsets. Current research centers on pathway exploration, immunotherapy and single-cell sequencing. This study summarizes TRMs’ research status, hotspots and trends in oncology, providing valuable insights for relevant collaborators and institutions.
This study investigated the role of COPB2 in gastric cancer (GC) pathogenesis. Analysis of TCGA datasets and tissue microarrays revealed its upregulation in GC tissues compared to normal adjacent tissues, which was correlated with advanced tumor stage and lymphatic invasion and demonstrated significant diagnostic value (AUC = 0.895 and 0.851). Functional assays using lentiviral-mediated silencing in GC cells showed that COPB2 knockdown suppressed cell proliferation and migration, induced G0/G1-phase arrest, and promoted apoptosis. Mechanistic investigations through microarray, KEGG, and IPA analyses indicated that COPB2 dysregulation inactivated the PI3K/AKT and NF-κB signaling pathways. This led to the downregulation of key oncogenic effectors including Slug, FN1, CDH2, F2RL1, CDK6, CCND1, MMP9, CDKN2A, and SQSTM1, while upregulating tumor suppressors CDKN1B, CDKN1A, and DDIT3. In conclusion, COPB2 acts as an oncogene in GC, driving tumor progression through modulation of the cell cycle and key signaling pathways, highlighting its potential as a therapeutic target.
Purpose Neutral cholesterol ester hydrolase 1 (NCEH1), a key enzyme in cellular lipid metabolism, is associated with cancer progression. Its molecular functions in breast cancer remain poorly understood.Methods This study evaluated the expression of NCEH1 in breast cancer patients using multiple databases. Functionally, the effects of NCEH1 silencing or overexpression on breast cancer cell growth and motility were investigated. RNA-seq was employed to identify downstream target genes and signalling pathways.Results The expression of NCEH1 in breast cancer tissues and cells was significantly higher than that in normal tissues and cells. Silencing NCEH1 suppressed breast cancer cell proliferation and migration. Mechanistically, NCEH1 regulated Neuropilin-1 (NRP1) expression, and both promoted malignant phenotypes in breast cancer by activating the TNF-α/NF-κB signalling pathway.Conclusion Our findings demonstrate that NCEH1 accelerates breast cancer progression by modulating NRP1 and activating the TNF-α/NF-κB signalling pathway. Collectively, NCEH1 represents a potential novel biomarker and therapeutic target for breast cancer.
Lactoferrin (LTF) has gained attention as a potential anti-cancer biomarker, but its role in left-sided colon cancer (LCC) remains poorly understood. This study explores the function of LTF in LCC and its underlying mechanisms. LTF expression was significantly elevated in tumor tissues compared to normal tissues (59.67-fold increase, p < .001). LTF overexpression significantly enhanced LCC cell proliferation, migration, and invasion (p < .01), while suppressing apoptosis (p < .05). In contrast, LTF knockdown markedly inhibited these oncogenic behaviors. Western blot analysis demonstrated that LTF overexpression led to increased phosphorylation of PI3K and Akt proteins (p < .01), suggesting activation of the PI3K/AKT signaling pathway, while LTF knockdown resulted in decreased phosphorylation levels (p < .01). This study identifies LTF as a promoter of LCC development via activation of the PI3K/AKT pathway, suggesting LTF as a promising therapeutic target. Further research is warranted to evaluate its clinical potential in LCC treatment.
We assessed the influence of telomerase inhibitors TMPyP4, BIBR 1532, or imetelstat on the ability of MCF7 and MDA-MB-231 breast cancer cells to form spheroids. TMPyP4 significantly impaired the adhesion potential and ability of both cell lines to form spheroids. BIBR 1532 treatment did not show any effect in MCF7 while it showed some effect in MDA-MB-231 cells, although this effect was less extensive comparing to TMPyP4. Application of Imetelstat provoked a dispersion effect in both cell lines but more single, separated distant cells were observed. Molecular docking and molecular dynamic studies showed that both BIBR 1532 and TMPyP4 exhibited affinity toward the structure of a G-quadruplex of human telomeric RNA (TERRA2 G4s) and the catalytic subunit of telomerase, hTERT. We showed that the use of telomerase expression/activity inhibitors to reduce the adhesive capacity and metastatic potential of breast cancer cells may play a significant role in anticancer strategy.
Gliomas are aggressive brain tumors whose infiltrative growth is mediated by intercellular crosstalk. Exosomes, small extracellular vesicles, play a key role in cell-cell communication but are difficult to visualize using conventional microscopy. Performing immunostaining for CD63, a known exosome marker, and using STED microscopy, we demonstrate exosome secretion in primary glioma cells. Applying mathematical deconvolution, we enhance the contrast and resolution for in-depth analysis of STED images. We identify CD63-positive cellular footprints and exosome deposits in the extracellular space. Quantitative analysis shows CD63-positive exosomes ranging 36.55-157.06 nm in size. CD63/actin co-staining demonstrates different actin polymerization states associated with exosomes. In conclusion, STED microscopy coupled with immunostaining allows exosome primary characterization at the single-vesicle level in the cellular spatial context.
This study examines Holocytochrome c synthase (HCCS) expression in lung adenocarcinoma (LUAD) and its impact on the tumor immune environment. By analyzing multiple tumor databases, the research highlights HCCS expression patterns across various cancer types, focusing on its correlation with M2-type macrophages, which aid tumor progression. Findings show that high HCCS expressionin LUAD is associated with increased M2-type macrophages, and variations in HCCS levels influence immune cell infiltration and cancer therapy responsiveness. It suggests that HCCS significantly shapes the immune landscape within tumors, promoting growth and spread, and underscores its potential as a therapeutic target in LUAD and other cancers with similar expression profiles.
MiR-646, a small non-coding RNA, poorly expressed in a variety of tumors. This study aimed to clarify the role of miR-646 and its underlying mechanisms in glioblastoma (GBM). In our study, we found that miR-646 mRNA levels were lower in tumor tissues than in non-cancer tissues. The ability of glioma cells to proliferate, invade, and migrate is diminished by miR-646 overexpression in vitro and in vivo. Mechanistically, miR-646 targeted sequestosome 1 (p62) in the 3'UTR and affected the Keap1/Nrf2 pathway, thus attenuating the expression of the HO-1 gene. In conclusion, this study provided a novel finding that miR-646 tampered with gliomagenesis by regulating the p62/Keap1/Nrf2 axis, which provides a potential target for GBM therapy.
