Journal of Cell Communication and Signaling最新文献

Prostate cancer (PCa) is a leading cause of cancer-related death in men, with its progression and treatment response being complex. The study focuses on the role of HIC1 (Hypermethylated in cancer 1) in PCa, revealing its downregulation in PCa tissues compared to normal counterparts. Using transcriptome sequencing and bioinformatics, it was found that HIC1 influences key cellular processes like cell growth, proliferation, invasion, and androgen receptor (AR) signaling in PCa. Specifically, AR was identified as a transcription factor for insulin receptor substrate 2 (IRS2), which activates the PI3K/AKT pathway, enhancing PCa cell proliferation and invasion. However, this effect could be reversed by IRS2 inhibition using NT157. Furthermore, HIC1 overexpression reduced castration resistance in PCa cells, with in vivo studies showing that HIC1 silencing increased PCa xenograft growth and resistance, and elevated Ki-67, Cleaved-caspase-3, EMT markers, and prostate-specific antigen (PSA) levels. Conversely, AR and IRS2 inhibitors like EPI-7170 and NT157 negatively affected PCa progression. These results underscore HIC1's potential as a therapeutic target in PCa, offering new insights into its role in cancer biology and treatment.

Endothelial-derived reactive oxygen species (ROS), modulated by free iron levels, are key drivers of neutrophil extracellular traps (NETs) formation and contribute to cerebral ischemia/reperfusion (CI/R) injury. Targeting ROS and iron could possibly reduce NETs formation and mitigate stroke. NETs were predominantly initiated by hypoxia/reoxygenation (H/R) in endothelial cells (ECs), rather than in neutrophils. Silencing Fpn1 in ECs significantly reduced extracellular iron, suppressed ROS production, and inhibited NETs formation—effects that were reversed by supplementation with iron or hemin. Additionally, both vitamin C (Vc) and deferoxamine (DFOM) suppressed blood coagulation on Fpn1-silenced ECs under H/R conditions. NETs formation on hypoxic ECs was further enhanced in the presence of co-cultured red blood cells. In a mouse model of middle cerebral artery occlusion, combined treatment with Vc and DFOM synergistically reduced infarct size. Although Vc or DFOM alone reduced NETs formation, their combined use showed a weaker effect than DFOM alone, possibly because better blood flow increased neutrophil contact with the endothelium. In conclusion, endothelial ROS and iron play critical roles in regulating NETs formation during CI/R injury. Combined treatment with Vc and DFOM offers a promising therapeutic strategy to reduce stroke-induced damage by modulating ROS levels and NETs formation.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder lacking effective pharmacological interventions. We identified CD5 molecule-like (CD5L) as a regulator of macrophage polarization in AAA via the phosphoinositide 3-kinase/protein kinase B/nuclear factor kappa B (PI3K/Akt/NF-κB) pathway. Transcriptomic analyses (GSE47472 and GSE57691) and angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE^−/−) mice showed CD5L upregulation, inversely correlated with M1 macrophage infiltration. In vitro CD5L overexpression reduced, whereas knockdown increased M1 polarization and pro-inflammatory cytokines in RAW264.7 cells and human monocyte-derived macrophages. In vivo, CD5L knockdown aggravated aortic dilation, vascular disruption, and inflammatory mediator expression. Pharmacological modulation confirmed PI3K/Akt as essential for CD5L's anti-inflammatory action: LY294002 amplified, whereas PI3K activator 740Y-P mitigated CD5L deficiency effects. RNA sequencing confirmed PI3K/Akt activation downstream of CD5L. These results define CD5L as an immunometabolic checkpoint that suppresses NF-κB-mediated inflammation, suggesting a therapeutic target for AAA.

Cellular communication network factor 2 (CCN2) with a nuclear localization signal-like peptide is known to promote fibrosis. However, translocation of CCN2 into the nucleus and its role in fibrosis remain unclear. We hypothesized that nuclear-translocated CCN2 is associated with purine-rich box 1 (PU.1), which is a transcription factor regulating the differentiation of myofibroblasts. Western blot analysis of the cytoplasmic and nuclear fractions of cell lysate and immunofluorescence analysis revealed that CCN2 was detectable in both the cytoplasm and nuclei of murine fibroblastic NIH3T3 cells. Additionally, chromatin immunoprecipitation (IP)-PCR and an electrophoretic mobility shift assay revealed that recombinant CCN2 protein bound to the regulatory region of Spi1, which encodes PU.1. Furthermore, IP-Western blot analysis showed that CCN2 interacted with PU.1. Finally, the forced expression of both Ccn2 and Spi1 significantly promoted the production of angiotensin II, and increased fibrosis-related molecules, such as Col1a1 and Acta2, at the gene and protein levels. These findings indicate that CCN2 translocated to the nucleus interacts with PU.1 and that the complex promotes the markers of myofibroblast differentiation, suggesting that CCN2 plays an important role in fibrosis via cooperation with PU.1, as a transcription co-factor.

Myopia, a leading global health challenge linked to severe ocular complications, remains poorly understood in terms of molecular mechanisms involving cellular senescence. This study integrates transcriptomic datasets (GSE112155 and GSE151631) from myopia and normal vision samples to unravel senescence-driven pathways and immune interactions underlying myopia pathogenesis. By constructing protein–protein interaction networks and post-transcriptional regulatory axes (mRNA–miRNA–TF), we identified core senescence-associated genes (Tp53, Cdkn1a, and Myc) as central regulators in myopia progression. Single-sample gene set enrichment analysis revealed significant immune dysregulation in myopia, marked by altered infiltration of γδ T cells, natural killer T cells, and neutrophils. Functional validation through Tp53 overexpression and Cdkn1a/Myc knockout in mice demonstrated their critical roles in exacerbating myopia phenotypes, including elongated eye axis and thickened retina. These findings highlight a synergistic interplay between cellular senescence and immune-mediated mechanisms in myopia, supported by multi-omics evidence and in vivo experiments. Our work not only maps the molecular networks bridging senescence and myopia but also proposes novel therapeutic targets for modulating these pathways. This study advances the understanding of myopia as a senescence-associated disorder and underscores the potential of targeting immune–senescence crosstalk for intervention.

Dedifferentiated renal tubular epithelial cell (RTEC) proliferation contributes to renal repair following acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) injury (RIRI). However, the fundamental mechanism underlying RTEC dedifferentiation remains unclear. An animal model of RIRI-induced AKI was established using I/R, and H₂O₂-treated murine (m) RTECs were used as the cell injury model. Pathological changes were assessed by hematoxylin and eosin and periodic acid–Schiff stain staining. Cell viability and migration were assessed using the cell counting kit-8 and wound healing assays, respectively. Apoptosis was examined using flow cytometry. Molecular interactions were investigated using coimmunoprecipitation and chromatin IP assays. Tri-domain proteins 27 (TRIM27) expression was reduced in RIRI mice and H₂O₂-treated mouse renal tubular epithelial cells (mRTECs). TRIM27 overexpression enhanced mRTECs dedifferentiation, proliferation, and migration while inhibiting apoptosis. Mechanistically, TRIM27 reduced polycomb repressive complex 2 (PRC2) activity in mRTECs through the mediation of Enhancer of zeste homolog 2 ubiquitination. Further, PRC2 reduced Gli-like transcription factor 1 (GLIS1) expression in mRTECs by regulating Histone H3 trimethylated at lysine 27 and DNA methylation. TRIM27 overexpression ameliorated RIRI-induced AKI in mice by enhancing mRTEC dedifferentiation. TRIM27 upregulation alleviates RIRI-induced AKI by reducing GLIS1 DNA methylation and promoting GLIS1 expression by inhibiting PRC2 activity.

Kidney renal clear cell carcinoma (KIRC) lacks sensitive early diagnostic markers and effective therapeutic guidance. Given the tight crosstalk between tumor metabolism and immunity, we investigated immunometabolism for biomarker discovery. Transcriptomes from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus were integrated. Immunometabolism-related genes were screened by weighted gene co-expression network analysis and differential expression, followed by three machine learning algorithms (least absolute shrinkage and selection operator, Support Vector Machine–Recursive Feature Elimination (SVM-RFE), and random forest) to select features and build a diagnostic model. Performance was validated in external cohorts. Multi-omics correlation, immune infiltration, drug-sensitivity, and survival analyses were conducted. Functional assays were performed in vitro and in vivo. Six biomarkers—ABCB1, Acyl-CoA Dehydrogenase Short/Branched Chain (ACADSB), PLA2G6, AKR1C3, PANK1, and Lactate Dehydrogenase B (LDHB)—were identified. The model showed strong discrimination (AUC 0.976 in TCGA; 0.902 in GSE126964; and 0.916 in GSE36895). The genes correlated with immune checkpoints, cytokine signaling, T-cell infiltration, and clinical parameters. Drug analyses suggested cisplatin and sunitinib downregulated oncogenic targets. Silencing ABCB1 or AKR1C3, or overexpressing LDHB, suppressed KIRC cell proliferation and migration in vitro; LDHB overexpression combined with sorafenib significantly reduced tumor growth in vivo. We propose a robust immunometabolism-based diagnostic model and six experimentally supported biomarkers for KIRC, providing mechanistic insight into tumor–immune interactions and potential avenues for personalized therapy.

Trans-Coumaryl acetate (T-CA) is formed by the esterification of coumarin with acetic acid and belongs to the reprogramming products of aromatic amino acid and fatty acid metabolism. Currently, the impact of T-CA on the progression of septic acute kidney injury (SAKI) and its underlying mechanisms are not clear. A lipopolysaccharide (LPS)-treated HK-2 cell injury model was constructed, and a mouse SAKI model was constructed using a cecum ligation and puncture method. The impacts of T-CA on HK-2 cell survival and cytotoxicity were examined using a Cell Counting Kit-8 assay and lactate dehydrogenase kit. Inflammatory factors, Superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS), adenosine 5′-triphosphate (ATP), and mitochondrial membrane potential levels were measured using different kits. Apoptosis was identified using Hoechst 33258 and Terminal Deoxynucleotidyl Transferase mediated dUTP Nick-End Labeling (TUNEL) staining. Changes in renal histopathological injury and indicator protein expression in SAKI mice were observed by transmission electron microscopy and pathological staining. Western blot was used to assess the levels of G protein-coupled receptor kinase 5 (GRK5)/NF-κB/nuclear factor erythroid-2 related factor 2 (Nrf2) pathway, apoptosis and mitochondrial damage-related proteins. T-CA (2.5–20 μM) treatment for 24 h did not negatively impact HK-2 cell viability. In vitro, T-CA attenuated LPS-induced HK-2 cell injury while reducing cell mortality, inflammatory factor levels and oxidative stress injury. In vivo, intraperitoneal injection of 40 mg/kg of T-CA attenuated renal histopathological damage and apoptosis in SAKI mice. Additionally, T-CA reduced mitochondrial damage, MDA and ROS levels, and increased SOD, GSH, and ATP levels. T-CA down-regulated GRK5 protein, hindered NF-κB activation and activated Nrf2 pathway, and NF-κB activator Phorbol 12-myristate 13-acetate (PMA), Nrf2 inhibitor ML385 treatment and overexpression of GRK5 weakened the protective effect of T-CA in SAKI model. T-CA has the potential to improve SAKI by inhibiting mitochondrial dysfunction, increase cell viability and ameliorate renal injury through the GRK5/NF-κB/Nrf2 pathway in SAKI models.

Gap junctions are essential channels of communication between cells including neurons in the central nervous system. These channels coordinate cell metabolic and electrical functions including such crucial ones for maintaining homeostasis as cell proliferation, differentiation, survival, and apoptosis. They create narrow passageways that allow rapid exchange of small molecules, ions, and secondary messengers between neighboring cells including the retina and optic nerve. Disruption in normal functioning of gap junctions may result in various neurodegenerative disorders. A comprehensive understanding of gap junction composition, function, and regulation is the key in determining novel approaches to neuroprotection and neuroregeneration. Here, we review the structure and the role of gap junctions in the retina and discuss the life cycle of connexins and their involvement in retinal neurodegenerations.

Ductal carcinoma in situ (DCIS) is a noninvasive precursor of breast cancer with a high potential for progression. Aberrant DNA methylation plays a pivotal role in early tumorigenesis, yet the regulatory mechanisms remain incompletely defined. Integrated bioinformatic analysis of methylation and transcriptomic datasets identified miR-217 as a candidate regulator of DNA methyltransferase 1 (DNMT1). Functional validation was conducted through RT-qPCR, dual-luciferase reporter assays, methylation-specific PCR, chromatin immunoprecipitation, and phenotypic assays in ZR-75-1 cells. An in vivo xenograft model using nude mice was employed to verify the regulatory axis. Expression of miR-217 was significantly reduced in DCIS tissues and inversely correlated with DNMT1 levels. Direct binding between miR-217 and the 3′ untranslated region of DNMT1 was confirmed. Overexpression of miR-217 suppressed DNMT1, resulting in hypomethylation of the teashirt zinc finger homeobox 2 (TSHZ2) promoter and restoration of TSHZ2 expression. Elevated TSHZ2 inhibited Hedgehog-GLI signaling, thereby reducing cell proliferation, migration, invasion, and tumorigenic potential. Reintroduction of DNMT1 or activation of Hedgehog-GLI signaling reversed these effects. In vivo, miR-217 overexpression suppressed tumor growth, downregulated DNMT1 and GLI1, and increased apoptosis. The miR-217/DNMT1/TSHZ2/Hedgehog-GLI signaling axis modulates DCIS progression by epigenetically reprogramming oncogenic pathways. Targeting this axis may offer a promising strategy for DCIS treatment.