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PubMed2025

Escape from TGF-β-induced senescence promotes aggressive hallmarks in epithelial hepatocellular carcinoma cells.

Transforming growth factor-β (TGF-β) signaling and cellular senescence are key hallmarks of hepatocellular carcinoma (HCC) pathogenesis. Despite provoking senescence-associated growth arrest in epithelial HCC cells, elevated TGF-β activity paradoxically correlates with increased aggressiveness and poor prognosis in advanced tumors. Whether the transition between these dichotomous functions involves modulation of the senescence phenotype during disease progression remains elusive. Exploiting the epithelial HCC cell line Huh7 as a robust model, we demonstrate that chronic exposure to TGF-β prompts escape from Smad3-mediated senescence, leading to the development of TGF-β resistance. This altered state is characterized by an optimal proliferation rate and the acquisition of molecular and functional traits of less-differentiated mesenchymal cells, coinciding with differential growth capacity in 2D and 3D culture conditions, epithelial-to-mesenchymal transition (EMT), and increased invasiveness in vitro, and metastasis in vivo. Mechanistically, resistant cells exhibit defective activation and nuclear trafficking of Smad molecules, particularly Smad3, as ectopic activation of the TGF-β/Smad3 axis is able to reinstate TGF-β sensitivity. An integrated transcriptomic landscape reveals both shared and distinct gene signatures associated with senescent and TGF-β resistant states. Importantly, genetic ablation and molecular studies identify microtubule affinity regulating kinase 1 (MARK1) and glutamate metabotropic receptor 8 (GRM8) as critical modulators of the resistance phenomenon, potentially by impairing spatiotemporal signaling dynamics of Smad activity. Our findings unveil a novel phenomenon wherein epithelial HCC cells may exploit senescence plasticity as a mechanism to oppose TGF-β anti-tumor responses and progress towards more aggressive HCC phenotypes.

Humans↗

PubMed2025

A First-in-Class Chemical-Induced Proximity System Achieves Dose-Dependent Control of Tumor Protein P53 Gene Activation in Preclinical Models of Gastric Cancer.

The tumor protein P53 (TP53) gene has long been studied in cancer research with genomic and epigenetic aberrations playing a driving role in cancer pathology, yet even after decades of work, only a few methods have been developed to specifically target TP53 therapeutically. Some cancers are driven by loss-of-function TP53 mutations, while others have wild-type TP53 in a transcriptionally repressed state; the latter is exploitable by advances in epigenome editing. In our previous work, we demonstrated that deactivated CRISPR/Cas9 systems (dCas9), combined with an FK-506-binding protein (FKBP) recruitment protein tag and chemical epigenetic modifier (CEM) small molecules, can elicit gene-specific changes in expression in a dose-dependent manner. Here, we describe the development, application, and characterization of the dCas9-FKBP-CEM technology to increase TP53 expression. We demonstrate that catalyzing increased TP53 expression via dCas9-FKBP-CEM87 induced apoptosis, cell cycle arrest, and tumor growth inhibition in a dose-dependent manner in preclinical models of gastric cancer.

CRISPR↗

PubMed2024

It's complicated: relationships between integrative and conjugative elements and their bacterial hosts.

Integrative and conjugative elements (ICEs) are typically found integrated in a bacterial host chromosome. They can excise, replicate, and transfer from cell to cell. Many contain genes that confer phenotypes to host cells, including antibiotic resistances, specialized metabolisms, phage defense, and symbiosis or pathogenesis determinants. Recent studies revealed that at least three ICEs (ICEclc, Tn916, and TnSmu1) cause growth arrest or death of host cells upon element activation. This review highlights the complex interactions between ICEs and their hosts, including the recent examples of the significant costs to host cells. We contrast two examples of killing, ICEclc and Tn916, in which killing, respectively, benefits or impairs conjugation and emphasize the importance of understanding the impacts of ICE-host relationships on conjugation. ICEs are typically only active in a small fraction of cells in a population, and we discuss how phenotypes normally occurring in a small subset of host cells can be uncovered.

Conjugation, Genetic↗

PubMed2026

Bovine Colostrum-Derived Extracellular Vesicles Impair Cancer Cell Proliferation Through Transcriptional Dysregulation.

Milk-derived extracellular vesicles (EVs) are a promising source of molecules with therapeutic potential. Bovine colostrum is particularly enriched in EVs, which carry cargo of proteins involved in immune regulation, development and cellular signalling. Some studies have explored their role as bioactive anti-cancer agents, however, their mechanistic effects remain underexplored. Here, we show that colostrum-derived EVs (Col-EVs) exert anti-proliferative effects in gastrointestinal cancer models, including cell lines and patient-derived organoids, which is independent of apoptosis induction. Using a multi-modal approach combining proteomics, imaging and functional assays, we demonstrate that Col-EVs induce a reversible growth-arrest state, characterized by widespread transcriptional and RNA-processing dysregulation, chromatin compaction, nuclear reorganization and cytoskeletal remodelling. Proteomic analyses reveal that Col-EV treatment disrupts key components of the transcriptional machinery and cell cycle regulatory pathways, effects that are reversible upon EV withdrawal and can be rescued pharmacologically using an EZH2 inhibitor. Col-EVs enhance the sensitivity of cancer cells as well to DNA-targeting chemotherapies such as 5-fluorouracil, indicating their potential as modulatory adjuvants rather than cytotoxic agents. Overall, our findings reveal that Col-EVs can reversibly suppress cancer cell proliferation by reprogramming transcriptional and nuclear architecture, offering a natural, biocompatible strategy for modulating tumour growth and sensitizing cancer cells to conventional therapies.

Extracellular Vesicles↗

PubMed2026

FANCI promotes esophageal squamous cell carcinoma progression and cell cycle regulation and interacts with FANCD2.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor clinical outcomes, and reliable molecular biomarkers and therapeutic targets remain limited. Fanconi anemia group I protein (FANCI) is a core component of the Fanconi anemia (FA) pathway, but its expression pattern, clinical significance, and functional role in ESCC have not been comprehensively defined. This study aimed to investigate FANCI expression and prognostic value in ESCC, assess its effects on malignant cellular phenotypes and tumor growth, and explore its potential mechanistic relationship with Fanconi anemia group D2 protein (FANCD2) and cell-cycle regulation. METHODS: Multi-cohort analyses were performed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, together with ESCC single-cell RNA sequencing (RNA-seq) data. FANCI functions were assessed by bidirectional gain- and loss-of-function experiments in vitro (proliferation, colony formation, migration, invasion, apoptosis, and cell-cycle assays) and by xenograft models in vivo. Mechanistic studies included protein-protein interaction (PPI) analyses, co-immunoprecipitation (Co-IP), and immunofluorescence (IF) colocalization. RESULTS: FANCI was consistently upregulated in ESCC across bulk transcriptomic datasets and was further supported by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC). FANCI discriminated ESCC from normal tissues in TCGA-ESCC and was independently validated in GSE53624 [area under the curve (AUC) =0.940 and 0.975, respectively]. FANCI was associated with poorer overall survival (OS) and shorter disease-free interval (DFI), and these findings were validated in an independent GEO cohort. Functionally, FANCI promoted ESCC cell proliferation, migration, and invasion, while inhibiting apoptosis; FANCI knockdown suppressed tumor growth in vivo and induced G2/M cell-cycle arrest. Mechanistically, FANCI physically interacted with FANCD2, colocalized with FANCD2 in the nucleus, and was associated with altered FANCD2 protein abundance, consistent with cell-cycle and DNA repair-related programs. Single-cell analysis indicated that FANCI was enriched in epithelial cells and associated with higher activity of malignant functional programs. In TCGA-ESCC, FANCI-high tumors showed distinct mutation profiles, a trend toward increased tumor mutation burden (TMB), and altered immune-associated signatures. CONCLUSIONS: FANCI is upregulated in ESCC and is associated with diagnostic and prognostic value. It promotes malignant phenotypes and tumor growth, potentially through a FANCI-FANCD2-linked cell-cycle/DNA repair program, supporting FANCI as a candidate biomarker and therapeutic target in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗

PubMed2026

LncRNA DNAJC3-AS1 promotes gastric cancer malignancy through miR-576-5p-mediated upregulation of LYPLA1.

Long non-coding RNAs (lncRNAs) are involved in tumor progression, but the role of lnc-DNAJC3-AS1 in gastric cancer (GC) remains unclear. This study aimed to investigate the biological function and regulatory mechanism of lnc-DNAJC3-AS1 in GC. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression levels of lnc-DNAJC3-AS1, miR-576-5p, and LYPLA1, and Western blot was used to analyze protein expression. The Cancer Genome Atlas (TCGA) database and clinical samples were used to evaluate their clinical relevance. Cell viability, cell cycle distribution, apoptosis, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing, Transwell, and immunofluorescence assays. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and rescue assays were performed to explore the potential regulatory relationship among lnc-DNAJC3-AS1, miR-576-5p, and LYPLA1. A xenograft tumor model was also established to evaluate the role of lnc-DNAJC3-AS1 in vivo. The results showed that lnc-DNAJC3-AS1 and LYPLA1 were upregulated, whereas miR-576-5p was downregulated in GC tissues and cells. Knockdown of lnc-DNAJC3-AS1 inhibited GC cell viability, migration, and invasion, induced G0/G1 phase arrest and apoptosis, and suppressed tumor growth in vivo. Mechanistically, lnc-DNAJC3-AS1 was mainly localized in the cytoplasm and was associated with miR-576-5p-related RNA-induced silencing complex (RISC) complexes. MiR-576-5p targeted LYPLA1, and restoration of miR-576-5p or knockdown of LYPLA1 partially attenuated the effects of lnc-DNAJC3-AS1 overexpression on GC cell phenotypes and LYPLA1 enzymatic activity. These findings suggest that lnc-DNAJC3-AS1 promotes GC progression, at least in part, through the miR-576-5p/LYPLA1 pathway, providing a potential target for GC treatment.

Gastric cancer↗

PubMed2020

Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer.

BACKGROUND: Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy. RESULTS: Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. CONCLUSIONS: The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.

Animals↗

PubMed2025

Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.

Polyploid Giant Cancer Cells (PGCCs) occur across multiple cancer types and are associated with therapy resistance, genome instability, disease progression, and metastasis. PGCCs can grow through endocycles, a variant cell cycle of alternating Growth (G) and DNA Synthesis (S) phases without cell division. Unlike programmed endocycles that occur during normal tissue development, PGCCs switch from mitotic cycles to unscheduled endocycles in response to stress. PGCCs can subsequently return to error-prone divisions which generate aneuploid daughter cells that contribute to disease progression. However, the regulation of PGCC cell cycles and contributions to cancer are still being defined. Filling this knowledge gap will lead to the development of improved cancer therapies. In this study, we used a molecular-genetic system in the model organism Drosophila melanogaster to examine how oncogenes interact with unscheduled endocycles in vivo. We found that several oncogenes promote bypass of an endocycle arrest, resulting in increased polyploid cell size and DNA content. The extent of this increased growth was dependent on the type of oncogenic mutation. When these polyploid cells returned to division, RasG12V promoted continued divisions of polyploid daughter cells with elevated genome instability. RasG12V expression during transient endocycles and subsequent divisions also induced expression of a matrix metalloprotease and a Wnt pathway ligand. Importantly, RasG12V with transient endocycles enhanced the growth of large, neoplastic tumors. These findings indicate that oncogenic mutations can synergize with transient, unscheduled endocycles to promote tumorigenesis with important broader implications for cancer prognosis and therapies.

Animals↗

PubMed2026

Increased expression of Ribonucleic acid export 1 (RAE1) gene promotes gastric carcinogenesis and is associated with Hippo signaling pathway.

BACKGROUND: Ribonucleic acid export 1 (RAE1) autoantibody may have good potential for early detection of gastric cancer (GC). However, the carcinogenicity of RAE1 in GC remains unknown. We aimed to explore the role and the potential mechanism for RAE1 in the carcinogenesis of GC. METHODS: Immunohistochemical assay was applied to analyze the expression of RAE1 in GC and precancerous lesion (PL) tissues and its relationship with clinical characteristics. The effects of RAE1 on proliferation, migration, apoptosis, and cell cycle were explored by constructing RAE1 knockdown and overexpression in GC cells. The effects of RAE1 knockdown on tumor growth were observed in a murine xenograft model. The signaling pathways involved in GC development that may be affected by RAE1 were investigated by transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: Immunohistochemical expression of RAE1 was significantly higher in early GC patients than in PL and normal tissues, and the RAE1 expression was correlated with clinical stage (P<0.001). In vitro, knockdown of RAE1 inhibited the proliferation and migration of GC cells with promoted apoptosis and arrested cell cycle in the S phase, while overexpression of RAE1 showed the opposite trend. In vivo, knockdown of RAE1 inhibited the growth of subcutaneous graft tumors in mice. Transcriptome sequencing and subsequent analysis of RAE1 knockdown cells revealed that the Hippo signaling pathway was activated by RAE1 knockdown. CONCLUSIONS: RAE1 promotes GC cells proliferation and migration and is associated with the inhibition of the Hippo signaling pathway, and may be a potential biomarker for early diagnosis and treatment of GC.

Gastric cancer (GC)↗

PubMed2025

ALDOC and PGK1 coordinately induce glucose metabolism reprogramming and promote development of colorectal cancer.

Colorectal cancer (CRC) remains a significant health challenge globally, demanding a comprehensive understanding of its molecular underpinnings for effective management. In this study, we investigated the role of Aldolase C (ALDOC), a glycolytic enzyme, in CRC pathogenesis. Transcriptomic analysis of CRC tissues from The Cancer Genome Atlas (TCGA) revealed a substantial upregulation of ALDOC, correlating with adverse clinical outcomes. Immunohistochemical (IHC) staining of locally collected patient-derived tissues corroborated these findings, demonstrating elevated ALDOC expression in tumor tissues, particularly in advanced stages. Functional studies elucidated the regulatory role of ALDOC in CRC cell phenotypes. ALDOC knockdown significantly inhibited cell proliferation, induced apoptosis, arrested cell cycle progression, and suppressed cell migration in vitro. Moreover, in vivo studies using xenograft models confirmed that ALDOC knockdown attenuated tumor growth. Mechanistically, ALDOC was found to interact with hypoxia-inducible factor 1 alpha (HIF1A) and enhance its transcriptional activity on phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme. Dual-luciferase reporter assays and chromatin immunoprecipitation experiments validated the ALDOC-mediated transcriptional activation of PGK1. Further functional rescue experiments revealed a synergistic interplay between ALDOC and PGK1 in regulating CRC cell phenotypes. Additionally, ALDOC was implicated in promoting aerobic glycolysis in CRC cells, potentially through PGK1 regulation. Collectively, our findings unveil ALDOC as a critical regulator of CRC pathogenesis, offering insights into its potential as a therapeutic target and highlighting the ALDOC/PGK1 axis as a promising avenue for further investigation in CRC.

Humans↗

PubMed2026

A refined MASH-HCC model identifies macrophage Gadd45b as a key orchestrator of inflammation-driven neoplastic progression.

Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a leading driver of hepatocellular carcinoma (HCC), yet the molecular mechanisms linking metabolic stress, chronic inflammation and tumorigenesis remain poorly understood. Here we established a metabolically relevant, time-efficient MASH-to-HCC model in C57BL/6N mice by combining a MASH diet with controlled CCl4 administration, enabling stepwise recapitulation of MASH-associated neoplastic progression. Using this model, we identified growth arrest and DNA damage 45b (Gadd45b) as a novel MASH-derived protumorigenic regulator selectively activated under metabolic stress. Integrated analyses of human bulk and single-cell transcriptomic datasets and mouse transcriptomic deconvolution revealed concordant macrophage remodeling and GADD45B/Gadd45b expression dynamics during MASH-to-HCC progression. Mechanistically, fatty acids and TNFα preferentially induced Gadd45b in macrophages, where it amplified TNFα-NF-κB signaling. Macrophage-derived inflammatory signals subsequently induced Gadd45b and NF-κB activation in hepatocytes, establishing a feed-forward inflammatory loop that promoted fibrogenic and partial EMT-like programs and tumor spheroid formation. Importantly, temporal profiling during spheroid formation and progression revealed transient induction of Gadd45b during early spheroid establishment, but not during later progression, indicating that Gadd45b-mediated inflammatory signaling primarily promotes tumor initiation rather than subsequent growth. Consistent with human data, Gadd45b expression increased with disease severity and positively correlated with inflammatory factors in the MASH-HCC model, whereas pharmacological inhibition attenuated the Gadd45b-inflammation signaling axis. Collectively, our findings establish macrophage Gadd45b as a key orchestrator linking metabolic stress, chronic inflammation, and neoplastic transformation during MASH-to-HCC progression. Our refined MASH-HCC model provides a robust platform for mechanistic studies and preclinical evaluation of inflammation-targeted therapies.

Journal Article↗

PubMed2025

Protein overabundance is driven by growth robustness.

Protein expression levels optimize cell fitness: Too low an expression level of essential proteins will slow growth by compromising essential processes; whereas overexpression slows growth by increasing the metabolic load. This trade-off naïvely predicts that cells maximize their fitness by sufficiency, expressing just enough of each essential protein for function. We test this prediction in the naturally-competent bacterium Acinetobacter baylyi by characterizing the proliferation dynamics of essential-gene knockouts at a single-cell scale (by imaging) as well as at a genome-wide scale. In these experiments, cells proliferate for multiple generations as target protein levels are diluted from their endogenous levels. This approach facilitates a proteome-scale analysis of the fitness landscape with respect to protein abundance. We find that most essential proteins are subject to a threshold-like fitness landscape: growth is independent of protein abundance above a critical threshold and arrests below that threshold. We have recently analyzed the implications of this landscape for growth robustness. Confirming signature predictions of this model, we find that (i) roughly 70% of essential proteins are overabundant, (ii) overabundance increases as the expression level decreases and (iii) the lowest abundance proteins are in vast excess (>10×) of what is required for growth in the typical cell. These results reveal that robustness plays a fundamental role in determining the expression levels of essential genes and that overabundance is a key mechanism for ensuring robust growth.

Journal Article↗

PubMed2026

Novel association of NAV3 with dilated cardiomyopathy and its role in cardiac fibrosis.

A genome-wide association study (GWAS) identified neuron navigator 3 (NAV3) as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicate that NAV3 expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with transforming growth factor β1 (TGF-β1) induced NAV3 expression in a dose and time-dependent manner. Small-interfering-RNA-mediated knockdown of NAV3 significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-smooth muscle actin (α-SMA), collagens, and fibronectin. RNA sequencing of NAV3-silenced fibroblasts, confirmed by Western blot, revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, NAV3 silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into NAV3's novel role in cardiac fibrosis, showing that reduced NAV3 expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM.NEW & NOTEWORTHY This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Humans↗

PubMed2004

Ternary complex factor-serum response factor complex-regulated gene activity is required for cellular proliferation and inhibition of apoptotic cell death.

Members of the ternary complex factor (TCF) subfamily of the ETS-domain transcription factors are activated through phosphorylation by mitogen-activated protein kinases (MAPKs) in response to a variety of mitogenic and stress stimuli. The TCFs bind and activate serum response elements (SREs) in the promoters of target genes in a ternary complex with a second transcription factor, serum response factor (SRF). The association of TCFs with SREs within immediate-early gene promoters is suggestive of a role for the ternary TCF-SRF complex in promoting cell cycle entry and proliferation in response to mitogenic signaling. Here we have investigated the downstream gene regulatory and phenotypic effects of inhibiting the activity of genes regulated by TCFs by expressing a dominantly acting repressive form of the TCF, Elk-1. Inhibition of ternary complex activity leads to the downregulation of several immediate-early genes. Furthermore, blocking TCF-mediated gene expression leads to growth arrest and triggers apoptosis. By using mutant Elk-1 alleles, we demonstrated that these effects are via an SRF-dependent mechanism. The antiapoptotic gene Mcl-1 is identified as a key target for the TCF-SRF complex in this system. Thus, our data confirm a role for TCF-SRF-regulated gene activity in regulating proliferation and provide further evidence to indicate a role in protecting cells from apoptotic cell death.

Alleles↗

PubMed2026

Transcription Factor SP1 Drives Myocardial Ischemia/reperfusion Injury By Transcription Activation-mediated GADD45G Upregulation.

Myocardial ischemia-reperfusion injury (MIRI) is an unresolved clinically fatal complication in the management of acute myocardial infarction (AMI). Growth arrest and DNA damage-inducible gene 45 Gamma (GADD45G) plays a vital role in the regulation of MIRI. However, the underlying mechanisms remain unclear. GADD45G and SP1 expression were upregulated in hypoxia/reoxygenation (H/R)-treated H9C2 cells. H/R treatment repressed H9C2 cell viability, and induced apoptosis, oxidative stress, and inflammatory response. Moreover, GADD45G deficiency could relieve H/R-triggered H9C2 cell injury. In mechanism, SP1 was a transcription factor of GADD45G and activated the transcription of GADD45G via binding to its promoter region. Besides, SP1 knockdown alleviated MI/R-induced pathological damage in the myocardial tissue of rats by regulating GADD45G. In conclusion, SP1 could promote H/R-induced cardiomyocyte injury and MI/R-caused rat myocardial tissue pathological injury by increasing GADD45G, providing a promising therapeutic target for MIRI treatment.

Animals↗

PubMed2026

Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.

UNLABELLED: Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in patients with recurrent high-grade glioma treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAM), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the TME. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2-M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62, and autophagosome accumulation and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and damage-associated molecular patterns (DAMP), such as IL1β, HMGB1, and extracellular ATP. Coculturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and proinflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the antitumor therapeutic efficacy of OD-0J1. SIGNIFICANCE: Leveraging JAG1 antagonism in the context of oncolytic virotherapy rewires macrophage polarization within the tumor microenvironment, which has wide implications for sensitizing tumors to antibodies, senolytic agents, and BiTE therapies.

Humans↗

PubMed2026

Protective TGFβ2/SMAD3 axis identified by TWAS in papillary thyroid cancer.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Although generally indolent, a subset shows aggressive behaviour. Furthermore, the genetic heterogeneity of PTC is not fully explained by known driver mutations, underscoring the need to identify additional susceptibility genes and regulatory mechanisms. To identify additional susceptibility genes and regulatory mechanisms, we integrated transcriptome-wide association studies (TWAS) with summary-data-based Mendelian randomisation (SMR), joint/conditional testing (JCT), and colocalisation analyses across multiple independent cohorts, followed by heterogeneity in dependent instruments (HEIDI) test. Gene prioritisation analyses consistently highlighted TGFB2 and SMAD3 as candidate susceptibility genes for PTC, with SMR supporting putative protective effects. Besides, GEPIA confirmed the positive correlation between TGFB2 and SMAD3 expression in TCGA-THCA. Functional experiments in TPC-1 cells showed that TGFβ2 treatment inhibited cell proliferation and migration, induced apoptosis, and resulted in G0/G1 cell-cycle arrest, accompanied by increased SMAD3 phosphorylation, suggesting activation of canonical TGFβ signalling. Collectively, these findings bridge population-based genetic inference with mechanistic validation and suggest convergent evidence supporting a tumour-suppressive role of the TGFβ2/SMAD3 axis in PTC.

Humans↗

PubMed2024

A pyruvate transporter in the apicoplast of apicomplexan parasites.

Pyruvate lies at a pivotal node of carbon metabolism in eukaryotes. It is involved in diverse metabolic pathways in multiple organelles, and its interorganelle shuttling is crucial for cell fitness. Many apicomplexan parasites harbor a unique organelle called the apicoplast that houses metabolic pathways like fatty acid and isoprenoid precursor biosyntheses, requiring pyruvate as a substrate. However, how pyruvate is supplied in the apicoplast remains enigmatic. Here, deploying the zoonotic parasite Toxoplasma gondii as a model apicomplexan, we identified two proteins residing in the apicoplast membranes that together constitute a functional apicoplast pyruvate carrier (APC) to mediate the import of cytosolic pyruvate. Depletion of APC results in reduced activities of metabolic pathways in the apicoplast and impaired integrity of this organelle, leading to parasite growth arrest. APC is a pyruvate transporter in diverse apicomplexan parasites, suggesting a common strategy for pyruvate acquisition by the apicoplast in these clinically relevant intracellular pathogens.

Apicoplasts↗