Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation an...Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAAs and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway, leading to the secretion of multiple cytokines and proteases, particularly C–X–C motif chemokine ligand 3 (CXCL3). Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, enhancing the mesenchymal phenotype, migration, and invasion of breast cancer cells. In addition, a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.展开更多
Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote i...Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.展开更多
Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LP...Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LPS)-induced septic rat model,revealed the hyperphosphorylation of tau and cognitive impairments,accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats.Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10)as a central regulator of neuroinflammation.LPS triggered CXCL10 secretion in astrocytes,and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits.Recombinant CXCL10 recapitulated these effects in vitro and in vivo.Blocking CXCL10–CXCR3 interaction reversed tau phosphorylation,synaptic impairment,and cognitive decline.Mechanistically,CXCL10–CXCR3 interaction activated CaMKII,driving tau hyperphosphorylation,while CaMKII inhibition restored synaptic protein levels.These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10–CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.展开更多
基金supported by grants from the National Natural Science Foundation of China(NSFC)(82260531 and 81760509)the Natural Science Foundation of Jiangxi Province of China(20181BAB205043 and 20224BAB206057)to X.X.
文摘Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAAs and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway, leading to the secretion of multiple cytokines and proteases, particularly C–X–C motif chemokine ligand 3 (CXCL3). Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, enhancing the mesenchymal phenotype, migration, and invasion of breast cancer cells. In addition, a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.
基金supported by the National Natural Science Foundation of China(Grant No.82060479)Key Research and Development Program of Ningxia Hui Autonomous Region(Grant No.2021BEG03062)Ningxia Natural Science Fund Key Project(Grant No.2024AAC02080).
文摘Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.
基金supported by Grants from the National Natural Science Foundation of China(82330041 and 82201326)the China Postdoctoral Research Foundation(GZC20230898)the Science and Technology Innovation Team Project to Xiaochuan Wang from the Department of Science and Technology of Hubei Province(2022-72-18).
文摘Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LPS)-induced septic rat model,revealed the hyperphosphorylation of tau and cognitive impairments,accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats.Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10)as a central regulator of neuroinflammation.LPS triggered CXCL10 secretion in astrocytes,and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits.Recombinant CXCL10 recapitulated these effects in vitro and in vivo.Blocking CXCL10–CXCR3 interaction reversed tau phosphorylation,synaptic impairment,and cognitive decline.Mechanistically,CXCL10–CXCR3 interaction activated CaMKII,driving tau hyperphosphorylation,while CaMKII inhibition restored synaptic protein levels.These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10–CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.
