Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and...Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.展开更多
目的:寻找影响胃癌发生发展的衰老基因,构建内源竞争性RNA (ceRNA)调控网络,为发掘胃癌有效的诊断、预后生物标志物和治疗靶点提供依据。方法:从癌症基因组图谱(TCGA)数据库下载胃癌的表达数据和临床生存数据,在Aging Atlas数据库中获...目的:寻找影响胃癌发生发展的衰老基因,构建内源竞争性RNA (ceRNA)调控网络,为发掘胃癌有效的诊断、预后生物标志物和治疗靶点提供依据。方法:从癌症基因组图谱(TCGA)数据库下载胃癌的表达数据和临床生存数据,在Aging Atlas数据库中获取衰老基因,使用R软件中“DESeq2”程序包进行差异分析并采用Cox回归及Kaplan-Meier生存分析的方法筛选在胃癌中表达差异且与预后相关的衰老基因。通过Starbase数据库筛选具有靶向关系的miRNAs和lncRNAs,分别进行相关性分析和生存分析用于构建ceRNA调控网络。结果:对502个衰老基因分析显示SERPINE1基因在胃癌组织中显著高表达,且其高表达时患者预后较差。之后以SERPINE1作为关键基因构建一个与胃癌患者预后相关的ceRNA网络,其包含1个mRNA、1个miRNA和1个lncRNA,并以此基因构建胃癌的预后风险模型,最后进行通路、功能及免疫相关性分析。结论:本研究对衰老基因的分析及ceRNA网络的构建有助于进一步探索胃癌发生发展的分子机制,对发现预后标志物和治疗靶点至关重要。Objective: Searching for aging genes affecting the occurrence and development of gastric cancer and constructing competitive endogenous RNA (ceRNA) regulatory networks provide evidence for exploring effective diagnostic and prognostic biomarkers and therapeutic targets of gastric cancer. Methods: Expression data and clinical survival data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Senescence-related genes were obtained from the Aging Atlas database. Differential analysis was performed using the “DESeq2” package in R software. Cox regression and Kaplan-Meier survival analysis methods were employed to screen for senescence-related genes that are differentially expressed in gastric cancer and associated with prognosis. The Starbase database was used to identify miRNAs and lncRNAs with target relationships. Correlation analysis and survival analysis were conducted to construct the ceRNA regulatory network. Results: The analysis of 502 aging genes showed that the SERPINE1 gene was highly expressed in gastric cancer tissues, and the prognosis of patients was poor when it was highly expressed. Then SERPINE1 was used as the key gene to construct a ceRNA network correlated with survival in gastric cancer patients, which included one mRNA, one miRNA, and one lncRNA. The prognostic risk model of gastric cancer was constructed with the SERPINE1 gene. Finally, the pathway, functional enrichment analysis, and immune correlation analysis were carried out. Conclusion: The analysis of aging genes and the construction of the ceRNA network in this study are helpful to further explore the molecular mechanism of the occurrence and development of gastric cancer, which is crucial for the discovery of the prognostic markers and therapeutic targets.展开更多
Background:Effective inhibition of pathological cardiac hypertrophy is critical for managing various cardiovascular diseases,especially in cold environments.The communication between cardiomyocytes and fibroblasts,med...Background:Effective inhibition of pathological cardiac hypertrophy is critical for managing various cardiovascular diseases,especially in cold environments.The communication between cardiomyocytes and fibroblasts,mediated by secreted proteins,plays a significant role in the development and progression of pathological cardiac hypertrophy.Serpin Family E Member 2(serpinE2),secreted by fibroblasts into the extracellular space,has been implicated in this process.However,whether serpinE2 can be internalized by cardiomyocytes and whether cold exposure influences this process remains unclear.Materials and methods:Mice were subjected to cold exposure(4°C,12 h/day for 8 weeks),and cardiac hypertrophy was induced by transverse aortic constriction(TAC).SerpinE2 expression was silenced by short interfering RNA(siRNA).Cardiac fibroblasts were stimulated with angiotensin II(Ang II)to induce serpinE2 secretion.Exogenous recombinant serpinE2,labeled with DyLight 488 or His-tag,was used to evaluate its internalization and functional role in cardiomyocytes.Internalization was inhibited by using antibodies against serpinE2,heparin,or endocytosis inhibitors(β-cyclodextrin,nystatin,dynasore,and chlorpromazine).Chromatin immunoprecipitation followed by quantitative polymerase chain reaction(PCR)was used to assess the binding of the transcription factor CDX1 to the serpinE2 promoter.Results:Cold exposure significantly increased serpinE2 mRNA and protein expression in mouse hearts.SerpinE2 levels were also upregulated in plasma and cardiac tissue following TAC.Knockdown of serpinE2 attenuated TAC-induced hypertrophy,restored left ventricular function,and reduced atrial natriuretic peptide,brain natriuretic peptide,andβ-myosin heavy chain fragment levels.Exogenous serpinE2 promoted cardiomyocyte hypertrophy,an effect that was reversed by serpinE2 knockdown.Co-culture with conditioned medium from Ang II-stimulated fibroblasts increased serpinE2 expression in cardiomyocytes.Exogenous serpinE2 was internalized via endocytosis,which was inhibited by antibodies,heparin,and endocytosis blockers.Internalized serpinE2 activated the protein kinase B(AKT)/β-catenin pathway in cardiomyocytes.CDX1 bound to the serpinE2 promoter and promoted its transcription in fibroblasts.CDX1 overexpression increased serpinE2 and collagen expression,while its suppression had the opposite effect.Administration of exogenous fibroblast growth factor 4(FGF4)or overexpression of FGF4 plasmid upregulated CDX1,serpinE2,and collagen expression in fibroblasts.Conclusions:SerpinE2 expression is responsive to cold stress and mediates intercellular communication between fibroblasts and cardiomyocytes.Fibroblast-secreted serpinE2 is internalized by cardiomyocytes via endocytosis,promoting hypertrophy through activation of the phosphatidylinositol 3-kinase(PI3K)-AKT/β-catenin pathway.The FGF4-CDX1 axis regulates serpinE2 expression and secretion in cardiac fibroblasts.展开更多
背景丝氨酸蛋白酶抑制剂家族E成员1(serine protease inhibitor family E member 1,SERPINE1)蛋白表达与多种癌细胞的增值、迁移和侵袭密切相关,目前缺乏对消化系统疾病的系统研究和报道.目的基于生物信息技术探究SERPINE1调节消化系统...背景丝氨酸蛋白酶抑制剂家族E成员1(serine protease inhibitor family E member 1,SERPINE1)蛋白表达与多种癌细胞的增值、迁移和侵袭密切相关,目前缺乏对消化系统疾病的系统研究和报道.目的基于生物信息技术探究SERPINE1调节消化系统癌症的内在机制.方法使用基因表达谱交互分析(gene expression profile analysis)进行SERPINE1表达分析,并使用Kaplan-Meier分析分析SERPINE1在临床预后中的潜力.结果SERPINE1表达与CD14、CD163以及CCL20相关,SERPINE1高表达可能通过促进巨噬细胞介导炎症,从而参与消化系统癌症的发生和发展.结论SERPINE1高表达可能通过促进巨噬细胞介导炎症,在消化系统癌症炎症和纤维化的调节中发挥重要作用.展开更多
BACKGROUND Gastric cancer(GC)is a malignant tumor originating from gastric mucosal epithelial cells that has high morbidity and mortality.microRNAs(miR)are important diagnostic markers and therapeutic targets in this ...BACKGROUND Gastric cancer(GC)is a malignant tumor originating from gastric mucosal epithelial cells that has high morbidity and mortality.microRNAs(miR)are important diagnostic markers and therapeutic targets in this disease.AIM To explore the mechanism of miR-125a-5p in the pathogenesis of GC.METHODS The expression levels of miR-125a-5p,SERPINE1 and DNMT1 in GC cells and tissues were detected by real-time polymerase chain reaction(PCR)and Western blotting.Methylation-specific PCR was used to detect the level of miR-125a-5p methylation.A cell counting kit 8 assay,scratch test,and a Transwell assay were performed to detect the proliferation,migration,and invasiveness of HGC27 cells,respectively.The expression of the epithelial mesenchymal transition(EMT)-related proteins E-cadherin,N-cadherin and vimentin in HGC27 cells was detected by Western blotting,while the expression of vimentin was detected by immunofluorescence.RESULTS This study revealed that miR-125a-5p was expressed at low levels in GC clinical samples and cells and that miR-125a-5p overexpression inhibited the proliferation,migration,invasiveness and EMT of GC cells.Mechanistically,miR-125a-5p can reduce GC cell proliferation,promote E-cadherin expression,inhibit N-cadherin and vimentin expression,and reduce the EMT of GC cells,thus constraining GC cells to a certain extent.Moreover,DNMT1 inhibited miR-125a-5p expression by increasing the methylation of the miR-125a-5p promoter,thereby promoting the expression of SERPINE1,which acts together with miR-125a-5p to exert antagonistic effects on GC.CONCLUSION Our study revealed that DNMT1 promoted SERPINE1 protein expression by inducing miR-125a-5p methylation,which led to the proliferation,migration and occurrence of EMT in GC cells.展开更多
BACKGROUND The upregulation of serpin family B member 5(SERPINB5)has been linked to the progression of rectal cancer.However,the specific roles and underlying mechanisms of SERPINB5 in rectal cancer are not fully unde...BACKGROUND The upregulation of serpin family B member 5(SERPINB5)has been linked to the progression of rectal cancer.However,the specific roles and underlying mechanisms of SERPINB5 in rectal cancer are not fully understood.AIM To investigate the roles and mechanisms of SERPINB5 in rectal cancer.METHODS SERPINB5 protein level in rectal cancer tissues and cell lines was measured through western blot analysis.SW480 cells were transfected with pcDNASERPINB5 or short-hairpin RNA targeting SERPINB5(sh-SERPINB5).Cell proliferation,invasion,and apoptosis were then evaluated.The interaction between SERPINB5 and heat shock protein 90 alpha class A member 1(HSP90AA1)was confirmed through a co-immunoprecipitation assay.Subsequently,pcDNAHSP90AA1 or sh-HSP90AA1 was transfected into SW480 cells,and cell progression was then detected.Moreover,rescue experiments were used to investigate the effect of the SERPINB5/HSP90AA1 axis on rectal cancer progression.Additionally,sh-SERPINB5-transfected SW480 cells were implanted into nude mice,and xenograft tumor growth was then evaluated.RESULTS SERPINB5 was prominently upregulated in rectal cancer tissues and cells.SERPINB5 overexpression increased SW480 cell proliferation and invasion while reducing apoptosis.In contrast,SERPINB5 knockdown had the opposite effects.Moreover,SERPINB5 could interact with HSP90AA1 and promote HSP90AA1 expression in SW480 cells.HSP90AA1 overexpression facilitated SW480 cell proliferation and invasion and restrained apoptosis.By contrast,HSP90AA1 knockdown suppressed cell progression.The upregulation of HSP90AA1 reversed the SERPINB5 silencing-mediated inhibition of SW480 cell progression.Additionally,SERPINB5 knockdown retarded the growth of rectal cancer tumors in vivo.CONCLUSION SERPINB5 knockdown inhibited rectal cancer cell proliferation and invasion and retarded xenograft tumor growth by inhibiting HSP90AA1 expression.展开更多
A number of studies have confirmed the existence of tissue-type plasminogen activator-independent roles of neuroserpin,a member of the serine protease inhibitor superfamily.In this review article,we aim to clarify thi...A number of studies have confirmed the existence of tissue-type plasminogen activator-independent roles of neuroserpin,a member of the serine protease inhibitor superfamily.In this review article,we aim to clarify this role.These unique roles of neuroserpin are involved in its neuroprotective effect during ischemic brain injury,its regulation of tumorigenesis,and the mediation of emotion and cognition through the inhibition of urokinase-type plasminogen activator and fibrinolysin,modification of Th cells,reducing plaque formation,promoting process growth and intracellular adhesion,and alterina the expression of cadherin and nuclear factor kaooa B.展开更多
基金support from the Sichuan Science and Technology Program(2024JDHJ0043 and 2025YFHZ0121).
文摘Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.
文摘目的:寻找影响胃癌发生发展的衰老基因,构建内源竞争性RNA (ceRNA)调控网络,为发掘胃癌有效的诊断、预后生物标志物和治疗靶点提供依据。方法:从癌症基因组图谱(TCGA)数据库下载胃癌的表达数据和临床生存数据,在Aging Atlas数据库中获取衰老基因,使用R软件中“DESeq2”程序包进行差异分析并采用Cox回归及Kaplan-Meier生存分析的方法筛选在胃癌中表达差异且与预后相关的衰老基因。通过Starbase数据库筛选具有靶向关系的miRNAs和lncRNAs,分别进行相关性分析和生存分析用于构建ceRNA调控网络。结果:对502个衰老基因分析显示SERPINE1基因在胃癌组织中显著高表达,且其高表达时患者预后较差。之后以SERPINE1作为关键基因构建一个与胃癌患者预后相关的ceRNA网络,其包含1个mRNA、1个miRNA和1个lncRNA,并以此基因构建胃癌的预后风险模型,最后进行通路、功能及免疫相关性分析。结论:本研究对衰老基因的分析及ceRNA网络的构建有助于进一步探索胃癌发生发展的分子机制,对发现预后标志物和治疗靶点至关重要。Objective: Searching for aging genes affecting the occurrence and development of gastric cancer and constructing competitive endogenous RNA (ceRNA) regulatory networks provide evidence for exploring effective diagnostic and prognostic biomarkers and therapeutic targets of gastric cancer. Methods: Expression data and clinical survival data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Senescence-related genes were obtained from the Aging Atlas database. Differential analysis was performed using the “DESeq2” package in R software. Cox regression and Kaplan-Meier survival analysis methods were employed to screen for senescence-related genes that are differentially expressed in gastric cancer and associated with prognosis. The Starbase database was used to identify miRNAs and lncRNAs with target relationships. Correlation analysis and survival analysis were conducted to construct the ceRNA regulatory network. Results: The analysis of 502 aging genes showed that the SERPINE1 gene was highly expressed in gastric cancer tissues, and the prognosis of patients was poor when it was highly expressed. Then SERPINE1 was used as the key gene to construct a ceRNA network correlated with survival in gastric cancer patients, which included one mRNA, one miRNA, and one lncRNA. The prognostic risk model of gastric cancer was constructed with the SERPINE1 gene. Finally, the pathway, functional enrichment analysis, and immune correlation analysis were carried out. Conclusion: The analysis of aging genes and the construction of the ceRNA network in this study are helpful to further explore the molecular mechanism of the occurrence and development of gastric cancer, which is crucial for the discovery of the prognostic markers and therapeutic targets.
基金supported by the National Natural Science Foundation of China(82370279,82170299,82330011,82003757).
文摘Background:Effective inhibition of pathological cardiac hypertrophy is critical for managing various cardiovascular diseases,especially in cold environments.The communication between cardiomyocytes and fibroblasts,mediated by secreted proteins,plays a significant role in the development and progression of pathological cardiac hypertrophy.Serpin Family E Member 2(serpinE2),secreted by fibroblasts into the extracellular space,has been implicated in this process.However,whether serpinE2 can be internalized by cardiomyocytes and whether cold exposure influences this process remains unclear.Materials and methods:Mice were subjected to cold exposure(4°C,12 h/day for 8 weeks),and cardiac hypertrophy was induced by transverse aortic constriction(TAC).SerpinE2 expression was silenced by short interfering RNA(siRNA).Cardiac fibroblasts were stimulated with angiotensin II(Ang II)to induce serpinE2 secretion.Exogenous recombinant serpinE2,labeled with DyLight 488 or His-tag,was used to evaluate its internalization and functional role in cardiomyocytes.Internalization was inhibited by using antibodies against serpinE2,heparin,or endocytosis inhibitors(β-cyclodextrin,nystatin,dynasore,and chlorpromazine).Chromatin immunoprecipitation followed by quantitative polymerase chain reaction(PCR)was used to assess the binding of the transcription factor CDX1 to the serpinE2 promoter.Results:Cold exposure significantly increased serpinE2 mRNA and protein expression in mouse hearts.SerpinE2 levels were also upregulated in plasma and cardiac tissue following TAC.Knockdown of serpinE2 attenuated TAC-induced hypertrophy,restored left ventricular function,and reduced atrial natriuretic peptide,brain natriuretic peptide,andβ-myosin heavy chain fragment levels.Exogenous serpinE2 promoted cardiomyocyte hypertrophy,an effect that was reversed by serpinE2 knockdown.Co-culture with conditioned medium from Ang II-stimulated fibroblasts increased serpinE2 expression in cardiomyocytes.Exogenous serpinE2 was internalized via endocytosis,which was inhibited by antibodies,heparin,and endocytosis blockers.Internalized serpinE2 activated the protein kinase B(AKT)/β-catenin pathway in cardiomyocytes.CDX1 bound to the serpinE2 promoter and promoted its transcription in fibroblasts.CDX1 overexpression increased serpinE2 and collagen expression,while its suppression had the opposite effect.Administration of exogenous fibroblast growth factor 4(FGF4)or overexpression of FGF4 plasmid upregulated CDX1,serpinE2,and collagen expression in fibroblasts.Conclusions:SerpinE2 expression is responsive to cold stress and mediates intercellular communication between fibroblasts and cardiomyocytes.Fibroblast-secreted serpinE2 is internalized by cardiomyocytes via endocytosis,promoting hypertrophy through activation of the phosphatidylinositol 3-kinase(PI3K)-AKT/β-catenin pathway.The FGF4-CDX1 axis regulates serpinE2 expression and secretion in cardiac fibroblasts.
文摘背景丝氨酸蛋白酶抑制剂家族E成员1(serine protease inhibitor family E member 1,SERPINE1)蛋白表达与多种癌细胞的增值、迁移和侵袭密切相关,目前缺乏对消化系统疾病的系统研究和报道.目的基于生物信息技术探究SERPINE1调节消化系统癌症的内在机制.方法使用基因表达谱交互分析(gene expression profile analysis)进行SERPINE1表达分析,并使用Kaplan-Meier分析分析SERPINE1在临床预后中的潜力.结果SERPINE1表达与CD14、CD163以及CCL20相关,SERPINE1高表达可能通过促进巨噬细胞介导炎症,从而参与消化系统癌症的发生和发展.结论SERPINE1高表达可能通过促进巨噬细胞介导炎症,在消化系统癌症炎症和纤维化的调节中发挥重要作用.
基金the Research Program of the Science and Technology Department of Yunnan Province,No.202101AY070001-204.
文摘BACKGROUND Gastric cancer(GC)is a malignant tumor originating from gastric mucosal epithelial cells that has high morbidity and mortality.microRNAs(miR)are important diagnostic markers and therapeutic targets in this disease.AIM To explore the mechanism of miR-125a-5p in the pathogenesis of GC.METHODS The expression levels of miR-125a-5p,SERPINE1 and DNMT1 in GC cells and tissues were detected by real-time polymerase chain reaction(PCR)and Western blotting.Methylation-specific PCR was used to detect the level of miR-125a-5p methylation.A cell counting kit 8 assay,scratch test,and a Transwell assay were performed to detect the proliferation,migration,and invasiveness of HGC27 cells,respectively.The expression of the epithelial mesenchymal transition(EMT)-related proteins E-cadherin,N-cadherin and vimentin in HGC27 cells was detected by Western blotting,while the expression of vimentin was detected by immunofluorescence.RESULTS This study revealed that miR-125a-5p was expressed at low levels in GC clinical samples and cells and that miR-125a-5p overexpression inhibited the proliferation,migration,invasiveness and EMT of GC cells.Mechanistically,miR-125a-5p can reduce GC cell proliferation,promote E-cadherin expression,inhibit N-cadherin and vimentin expression,and reduce the EMT of GC cells,thus constraining GC cells to a certain extent.Moreover,DNMT1 inhibited miR-125a-5p expression by increasing the methylation of the miR-125a-5p promoter,thereby promoting the expression of SERPINE1,which acts together with miR-125a-5p to exert antagonistic effects on GC.CONCLUSION Our study revealed that DNMT1 promoted SERPINE1 protein expression by inducing miR-125a-5p methylation,which led to the proliferation,migration and occurrence of EMT in GC cells.
基金Supported by the Medical Science Research Project Plan of the Hebei Provincial Health Commission,No.20210027.
文摘BACKGROUND The upregulation of serpin family B member 5(SERPINB5)has been linked to the progression of rectal cancer.However,the specific roles and underlying mechanisms of SERPINB5 in rectal cancer are not fully understood.AIM To investigate the roles and mechanisms of SERPINB5 in rectal cancer.METHODS SERPINB5 protein level in rectal cancer tissues and cell lines was measured through western blot analysis.SW480 cells were transfected with pcDNASERPINB5 or short-hairpin RNA targeting SERPINB5(sh-SERPINB5).Cell proliferation,invasion,and apoptosis were then evaluated.The interaction between SERPINB5 and heat shock protein 90 alpha class A member 1(HSP90AA1)was confirmed through a co-immunoprecipitation assay.Subsequently,pcDNAHSP90AA1 or sh-HSP90AA1 was transfected into SW480 cells,and cell progression was then detected.Moreover,rescue experiments were used to investigate the effect of the SERPINB5/HSP90AA1 axis on rectal cancer progression.Additionally,sh-SERPINB5-transfected SW480 cells were implanted into nude mice,and xenograft tumor growth was then evaluated.RESULTS SERPINB5 was prominently upregulated in rectal cancer tissues and cells.SERPINB5 overexpression increased SW480 cell proliferation and invasion while reducing apoptosis.In contrast,SERPINB5 knockdown had the opposite effects.Moreover,SERPINB5 could interact with HSP90AA1 and promote HSP90AA1 expression in SW480 cells.HSP90AA1 overexpression facilitated SW480 cell proliferation and invasion and restrained apoptosis.By contrast,HSP90AA1 knockdown suppressed cell progression.The upregulation of HSP90AA1 reversed the SERPINB5 silencing-mediated inhibition of SW480 cell progression.Additionally,SERPINB5 knockdown retarded the growth of rectal cancer tumors in vivo.CONCLUSION SERPINB5 knockdown inhibited rectal cancer cell proliferation and invasion and retarded xenograft tumor growth by inhibiting HSP90AA1 expression.
基金supported by the National Natural Science Foundation of China,No.30700908,30772343 and 30973215
文摘A number of studies have confirmed the existence of tissue-type plasminogen activator-independent roles of neuroserpin,a member of the serine protease inhibitor superfamily.In this review article,we aim to clarify this role.These unique roles of neuroserpin are involved in its neuroprotective effect during ischemic brain injury,its regulation of tumorigenesis,and the mediation of emotion and cognition through the inhibition of urokinase-type plasminogen activator and fibrinolysin,modification of Th cells,reducing plaque formation,promoting process growth and intracellular adhesion,and alterina the expression of cadherin and nuclear factor kaooa B.
