STAT2是信号转导和转录激活因子(signal transducers and activators of transcription,STAT)家族中的一员,它被激活后转入细胞核内与特异性DNA结合,影响基因转录,参与细胞的生长、分化、生存和凋亡。重要的是,目前研究表明,STAT2基因...STAT2是信号转导和转录激活因子(signal transducers and activators of transcription,STAT)家族中的一员,它被激活后转入细胞核内与特异性DNA结合,影响基因转录,参与细胞的生长、分化、生存和凋亡。重要的是,目前研究表明,STAT2基因缺失或过表达对肿瘤发生发展有着重要影响,与肿瘤血管生成、肿瘤增殖及肿瘤凋亡密切相关,并且在肿瘤的干扰素治疗中扮演着重要角色。本文就STAT2与肿瘤研究进展做一综述。展开更多
Objective:To measure the expression pattern of STAT2 in cenical cancer initiation and progression in tissue sections from patients with cervicitis,dysplasia,and cenical cancer. Methods:Antibody against human STAT2 was...Objective:To measure the expression pattern of STAT2 in cenical cancer initiation and progression in tissue sections from patients with cervicitis,dysplasia,and cenical cancer. Methods:Antibody against human STAT2 was confirmed by plasmids transient transfection and Western blot Immunohistochemistry was used to delect STAT2 expression in the cervical biopsies by using the confirmed antibody against STAT2 as the primary antibody.Results:It was found that the overall rate of positive STAT2 expression in the cervicitis,dysplasia and cenical cancer groups were 38.5%,69.49%and 76.991,respectively.The STAT2 levels are significantly increased in premalignant dysplasia and cervical cancer,as compared lo cervicitis(P【 0.05). Noticeably,STAT2 signals were mainly found in the cytoplasm,implying that STAT2 was not biologically active.Conclusions:These findings reveal an association between cenical cancer progression and augmented STAT2 expression.In conclusion.STAT2 increase appears to be an early detectable cellular event in cenical cancer development.展开更多
目的研究慢性丙型病毒性肝炎患者外周血单核细胞(PBMC)中2’,5’寡腺苷酸合成酶(2’,5’-Oligoadenylate synthetase,2-5AS)的表达及其传导与转录激活因子(Signal transducer and activator of transcription,Stat)Stat1和Stat2等的水...目的研究慢性丙型病毒性肝炎患者外周血单核细胞(PBMC)中2’,5’寡腺苷酸合成酶(2’,5’-Oligoadenylate synthetase,2-5AS)的表达及其传导与转录激活因子(Signal transducer and activator of transcription,Stat)Stat1和Stat2等的水平相关性分析。方法选择60例慢性丙肝患者,抽取外周血分离PBMC。首先测定每份标本的2-5AS活性。然后将所有丙肝患者的PBMC标本按按编号单双数分为对照组和实验组,进行体外培养。其中,对照组PBMC不添加干扰素α(interferon alpha,IFN-α),而实验组PBMC添加1000IU/ml IFN-α。体外培养大约24小时后,测定PBMC中2-5AS活性、Stat1和Stat2等的表达量。结果和对照组相比,实验组PBMC的2-5AS活性明显升高(P<0.05)。实验组PBMC中,在2-5AS活性增高的同时,Stat1和Stat2等表达量也呈现明显增多的趋势(P<0.05)。结论基础的2-5AS活性与加入IFNα刺激培养后Stat1的改变幅度呈负相关(P<0.05);2-5AS基础水平和IFNα刺激后的Stat2表达的变化没有相关性(P>0.05)。展开更多
Although much progress has been made in identifying the signaling pathways that mediate viral RNA-induced apoptosis and activation of interferon-stimulated genes, the role that bacterial RNA plays in regulating these ...Although much progress has been made in identifying the signaling pathways that mediate viral RNA-induced apoptosis and activation of interferon-stimulated genes, the role that bacterial RNA plays in regulating these responses has remained undetermined. Herein, we identified bacterial RNA as a novel inducer of the apoptotic cell death. Unlike the parental cells, STAT1 and STAT2 mutants display apoptotic defects which were reversed by restoring the expression of wild type proteins. While STAT1 mutants lacking tyrosine-701 or a functional SH2 domain were effective as the wild-type protein in restoring the apoptotic response, the mutant carrying a point mutation at serine-727 of STAT1 was resistant to bacterial RNA-induced apoptosis. We also determined that the lack of apoptosis in the STAT1 and STAT2 mutants was correlated with the constitutive and inducible activation of apoptosis regulating proteins. Furthermore, we show that bacterial RNA induces transcriptional activation of STAT1, STAT2, IRF1, and ISGF3, which was impaired in STAT1 or STAT2 mutants. These observations suggested that the participation of STATs in regulating the apoptotic response is independent of their downstream functions as cytokine-induced transcriptional activators. In addition to bacterial immunity, the results presented here may also have implications in cellular pathophysiology and RNA-based therapy.展开更多
Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeuti...Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:The FBN1/VEGFR2/STAT2 signaling axis may induce chemore-sistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis.The present study suggested a novel FBNl-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.展开更多
Background:Circular RNAs(circRNAs)generated by back-splicing of precursor mRNAs(pre-mRNAs)are often aberrantly expressed in cancer cells.Accumulating evidence has revealed that circRNAs play a critical role in the pro...Background:Circular RNAs(circRNAs)generated by back-splicing of precursor mRNAs(pre-mRNAs)are often aberrantly expressed in cancer cells.Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers,including colorectal cancer(CRC).However,the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited.Here,we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis.Methods:circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients.The expression of circRNAs were determined by quantitative PCR(qPCR)and in situ hybridization(ISH).The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs.The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array,RNA pull-down/mass spectrometry,RNA immunoprecipitation assay,luciferase reporter assay,chromatin immunoprecipitation analysis,and fluorescence in situ hybridization(FISH).Results:Among circRNAs,circCAPRIN1 was most significantly upregulated in CRC tissue specimens.circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients.Downregulation of circCAPRIN1 suppressed proliferation,migration,and epithelial-mesenchymal transition of CRC cells,while circCAPRIN1 overexpression had opposite effects.RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism.Moreover,circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1(ACC1)expression.Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2(STAT2)to activate ACC1 transcription,thus regulating lipid metabolism and facilitating CRC tumorigenesis.Conclusions:These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC.circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1.circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.展开更多
目的:探讨M2型肿瘤相关巨噬细胞(M2 type tumor-associated macrophage,M2-TAMs)介导白细胞介素6(interleukin-6,IL-6)-Janus激酶2(Janus kinase 2,JAK2)/信号转导及转录激活因子3(signal transducer and activator of transcription 3,...目的:探讨M2型肿瘤相关巨噬细胞(M2 type tumor-associated macrophage,M2-TAMs)介导白细胞介素6(interleukin-6,IL-6)-Janus激酶2(Janus kinase 2,JAK2)/信号转导及转录激活因子3(signal transducer and activator of transcription 3,STAT3)轴促进胃癌干性和侵袭迁移的作用机制。方法:应用TCGA数据库分析胃癌及癌旁正常组织M2-TAMs的分布与干性指标的关系,并在胃癌患者组织水平进行验证。体外通过成球实验检测胃癌细胞的干性潜能并构建M2-TAMs体外共培养体系,运用qRT-PCR和Western blot技术检测肿瘤干性标志物CD44和醛脱氢酶1(aldehyde dehydrogenase 1,ALDH1)的变化,通过Transwell实验探究胃癌迁移、侵袭能力的变化。利用转录组测序筛选差异基因,通过KEGG富集分析探寻关键通路,并采用中和抗体及通路抑制剂进行相关性验证。结果:TCGA数据库分析和体内组织验证结果均表明胃癌组织中M2-TAMs的密度显著高于癌旁正常组织,且其数量的增加与肿瘤干性标志(CD44和ALDH1)呈正相关。与M2-TAMs共培养的胃癌细胞在CD44和ALDH1的mRNA及蛋白表达水平较对照组显著升高,同时共培养组肿瘤细胞成球率和侵袭迁移能力均显著增强,JAK2/STAT3信号通路关键蛋白表达水平显著升高。KEGG通路分析发现STAT3是肿瘤干性调控的关键基因。与极化前的巨噬细胞相比,极化的M2-TAMs有22个上调分泌因子,其中IL-6显著升高,且与患者不良预后相关。加入stattic(选择性STAT3信号通路抑制剂)和(或)IL-6中和抗体均能抑制胃癌细胞的干性、迁移和侵袭。以上结果P值均<0.05。结论:M2-TAMs通过分泌IL-6介导JAK2/STAT3信号通路激活胃癌细胞干性潜能,进而促进胃癌的侵袭和迁移。展开更多
文摘STAT2是信号转导和转录激活因子(signal transducers and activators of transcription,STAT)家族中的一员,它被激活后转入细胞核内与特异性DNA结合,影响基因转录,参与细胞的生长、分化、生存和凋亡。重要的是,目前研究表明,STAT2基因缺失或过表达对肿瘤发生发展有着重要影响,与肿瘤血管生成、肿瘤增殖及肿瘤凋亡密切相关,并且在肿瘤的干扰素治疗中扮演着重要角色。本文就STAT2与肿瘤研究进展做一综述。
基金funded by 'Chinese National Nature Science Foundation(30771122)''Chinese Ministry of Education,Research Start-up Funding for Home Smdents' to Ming Li
文摘Objective:To measure the expression pattern of STAT2 in cenical cancer initiation and progression in tissue sections from patients with cervicitis,dysplasia,and cenical cancer. Methods:Antibody against human STAT2 was confirmed by plasmids transient transfection and Western blot Immunohistochemistry was used to delect STAT2 expression in the cervical biopsies by using the confirmed antibody against STAT2 as the primary antibody.Results:It was found that the overall rate of positive STAT2 expression in the cervicitis,dysplasia and cenical cancer groups were 38.5%,69.49%and 76.991,respectively.The STAT2 levels are significantly increased in premalignant dysplasia and cervical cancer,as compared lo cervicitis(P【 0.05). Noticeably,STAT2 signals were mainly found in the cytoplasm,implying that STAT2 was not biologically active.Conclusions:These findings reveal an association between cenical cancer progression and augmented STAT2 expression.In conclusion.STAT2 increase appears to be an early detectable cellular event in cenical cancer development.
文摘目的研究慢性丙型病毒性肝炎患者外周血单核细胞(PBMC)中2’,5’寡腺苷酸合成酶(2’,5’-Oligoadenylate synthetase,2-5AS)的表达及其传导与转录激活因子(Signal transducer and activator of transcription,Stat)Stat1和Stat2等的水平相关性分析。方法选择60例慢性丙肝患者,抽取外周血分离PBMC。首先测定每份标本的2-5AS活性。然后将所有丙肝患者的PBMC标本按按编号单双数分为对照组和实验组,进行体外培养。其中,对照组PBMC不添加干扰素α(interferon alpha,IFN-α),而实验组PBMC添加1000IU/ml IFN-α。体外培养大约24小时后,测定PBMC中2-5AS活性、Stat1和Stat2等的表达量。结果和对照组相比,实验组PBMC的2-5AS活性明显升高(P<0.05)。实验组PBMC中,在2-5AS活性增高的同时,Stat1和Stat2等表达量也呈现明显增多的趋势(P<0.05)。结论基础的2-5AS活性与加入IFNα刺激培养后Stat1的改变幅度呈负相关(P<0.05);2-5AS基础水平和IFNα刺激后的Stat2表达的变化没有相关性(P>0.05)。
文摘Although much progress has been made in identifying the signaling pathways that mediate viral RNA-induced apoptosis and activation of interferon-stimulated genes, the role that bacterial RNA plays in regulating these responses has remained undetermined. Herein, we identified bacterial RNA as a novel inducer of the apoptotic cell death. Unlike the parental cells, STAT1 and STAT2 mutants display apoptotic defects which were reversed by restoring the expression of wild type proteins. While STAT1 mutants lacking tyrosine-701 or a functional SH2 domain were effective as the wild-type protein in restoring the apoptotic response, the mutant carrying a point mutation at serine-727 of STAT1 was resistant to bacterial RNA-induced apoptosis. We also determined that the lack of apoptosis in the STAT1 and STAT2 mutants was correlated with the constitutive and inducible activation of apoptosis regulating proteins. Furthermore, we show that bacterial RNA induces transcriptional activation of STAT1, STAT2, IRF1, and ISGF3, which was impaired in STAT1 or STAT2 mutants. These observations suggested that the participation of STATs in regulating the apoptotic response is independent of their downstream functions as cytokine-induced transcriptional activators. In addition to bacterial immunity, the results presented here may also have implications in cellular pathophysiology and RNA-based therapy.
基金Shanghai Municipal Health Commission,Grant/Award Number:20194Y0039Natural Science Foundation of China,Grant/Award Numbers:81872117,81502235funded by Project of the Shanghai Municipal Health Com-mission(No.20194Y0039 to HZ.S)and Natural Science Foundation of China(No.81872117 and 81502235 to ZL.W).
文摘Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:The FBN1/VEGFR2/STAT2 signaling axis may induce chemore-sistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis.The present study suggested a novel FBNl-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.
基金National Natural Science Foundation of China,Grant/Award Numbers:81972260,82103259Shanghai Municipal Natural Science Foundation,Grant/Award Number:21ZR1414400Shanghai Medical Innovation Research Project,Grant/Award Number:22Y11907600。
文摘Background:Circular RNAs(circRNAs)generated by back-splicing of precursor mRNAs(pre-mRNAs)are often aberrantly expressed in cancer cells.Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers,including colorectal cancer(CRC).However,the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited.Here,we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis.Methods:circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients.The expression of circRNAs were determined by quantitative PCR(qPCR)and in situ hybridization(ISH).The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs.The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array,RNA pull-down/mass spectrometry,RNA immunoprecipitation assay,luciferase reporter assay,chromatin immunoprecipitation analysis,and fluorescence in situ hybridization(FISH).Results:Among circRNAs,circCAPRIN1 was most significantly upregulated in CRC tissue specimens.circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients.Downregulation of circCAPRIN1 suppressed proliferation,migration,and epithelial-mesenchymal transition of CRC cells,while circCAPRIN1 overexpression had opposite effects.RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism.Moreover,circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1(ACC1)expression.Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2(STAT2)to activate ACC1 transcription,thus regulating lipid metabolism and facilitating CRC tumorigenesis.Conclusions:These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC.circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1.circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.
文摘目的:探讨M2型肿瘤相关巨噬细胞(M2 type tumor-associated macrophage,M2-TAMs)介导白细胞介素6(interleukin-6,IL-6)-Janus激酶2(Janus kinase 2,JAK2)/信号转导及转录激活因子3(signal transducer and activator of transcription 3,STAT3)轴促进胃癌干性和侵袭迁移的作用机制。方法:应用TCGA数据库分析胃癌及癌旁正常组织M2-TAMs的分布与干性指标的关系,并在胃癌患者组织水平进行验证。体外通过成球实验检测胃癌细胞的干性潜能并构建M2-TAMs体外共培养体系,运用qRT-PCR和Western blot技术检测肿瘤干性标志物CD44和醛脱氢酶1(aldehyde dehydrogenase 1,ALDH1)的变化,通过Transwell实验探究胃癌迁移、侵袭能力的变化。利用转录组测序筛选差异基因,通过KEGG富集分析探寻关键通路,并采用中和抗体及通路抑制剂进行相关性验证。结果:TCGA数据库分析和体内组织验证结果均表明胃癌组织中M2-TAMs的密度显著高于癌旁正常组织,且其数量的增加与肿瘤干性标志(CD44和ALDH1)呈正相关。与M2-TAMs共培养的胃癌细胞在CD44和ALDH1的mRNA及蛋白表达水平较对照组显著升高,同时共培养组肿瘤细胞成球率和侵袭迁移能力均显著增强,JAK2/STAT3信号通路关键蛋白表达水平显著升高。KEGG通路分析发现STAT3是肿瘤干性调控的关键基因。与极化前的巨噬细胞相比,极化的M2-TAMs有22个上调分泌因子,其中IL-6显著升高,且与患者不良预后相关。加入stattic(选择性STAT3信号通路抑制剂)和(或)IL-6中和抗体均能抑制胃癌细胞的干性、迁移和侵袭。以上结果P值均<0.05。结论:M2-TAMs通过分泌IL-6介导JAK2/STAT3信号通路激活胃癌细胞干性潜能,进而促进胃癌的侵袭和迁移。
