AIM: Signal transducers and activators of transcription (STATs) are a family of transcription factors activated in response to cytokines and growth factors. Constitutive activation of Stat3 has been observed in a grow...AIM: Signal transducers and activators of transcription (STATs) are a family of transcription factors activated in response to cytokines and growth factors. Constitutive activation of Stat3 has been observed in a growing number of tumor-derived cell lines, as well as tumor specimens from human cancers. The purpose of this study was to investigate the expression of p-Stat3, activated form of Stat3, and its downstream mediators including cyclin D1 and Bcl-XL in colorectal carcinoma (CRC), and to explore the possible mechanism of Stat3 signaling pathway in the tumorigenesis of colorectal carcinoma. METHODS: Tissue samples from 45 patients of primary colorectal carcinoma were selected for studying Stat3 signaling pathway protein expression. Western blot analysis was used to measure the expression of p-Stat3, cyclin D1, and Bcl-xu proteins in colorectal carcinomas. Furthermore, the expression patterns of these proteins were analyzed for their distribution at the cellular level by immunohistochemical staining of the tissues. RESULTS: Protein levels of p-Stat3, cyclin D1, and Bcl-XL were increased in colorectal carcinomas compared with adjacent normal mucosae (P<0.05). Elevated levels of pStat3 were correlated with the nodal metastasis and the stage (P<0.05). Overexpression of cyclin D1 was associated with the nodal metastasis (P<0.05). There was also a significant correlation between the expressions of p-Stat3 and cyclin D1 (r=0.382, P<0.05). CONCLUSION: Constitutive activation of Stat3 may play an important role in the tumorigenesis of colorectal carcinoma, and the detailed mechanism of Stat3 signaling pathway in CRC deserves further investigation.展开更多
Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is...Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.展开更多
Ischemic stroke is a common disease with high mortality and morbidity worldwide.One of the important pathophysiological effects of ischemic stroke is apoptosis.A neuroprotective effect is defined as the inhibition of ...Ischemic stroke is a common disease with high mortality and morbidity worldwide.One of the important pathophysiological effects of ischemic stroke is apoptosis.A neuroprotective effect is defined as the inhibition of neuronal apoptosis to rescue or delay the infarction in the surviving ischemic penumbra.Resveratrol is a natural polyphenol that reportedly prevents cerebral ischemia injury by regulating the expression of PI3K/AKT/mTOR.Therefore,this study aimed to elucidate the neuroprotective effect of resveratrol on cerebral ischemia/reperfusion injury and to investigate the signaling pathways and mechanisms through which resveratrol regulates apoptosis in the ischemic penumbra.Rats were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion.Cerebral infarct volume was measured using 2%TTC staining.TUNEL staining was conducted to evaluate neuronal apoptosis.Western blotting and immunohistochemistry were used to detect the proteins involved in the JAK2/STAT3/PI3K/AKT/mTOR pathway.The results suggested that resveratrol significantly improved neurological function,reduced cerebral infarct volume,decreased neuronal damage,and markedly attenuated neuronal apoptosis;these effects were attenuated by the inhibition of PI3K/AKT with LY294002 and JAK2/STAT3 with AG490.We also found that resveratrol significantly upregulated the expression of p-JAK2,p-STAT3,p-AKT,p-mTOR,and BCL-2 and downregulated expression of cleaved caspase-3 and BAX,which was partially reversed by LY294002 and AG490.These results suggested that resveratrol provides a neuroprotective effect against cerebral ischemia/reperfusion injury,which is partially mediated by the activation of JAK2/STAT3 and PI3K/AKT/mTOR.Resveratrol may indirectly upregulate the PI3K/AKT/mTOR pathway by activating JAK2/STAT3.展开更多
Although links between cancer and inflammation were fi rstly proposed in the nineteenth century,the molecular mechanism has not yet been clearly understood.Epidemiological studies have identified chronic infections an...Although links between cancer and inflammation were fi rstly proposed in the nineteenth century,the molecular mechanism has not yet been clearly understood.Epidemiological studies have identified chronic infections and infl ammation as major risk factors for various types of cancer.NF-κB transcription factors and the signaling pathways are central coordinators in innate and adaptive immune responses.STAT3 regulates the expression of a variety of genes in response to cellular stimuli,and thus plays a key role in cell growth and apoptosis.Recently,roles of NF-κB and STAT3 in colon,gastric and liver cancers have been extensively investigated.The activation and interaction between STAT3 and NF-κB play vital roles in control of the communication between cancer cells and infl ammatory cells.NF-κB and STAT3 are two major factors controlling the ability of pre-neoplastic and malignant cells to resist apoptosis-based tumor-surveillance and regulating tumor angiogenesis and invasiveness.Understanding the molecular mechanisms of NF-κB and STAT3 cooperation in cancer will offer opportunities for the design of new chemo-preventive and chemotherapeutic approaches.展开更多
炎症与肿瘤是近年来肿瘤领域的研究热点.在肿瘤发生、发展过程中,白介素6(interleukin-6,IL-6)等炎症因子可将肿瘤细胞与其所处的肿瘤微环境编织成一个炎性网络,而信号传导蛋白和转录激活物(signal transducers and activators of trans...炎症与肿瘤是近年来肿瘤领域的研究热点.在肿瘤发生、发展过程中,白介素6(interleukin-6,IL-6)等炎症因子可将肿瘤细胞与其所处的肿瘤微环境编织成一个炎性网络,而信号传导蛋白和转录激活物(signal transducers and activators of transcription 3,STAT3)正是这一炎性网络中的关键节点,在慢性炎症介导肿瘤形成的过程中发挥重要作用.本文从STAT3的信号通路构成入手,由肿瘤细胞及肿瘤微环境两方面展开,综述了肿瘤发生发展过程中STAT3在肿瘤细胞及各种炎症/免疫细胞中的作用,以及靶向STAT3治疗肿瘤的转化医学研究进展.展开更多
Naive CD4 T cells can differentiate into at least two different types ofT helpers, Thl and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathog...Naive CD4 T cells can differentiate into at least two different types ofT helpers, Thl and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including StatS, Gfi- 1 and GATA-3. Stats activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stats signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation （both IL-4 dependent and IL-4 independent） and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Thl differentiation.展开更多
Interleukin-22 (IL-22) is a recently identified T cell-derived cytokine whose biological significance remains obscure.Previously,we have shown that IL-22 plays a protective role in T cell-mediated hepatitis induced by...Interleukin-22 (IL-22) is a recently identified T cell-derived cytokine whose biological significance remains obscure.Previously,we have shown that IL-22 plays a protective role in T cell-mediated hepatitis induced by Concanavalin A (Con A),acting as a survival factor for hepatocytes.In the present paper,we demonstrate that hydrodynamic gene delivery of IL-22 cDNA driven either by a liver-specific albumin promoter or a human cytomegalovirus (CMV) promoter results in IL-22 protein expression,STAT3 activation,and expression of several anti-apoptotic proteins,including Bcl-xL,Bcl-2,and Mcl-1 in the liver.Immunohistochemical analysis reveals that IL-22 protein expression is mainly detected in the cytoplasm of hepatocytes.Overexpression of IL-22 by hydrodynamic gene delivery significantly protects against liver injury,necrosis,and apoptosis induced by administration of Con A,carbon tetrachloride (CCl_4),or the Fas agonist Jo-2 mAb.Western blot analyses show that overexpression of IL-22 significantly enhances activation of STAT3 and expression of Bcl-xL,Bcl-2, and Mcl-1 proteins in liver injury induced by Con A.In conclusion,hydrodynamic gene delivery of IL-22 protects against liver injury induced by a variety of toxins,suggesting the therapeutic potential of IL-22 in treating human liver disease.Cellular & Molecular Immunology.2004;1(1):43-49.展开更多
肿瘤转移与多种细胞信号通路作用有关,其中与JAK2/STAT3/SOCS3通路关系尤为密切,JAK2/STAT3信号通路的激活参与了肿瘤发生、发展、侵袭和转移等多个环节。细胞因子信号转导抑制蛋白3(suppressors of cytokine signaling 3,SOCS3)负性调...肿瘤转移与多种细胞信号通路作用有关,其中与JAK2/STAT3/SOCS3通路关系尤为密切,JAK2/STAT3信号通路的激活参与了肿瘤发生、发展、侵袭和转移等多个环节。细胞因子信号转导抑制蛋白3(suppressors of cytokine signaling 3,SOCS3)负性调控JAK2/STAT3通路,进而抑制肿瘤的增殖和生长;信号转导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)信号通路的激活促成了肿瘤炎性微环境的形成,参与了肿瘤血管生成、上皮间质转化和细胞外基质降解等多个环节,在肿瘤的侵袭和转移过程中发挥重要作用。本文着重对JAK2/STAT3/SOCS3信号通路与肿瘤转移的关系进行综述,针对JAK2/STAT3/SOCS3细胞信号动态网络在肿瘤中作用机制研究和药物设计为肿瘤治疗提供了新方向。展开更多
基金Supported by the National Natural Science Foundation of China,No.30271269
文摘AIM: Signal transducers and activators of transcription (STATs) are a family of transcription factors activated in response to cytokines and growth factors. Constitutive activation of Stat3 has been observed in a growing number of tumor-derived cell lines, as well as tumor specimens from human cancers. The purpose of this study was to investigate the expression of p-Stat3, activated form of Stat3, and its downstream mediators including cyclin D1 and Bcl-XL in colorectal carcinoma (CRC), and to explore the possible mechanism of Stat3 signaling pathway in the tumorigenesis of colorectal carcinoma. METHODS: Tissue samples from 45 patients of primary colorectal carcinoma were selected for studying Stat3 signaling pathway protein expression. Western blot analysis was used to measure the expression of p-Stat3, cyclin D1, and Bcl-xu proteins in colorectal carcinomas. Furthermore, the expression patterns of these proteins were analyzed for their distribution at the cellular level by immunohistochemical staining of the tissues. RESULTS: Protein levels of p-Stat3, cyclin D1, and Bcl-XL were increased in colorectal carcinomas compared with adjacent normal mucosae (P<0.05). Elevated levels of pStat3 were correlated with the nodal metastasis and the stage (P<0.05). Overexpression of cyclin D1 was associated with the nodal metastasis (P<0.05). There was also a significant correlation between the expressions of p-Stat3 and cyclin D1 (r=0.382, P<0.05). CONCLUSION: Constitutive activation of Stat3 may play an important role in the tumorigenesis of colorectal carcinoma, and the detailed mechanism of Stat3 signaling pathway in CRC deserves further investigation.
文摘Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.
基金supported by the Foundation for Science and Technology Research Project of Chongqing(cstc2012ggB1002).
文摘Ischemic stroke is a common disease with high mortality and morbidity worldwide.One of the important pathophysiological effects of ischemic stroke is apoptosis.A neuroprotective effect is defined as the inhibition of neuronal apoptosis to rescue or delay the infarction in the surviving ischemic penumbra.Resveratrol is a natural polyphenol that reportedly prevents cerebral ischemia injury by regulating the expression of PI3K/AKT/mTOR.Therefore,this study aimed to elucidate the neuroprotective effect of resveratrol on cerebral ischemia/reperfusion injury and to investigate the signaling pathways and mechanisms through which resveratrol regulates apoptosis in the ischemic penumbra.Rats were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion.Cerebral infarct volume was measured using 2%TTC staining.TUNEL staining was conducted to evaluate neuronal apoptosis.Western blotting and immunohistochemistry were used to detect the proteins involved in the JAK2/STAT3/PI3K/AKT/mTOR pathway.The results suggested that resveratrol significantly improved neurological function,reduced cerebral infarct volume,decreased neuronal damage,and markedly attenuated neuronal apoptosis;these effects were attenuated by the inhibition of PI3K/AKT with LY294002 and JAK2/STAT3 with AG490.We also found that resveratrol significantly upregulated the expression of p-JAK2,p-STAT3,p-AKT,p-mTOR,and BCL-2 and downregulated expression of cleaved caspase-3 and BAX,which was partially reversed by LY294002 and AG490.These results suggested that resveratrol provides a neuroprotective effect against cerebral ischemia/reperfusion injury,which is partially mediated by the activation of JAK2/STAT3 and PI3K/AKT/mTOR.Resveratrol may indirectly upregulate the PI3K/AKT/mTOR pathway by activating JAK2/STAT3.
基金supported by the NIH/NINDS grant 1R01NS072420-01.
文摘Although links between cancer and inflammation were fi rstly proposed in the nineteenth century,the molecular mechanism has not yet been clearly understood.Epidemiological studies have identified chronic infections and infl ammation as major risk factors for various types of cancer.NF-κB transcription factors and the signaling pathways are central coordinators in innate and adaptive immune responses.STAT3 regulates the expression of a variety of genes in response to cellular stimuli,and thus plays a key role in cell growth and apoptosis.Recently,roles of NF-κB and STAT3 in colon,gastric and liver cancers have been extensively investigated.The activation and interaction between STAT3 and NF-κB play vital roles in control of the communication between cancer cells and infl ammatory cells.NF-κB and STAT3 are two major factors controlling the ability of pre-neoplastic and malignant cells to resist apoptosis-based tumor-surveillance and regulating tumor angiogenesis and invasiveness.Understanding the molecular mechanisms of NF-κB and STAT3 cooperation in cancer will offer opportunities for the design of new chemo-preventive and chemotherapeutic approaches.
文摘炎症与肿瘤是近年来肿瘤领域的研究热点.在肿瘤发生、发展过程中,白介素6(interleukin-6,IL-6)等炎症因子可将肿瘤细胞与其所处的肿瘤微环境编织成一个炎性网络,而信号传导蛋白和转录激活物(signal transducers and activators of transcription 3,STAT3)正是这一炎性网络中的关键节点,在慢性炎症介导肿瘤形成的过程中发挥重要作用.本文从STAT3的信号通路构成入手,由肿瘤细胞及肿瘤微环境两方面展开,综述了肿瘤发生发展过程中STAT3在肿瘤细胞及各种炎症/免疫细胞中的作用,以及靶向STAT3治疗肿瘤的转化医学研究进展.
文摘Naive CD4 T cells can differentiate into at least two different types ofT helpers, Thl and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including StatS, Gfi- 1 and GATA-3. Stats activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stats signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation （both IL-4 dependent and IL-4 independent） and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Thl differentiation.
文摘Interleukin-22 (IL-22) is a recently identified T cell-derived cytokine whose biological significance remains obscure.Previously,we have shown that IL-22 plays a protective role in T cell-mediated hepatitis induced by Concanavalin A (Con A),acting as a survival factor for hepatocytes.In the present paper,we demonstrate that hydrodynamic gene delivery of IL-22 cDNA driven either by a liver-specific albumin promoter or a human cytomegalovirus (CMV) promoter results in IL-22 protein expression,STAT3 activation,and expression of several anti-apoptotic proteins,including Bcl-xL,Bcl-2,and Mcl-1 in the liver.Immunohistochemical analysis reveals that IL-22 protein expression is mainly detected in the cytoplasm of hepatocytes.Overexpression of IL-22 by hydrodynamic gene delivery significantly protects against liver injury,necrosis,and apoptosis induced by administration of Con A,carbon tetrachloride (CCl_4),or the Fas agonist Jo-2 mAb.Western blot analyses show that overexpression of IL-22 significantly enhances activation of STAT3 and expression of Bcl-xL,Bcl-2, and Mcl-1 proteins in liver injury induced by Con A.In conclusion,hydrodynamic gene delivery of IL-22 protects against liver injury induced by a variety of toxins,suggesting the therapeutic potential of IL-22 in treating human liver disease.Cellular & Molecular Immunology.2004;1(1):43-49.
文摘肿瘤转移与多种细胞信号通路作用有关,其中与JAK2/STAT3/SOCS3通路关系尤为密切,JAK2/STAT3信号通路的激活参与了肿瘤发生、发展、侵袭和转移等多个环节。细胞因子信号转导抑制蛋白3(suppressors of cytokine signaling 3,SOCS3)负性调控JAK2/STAT3通路,进而抑制肿瘤的增殖和生长;信号转导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)信号通路的激活促成了肿瘤炎性微环境的形成,参与了肿瘤血管生成、上皮间质转化和细胞外基质降解等多个环节,在肿瘤的侵袭和转移过程中发挥重要作用。本文着重对JAK2/STAT3/SOCS3信号通路与肿瘤转移的关系进行综述,针对JAK2/STAT3/SOCS3细胞信号动态网络在肿瘤中作用机制研究和药物设计为肿瘤治疗提供了新方向。
