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introduction
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Glioblastoma multiforme (GBM) is the most common primary malignancy of the central nervous system (CNS), with an incidence of 3.19 per 100,000 and a five-year survival rate of less than 5% [>>1<<,2]. GBM’s molecular heterogeneity, genomic instability, radio- and chemo-resistance, infiltrative capacity, and immune evasion are important contributing factors in GBM pathogenesis.
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Glioblastoma multiforme (GBM) is the most common primary malignancy of the central nervous system (CNS), with an incidence of 3.19 per 100,000 and a five-year survival rate of less than 5% [1,>>2<<]. GBM’s molecular heterogeneity, genomic instability, radio- and chemo-resistance, infiltrative capacity, and immune evasion are important contributing factors in GBM pathogenesis.
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n2:11937180
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [>>3<<,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,>>4<<,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme
n3:mentions
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,>>5<<,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme
n3:mentions
n2:16282176
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,>>6<<], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme
n3:mentions
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [>>7<<,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have
n3:mentions
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,>>8<<], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have
n3:mentions
n2:15967113
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [>>9<<,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular
n3:mentions
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,>>10<<,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies
n3:mentions
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Genetic and molecular alterations in the epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,>>11<<] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies for
n3:mentions
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epidermal growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [>>12<<], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies for both primary and secondary GBMs.
n3:mentions
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growth factor receptor (EGFR) [3,4,5,6], molecular target of rapamycin (mTOR) [7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [>>13<<] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [14] have been described as possible bases of molecular therapies for both primary and secondary GBMs.
n3:mentions
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[7,8], and vascular endothelial growth factor (VEGF) [9,10,11] signaling pathways, as well as mutations of isocitrate dehydrogenase (IDH)-1 and -2 [12], PTEN [13] and DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) [>>14<<] have been described as possible bases of molecular therapies for both primary and secondary GBMs.
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STAT3 has emerged as a key initiator and master regulator of mesenchymal transformation in malignant gliomas [>>15<<]. Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,17,18,19]. STAT3 can be activated by growth factor receptors including EGFR and
n3:mentions
n2:20032975
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Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [>>16<<,17,18,19].
n3:mentions
n2:17471161
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Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,>>17<<,18,19]. STAT3 can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family
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n2:23096132
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Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,17,>>18<<,19]. STAT3 can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family
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Constitutive STAT3 activation has been implicated in the suppression of host antitumor immune response, thereby facilitating unregulated tumor growth [16,17,18,>>19<<]. STAT3 can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family
n3:mentions
n2:14499117
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can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [>>16<<,20,21,22,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24].
n3:mentions
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can be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,>>20<<,21,22,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24].
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be activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,20,>>21<<,22,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24].
n3:mentions
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activated by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,20,21,>>22<<,23]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24].
n3:mentions
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by growth factor receptors including EGFR and platelet-derived growth factor receptors (PDGFR), as well as interleukin-6 receptor (IL-6R/gp130), Janus family kinases (JAK), Abl family kinases, and Src family kinases [16,20,21,22,>>23<<]. It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,24].
n3:mentions
n2:9566874
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It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [>>17<<,24].
n3:mentions
n2:23096132
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It has also been shown to be a potent regulator of gliomagenesis by inducing local angiogenesis and promoting immune evasion and tumor invasion [17,>>24<<].
n3:mentions
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Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [>>17<<,25,26,27,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM.
n3:mentions
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Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,>>25<<,26,27,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM.
n3:mentions
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Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,25,>>26<<,27,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM.
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Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,25,26,>>27<<,28]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM.
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Several preclinical studies have demonstrated the anti-tumor effects of STAT3 knockdown using small interfering RNA (siRNA), micro-RNA (miRNA), or small molecule inhibitors [17,25,26,27,>>28<<]. However, the varying efficacy of these treatments with respect to cell type, in vitro versus in vivo model, and therapeutic modality underscore our incomplete understanding of the role of STAT3 activation in GBM.
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stat3 signaling pathways
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STAT proteins are a family of cytoplasmic transcription factors that are activated by tyrosine kinases and mediate cellular response to inflammatory and proliferative signals [>>29<<,30]. These tyrosine kinases include growth factor receptors, such as EGFR and PDGFR, and cytoplasmic enzymes, specifically the JAK and Src kinase families [23].
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STAT proteins are a family of cytoplasmic transcription factors that are activated by tyrosine kinases and mediate cellular response to inflammatory and proliferative signals [29,>>30<<]. These tyrosine kinases include growth factor receptors, such as EGFR and PDGFR, and cytoplasmic enzymes, specifically the JAK and Src kinase families [23].
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rdf:value
These tyrosine kinases include growth factor receptors, such as EGFR and PDGFR, and cytoplasmic enzymes, specifically the JAK and Src kinase families [>>23<<]. Phosphorylated STAT proteins dimerize via reciprocal phosphotyrosine-SH2 interactions and undergo nuclear translocation. There, they bind consensus STAT binding proteins, or DNA-response elements of the targeted sequences to regulate
n3:mentions
n2:9566874
Subject Item
_:vb28707740
rdf:type
n3:Context
rdf:value
Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [>>23<<,31,32,33].
n3:mentions
n2:9566874
Subject Item
_:vb28707741
rdf:type
n3:Context
rdf:value
Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [23,>>31<<,32,33]. STAT3 signaling is tightly regulated by several upstream and downstream checkpoints to ensure an appropriate growth response to activation. Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and
n3:mentions
n2:12209125
Subject Item
_:vb28707742
rdf:type
n3:Context
rdf:value
Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [23,31,>>32<<,33]. STAT3 signaling is tightly regulated by several upstream and downstream checkpoints to ensure an appropriate growth response to activation. Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and
n3:mentions
n2:10023769
Subject Item
_:vb28707743
rdf:type
n3:Context
rdf:value
Transcription activity can be maximized by serine phosphorylation of STAT dimers by intranuclear protein serine kinases (PSKs) [23,31,32,>>33<<]. STAT3 signaling is tightly regulated by several upstream and downstream checkpoints to ensure an appropriate growth response to activation. Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and
n3:mentions
n2:10851059
Subject Item
_:vb28707744
rdf:type
n3:Context
rdf:value
Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and inactivate ligand-receptor complexes and phosphorylated-STAT (pSTAT) dimers [>>34<<,35]. Suppressor of cytokine signaling (SOCS) proteins negatively feedback on the JAK/STAT signaling pathway by disrupting or degrading JAKs [36]. In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block
n3:mentions
n2:12359225
Subject Item
_:vb28707745
rdf:type
n3:Context
rdf:value
Inhibitory molecules, such as protein tyrosine phosphatases, act to dephosphorylate and inactivate ligand-receptor complexes and phosphorylated-STAT (pSTAT) dimers [34,>>35<<]. Suppressor of cytokine signaling (SOCS) proteins negatively feedback on the JAK/STAT signaling pathway by disrupting or degrading JAKs [36]. In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block
n3:mentions
n2:17360477
Subject Item
_:vb28707746
rdf:type
n3:Context
rdf:value
Suppressor of cytokine signaling (SOCS) proteins negatively feedback on the JAK/STAT signaling pathway by disrupting or degrading JAKs [>>36<<]. In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block STAT protein’s DNA-binding activity, thereby inhibiting gene transcription [37]. Furthermore, STAT3 interacting protein (StIP1) may block STAT3
n3:mentions
n2:11326271
Subject Item
_:vb28707747
rdf:type
n3:Context
rdf:value
In response to cytokine stimulation, protein inhibitor of activated STAT3 (PIAS3) can block STAT protein’s DNA-binding activity, thereby inhibiting gene transcription [>>37<<]. Furthermore, STAT3 interacting protein (StIP1) may block STAT3 activation, translocation, and reporter gene induction via overexpression of its STAT3-binding domain [38].
n3:mentions
n2:10851063
Subject Item
_:vb28707748
rdf:type
n3:Context
rdf:value
Furthermore, STAT3 interacting protein (StIP1) may block STAT3 activation, translocation, and reporter gene induction via overexpression of its STAT3-binding domain [>>38<<].
n3:mentions
n2:10954736
Subject Item
_:vb28707749
rdf:type
n3:Context
rdf:value
These molecules play a significant role in regulating the STAT3 signaling cascade, and under normal physiologic conditions, represent important checkpoints in the activation and deactivation of cell proliferation [>>39<<]. However, under pathologic or experimental conditions, these regulatory molecules serve as natural targets for STAT3 signal disruption or even constitutive activation.
n3:mentions
n2:22748651
Subject Item
_:vb28707750
rdf:type
n3:Context
rdf:value
Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [>>5<<,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators
n3:mentions
n2:16282176
Subject Item
_:vb28707751
rdf:type
n3:Context
rdf:value
Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,>>40<<]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators
n3:mentions
n2:21590492
Subject Item
_:vb28707752
rdf:type
n3:Context
rdf:value
Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [>>15<<,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3
n3:mentions
n2:20032975
Subject Item
_:vb28707753
rdf:type
n3:Context
rdf:value
Site of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,>>20<<,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3
n3:mentions
n2:9566875
Subject Item
_:vb28707754
rdf:type
n3:Context
rdf:value
of disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,>>21<<,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3
n3:mentions
n2:7541555
Subject Item
_:vb28707755
rdf:type
n3:Context
rdf:value
disruptionPotential mediators of disruptionCell surface receptor-ligand interactionLigand/receptor antagonists, i.e., anti-EGF-R antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,>>28<<]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3
n3:mentions
n2:20514402
Subject Item
_:vb28707756
rdf:type
n3:Context
rdf:value
antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [>>36<<,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of
n3:mentions
n2:11326271
Subject Item
_:vb28707757
rdf:type
n3:Context
rdf:value
antibodies [5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,>>37<<,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of
n3:mentions
n2:10851063
Subject Item
_:vb28707758
rdf:type
n3:Context
rdf:value
[5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,>>41<<,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of
n3:mentions
n2:18829483
Subject Item
_:vb28707759
rdf:type
n3:Context
rdf:value
[5,40]Tyrosine or serine kinase activityTRK, EGF-R, FBGF-R, JAK, Src, PSK inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,>>42<<]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear
n3:mentions
n2:21906308
Subject Item
_:vb28707760
rdf:type
n3:Context
rdf:value
inhibitors [15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [>>25<<,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy
n3:mentions
n2:23612755
Subject Item
_:vb28707761
rdf:type
n3:Context
rdf:value
[15,20,21,28]Endogenous STAT3 activity or functionBiological protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,>>43<<]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy
n3:mentions
n2:17114005
Subject Item
_:vb28707762
rdf:type
n3:Context
rdf:value
protein inhibitors of STAT3 activity, i.e., SOCS, PIAS3, StIP1 modulators [36,37,41,42]De-phosphorylation of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [>>43<<]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,47]3.
n3:mentions
n2:17114005
Subject Item
_:vb28707763
rdf:type
n3:Context
rdf:value
of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [>>43<<,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,47]3.
n3:mentions
n2:17114005
Subject Item
_:vb28707764
rdf:type
n3:Context
rdf:value
of phospho-STATsProtein tyrosine or serine phosphatases [25,43]STAT3 dimerizationSmall molecule inhibitors of dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,>>44<<]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,47]3.
n3:mentions
n2:12093727
Subject Item
_:vb28707765
rdf:type
n3:Context
rdf:value
dimerization [43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [>>45<<,46,47]3. Constitutive
n3:mentions
n2:18415045
Subject Item
_:vb28707766
rdf:type
n3:Context
rdf:value
[43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,>>46<<,47]3. Constitutive
n3:mentions
n2:12640143
Subject Item
_:vb28707767
rdf:type
n3:Context
rdf:value
[43]STAT3 nuclear translocationSmall molecule inhibitors of dimerization, inhibitors of nuclear endocytosis [43,44]STAT3 transcription activationAntisense or STAT3 decoy oligonucleotide sequences, dominant negative mutants [45,46,>>47<<]3. Constitutive
n3:mentions
n2:24058785
Subject Item
_:vb28707768
rdf:type
n5:Section
dc:title
constitutive activation
n5:contains
_:vb28707772 _:vb28707773 _:vb28707774 _:vb28707775 _:vb28707769 _:vb28707770 _:vb28707771 _:vb28707780 _:vb28707781 _:vb28707782 _:vb28707783 _:vb28707776 _:vb28707777 _:vb28707778 _:vb28707779 _:vb28707788 _:vb28707789 _:vb28707790 _:vb28707791 _:vb28707784 _:vb28707785 _:vb28707786 _:vb28707787 _:vb28707796 _:vb28707797 _:vb28707798 _:vb28707799 _:vb28707792 _:vb28707793 _:vb28707794 _:vb28707795 _:vb28707800 _:vb28707801 _:vb28707802 _:vb28707803
Subject Item
_:vb28707769
rdf:type
n3:Context
rdf:value
Persistent STAT3 activation—secondary to intrinsic hyperactivity, aberrant upstream signaling, or defective negative regulation—can lead to abnormal survival and tumorigenesis [>>48<<]. Constitutive STAT3 activation has been reported in 50%–90% of human cancers [48,49].
n3:mentions
n2:11948098
Subject Item
_:vb28707770
rdf:type
n3:Context
rdf:value
Constitutive STAT3 activation has been reported in 50%–90% of human cancers [>>48<<,49]. This prevalence can be attributed to STAT3’s position as the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met,
n3:mentions
n2:11948098
Subject Item
_:vb28707771
rdf:type
n3:Context
rdf:value
Constitutive STAT3 activation has been reported in 50%–90% of human cancers [48,>>49<<]. This prevalence can be attributed to STAT3’s position as the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met,
n3:mentions
n2:14964307
Subject Item
_:vb28707772
rdf:type
n3:Context
rdf:value
as the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [>>16<<,21,22,29,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases.
n3:mentions
n2:17471161
Subject Item
_:vb28707773
rdf:type
n3:Context
rdf:value
the convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,>>21<<,22,29,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases.
n3:mentions
n2:7541555
Subject Item
_:vb28707774
rdf:type
n3:Context
rdf:value
convergence point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,>>22<<,29,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases.
n3:mentions
n2:11404481
Subject Item
_:vb28707775
rdf:type
n3:Context
rdf:value
point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,22,>>29<<,49,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases.
n3:mentions
n2:8140422
Subject Item
_:vb28707776
rdf:type
n3:Context
rdf:value
point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,22,29,>>49<<,50]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases.
n3:mentions
n2:14964307
Subject Item
_:vb28707777
rdf:type
n3:Context
rdf:value
point of several major oncogenic signaling pathways (Figure 1), including EGFR, heregulin-2/neuregulin receptor (Her2/Neu), platelet-PDGFR, IL-6R/gp130, c-Met, Abelson leukemia protein (ABL), and Src tyrosine kinases [16,21,22,29,49,>>50<<]. Thus, constitutive STAT3 activation commonly results from gain-of-function mutations or overexpression of upstream growth factor receptors or signaling kinases.
n3:mentions
n2:16199153
Subject Item
_:vb28707778
rdf:type
n3:Context
rdf:value
For example, aberrant methylation silencing of SOCS-3 has been associated with constitutive JAK/STAT activity and higher levels of pSTATs in non-small cell lung cancer [>>51<<].
n3:mentions
n2:14617776
Subject Item
_:vb28707779
rdf:type
n3:Context
rdf:value
This mechanism has been described in multiple myeloma, where IL-6 overexpression led to increased JAK/STAT3 activity [>>52<<], as well as in squamous cell carcinoma of the head and neck, where elevated levels of transforming growth factor-α (TGF-α) and subsequent STAT3 activation abrogated apoptosis of epithelial cells [53].
n3:mentions
n2:10023775
Subject Item
_:vb28707780
rdf:type
n3:Context
rdf:value
led to increased JAK/STAT3 activity [52], as well as in squamous cell carcinoma of the head and neck, where elevated levels of transforming growth factor-α (TGF-α) and subsequent STAT3 activation abrogated apoptosis of epithelial cells [>>53<<].
n3:mentions
n2:10760290
Subject Item
_:vb28707781
rdf:type
n3:Context
rdf:value
The presence of STAT3 activation in GBMs varies considerably, with detection rates of most retrospective, immunohistochemistry-based studies ranging from 9%–83% [>>54<<]. These discrepant data could be attributed to the varying tumor grades of the brain tissue sampled in each study.
n3:mentions
n2:23688441
Subject Item
_:vb28707782
rdf:type
n3:Context
rdf:value
In 2006, Mizoguchi et al. demonstrated similar rates of STAT3 activation in anaplastic astrocytomas (AA) and GBMs (55.6% and 56.4%, respectively) [>>55<<]. Abou-Ghazal reported similar results in 2008, with 50% of AA and 51% of GBM samples staining positively for pSTAT3 [56]. Lo et al. expanded on these findings by describing a positive correlation between glioma grade and extent of STAT3
n3:mentions
n2:17146292
Subject Item
_:vb28707783
rdf:type
n3:Context
rdf:value
Abou-Ghazal reported similar results in 2008, with 50% of AA and 51% of GBM samples staining positively for pSTAT3 [>>56<<]. Lo et al. expanded on these findings by describing a positive correlation between glioma grade and extent of STAT3 activation. Constitutive activation was detected in 60% of primary high grade/malignant gliomas, secondary to JAK2, EGFR
n3:mentions
n2:19088040
Subject Item
_:vb28707784
rdf:type
n3:Context
rdf:value
In comparison, only 27%, 29%, and 57% of Grade I, II, and III gliomas, respectively, were found to have similar activation [>>41<<]. These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [57,58,59]. In contrast, Wang et al. reported STAT3
n3:mentions
n2:18829483
Subject Item
_:vb28707785
rdf:type
n3:Context
rdf:value
These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [>>57<<,58,59]. In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [60]. However differing methods in protein detection is a possible explanation for inconsistent
n3:mentions
n2:18676737
Subject Item
_:vb28707786
rdf:type
n3:Context
rdf:value
These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [57,>>58<<,59]. In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [60]. However differing methods in protein detection is a possible explanation for inconsistent
n3:mentions
n2:11960378
Subject Item
_:vb28707787
rdf:type
n3:Context
rdf:value
These conclusions were further supported by tissue electrophoresis and western blot assays, which also showed a correlation between histopathological grade and STAT3 phosphorylation [57,58,>>59<<]. In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [60]. However differing methods in protein detection is a possible explanation for inconsistent results
n3:mentions
n2:15064729
Subject Item
_:vb28707788
rdf:type
n3:Context
rdf:value
In contrast, Wang et al. reported STAT3 activation in only 9% of AA and 9% of GBM samples, and found no correlation with tumor grade [>>60<<]. However differing methods in protein detection is a possible explanation for inconsistent results between studies [54].
n3:mentions
n2:15184909
Subject Item
_:vb28707789
rdf:type
n3:Context
rdf:value
However differing methods in protein detection is a possible explanation for inconsistent results between studies [>>54<<].
n3:mentions
n2:23688441
Subject Item
_:vb28707790
rdf:type
n3:Context
rdf:value
The majority of STAT3 activity in U251 cells was catalyzed by gp130-associated JAKs secondary to IL-6, a cytokine secreted by GBM cells both in vivo and in vitro [>>61<<]. Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,63,64,65]. Furthermore, IL-6 gene amplification has been associated with a
n3:mentions
n2:12466961
Subject Item
_:vb28707791
rdf:type
n3:Context
rdf:value
Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [>>62<<,63,64,65].
n3:mentions
n2:11147905
Subject Item
_:vb28707792
rdf:type
n3:Context
rdf:value
Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,>>63<<,64,65]. Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [65].
n3:mentions
n2:16326273
Subject Item
_:vb28707793
rdf:type
n3:Context
rdf:value
Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,63,>>64<<,65]. Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [65].
n3:mentions
n2:11517969
Subject Item
_:vb28707794
rdf:type
n3:Context
rdf:value
Several studies have shown IL-6 mRNA expression to be significantly elevated in GBM patient samples as compared to those with lower grade gliomas [62,63,64,>>65<<]. Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [65].
n3:mentions
n2:11506489
Subject Item
_:vb28707795
rdf:type
n3:Context
rdf:value
Furthermore, IL-6 gene amplification has been associated with a significantly lower overall survival among GBM patients [>>65<<].
n3:mentions
n2:11506489
Subject Item
_:vb28707796
rdf:type
n3:Context
rdf:value
In particular, missense mutations of EGFR genes may lead to constitutive downstream activation, and have been implicated in de novo GBMs in older patients [>>66<<,67,68]. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [69].
n3:mentions
n2:17177598
Subject Item
_:vb28707797
rdf:type
n3:Context
rdf:value
In particular, missense mutations of EGFR genes may lead to constitutive downstream activation, and have been implicated in de novo GBMs in older patients [66,>>67<<,68]. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [69].
n3:mentions
n2:16007122
Subject Item
_:vb28707798
rdf:type
n3:Context
rdf:value
In particular, missense mutations of EGFR genes may lead to constitutive downstream activation, and have been implicated in de novo GBMs in older patients [66,67,>>68<<]. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [69].
n3:mentions
n2:20824044
Subject Item
_:vb28707799
rdf:type
n3:Context
rdf:value
Bone marrow X-linked (BMX) nonreceptor tyrosine kinase, which is differentially expressed in GBM stem cells, may contribute to self-renewal and tumorigenic potential via STAT3 activation [>>69<<].
n3:mentions
n2:21481791
Subject Item
_:vb28707800
rdf:type
n3:Context
rdf:value
Brantley et al. demonstrated a negative correlation between transcription inhibitor PIAS3 and phospho-STAT3 expression, with subsequent PIAS3 overexpression leading to decreased STAT3 transcriptional activity and cell proliferation [>>57<<]. Protein tyrosine phosphatase receptor delta (PTPRD), a STAT3 phosphatase, has been implicated as a suppressor of neuroectoderm-derived tumors.
n3:mentions
n2:18676737
Subject Item
_:vb28707801
rdf:type
n3:Context
rdf:value
Focal deletions, missense, and nonsense mutations of the PTPRD gene have been identified in up to 41% of GBM samples [>>70<<,71]. Furthermore, Veeriah et al. observed a greater frequency of PTPRD expression loss in GBM versus lower grade gliomas. Decreased PTPRD expression was also predictive of poorer prognosis in GBM patients [71].
n3:mentions
n2:19074898
Subject Item
_:vb28707802
rdf:type
n3:Context
rdf:value
Focal deletions, missense, and nonsense mutations of the PTPRD gene have been identified in up to 41% of GBM samples [70,>>71<<]. Furthermore, Veeriah et al. observed a greater frequency of PTPRD expression loss in GBM versus lower grade gliomas. Decreased PTPRD expression was also predictive of poorer prognosis in GBM patients [71].
n3:mentions
n2:19478061
Subject Item
_:vb28707803
rdf:type
n3:Context
rdf:value
Decreased PTPRD expression was also predictive of poorer prognosis in GBM patients [>>71<<].
n3:mentions
n2:19478061
Subject Item
_:vb28707804
rdf:type
n5:Section
dc:title
role of stat3 in tumorigenesis
n5:contains
_:vb28707805 _:vb28707806 _:vb28707807 _:vb28707828 _:vb28707829 _:vb28707830 _:vb28707831 _:vb28707824 _:vb28707825 _:vb28707826 _:vb28707827 _:vb28707836 _:vb28707837 _:vb28707838 _:vb28707839 _:vb28707832 _:vb28707833 _:vb28707834 _:vb28707835 _:vb28707812 _:vb28707813 _:vb28707814 _:vb28707815 _:vb28707808 _:vb28707809 _:vb28707810 _:vb28707811 _:vb28707820 _:vb28707821 _:vb28707822 _:vb28707823 _:vb28707816 _:vb28707817 _:vb28707818 _:vb28707819 _:vb28707856 _:vb28707857 _:vb28707858 _:vb28707844 _:vb28707845 _:vb28707846 _:vb28707847 _:vb28707840 _:vb28707841 _:vb28707842 _:vb28707843 _:vb28707852 _:vb28707853 _:vb28707854 _:vb28707855 _:vb28707848 _:vb28707849 _:vb28707850 _:vb28707851
Subject Item
_:vb28707805
rdf:type
n3:Context
rdf:value
Under normal physiologic conditions, STAT3 activity is tightly regulated via ligand-dependent receptor and non-receptor tyrosine phosphorylation [>>72<<]. Coordinated interactions with protein tyrosine phosphatases, direct protein inhibitor, and SOCS proteins allow for multiple checkpoints and feedback inhibition [16].
n3:mentions
n2:15653507
Subject Item
_:vb28707806
rdf:type
n3:Context
rdf:value
Coordinated interactions with protein tyrosine phosphatases, direct protein inhibitor, and SOCS proteins allow for multiple checkpoints and feedback inhibition [>>16<<]. However, loss of any counter-regulatory mechanisms can lead to uninhibited proliferation and survival. Constitutive STAT3 activation may confer resistance to apoptosis and promote cell cycle progression through its interactions with the
n3:mentions
n2:17471161
Subject Item
_:vb28707807
rdf:type
n3:Context
rdf:value
Constitutive STAT3 activation may confer resistance to apoptosis and promote cell cycle progression through its interactions with the IL-6 signal transducer, gp130 [>>73<<]. STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,74,75,76]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of
n3:mentions
n2:10851053
Subject Item
_:vb28707808
rdf:type
n3:Context
rdf:value
STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [>>52<<,74,75,76].
n3:mentions
n2:10023775
Subject Item
_:vb28707809
rdf:type
n3:Context
rdf:value
STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,>>74<<,75,76]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [61]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3
n3:mentions
n2:20069389
Subject Item
_:vb28707810
rdf:type
n3:Context
rdf:value
STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,74,>>75<<,76]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [61]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3
n3:mentions
n2:11160159
Subject Item
_:vb28707811
rdf:type
n3:Context
rdf:value
STAT3 activity is associated with upregulation of anti-apoptotic molecules such as Bcl-XL, Mcl-1, and survivin [52,74,75,>>76<<]. STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [61]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3
n3:mentions
n2:12393476
Subject Item
_:vb28707812
rdf:type
n3:Context
rdf:value
STAT3 inhibition has been shown to result in a concomitant reduction in the steady-state levels of anti-apoptotic molecules Bcl-XL, Bcl-2, and Mcl-1 [>>61<<]. Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [77,78,79]. Furthermore, STAT3 may be required for the maintenance
n3:mentions
n2:12466961
Subject Item
_:vb28707813
rdf:type
n3:Context
rdf:value
Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [>>77<<,78,79]. Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC’s) [80]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of
n3:mentions
n2:17043651
Subject Item
_:vb28707814
rdf:type
n3:Context
rdf:value
Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [77,>>78<<,79]. Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC’s) [80]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal
n3:mentions
n2:20113523
Subject Item
_:vb28707815
rdf:type
n3:Context
rdf:value
Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [77,78,>>79<<]. Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC’s) [80]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal
n3:mentions
n2:19926287
Subject Item
_:vb28707816
rdf:type
n3:Context
rdf:value
Furthermore, STAT3 may be required for the maintenance of highly tumorigenic GBM stem cells (GBM-SC’s) [>>80<<]. Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal capacities in GBM stem cells [81]. STAT3 tyrosine (Y) phosphorylation has also been associated with more
n3:mentions
n2:23262510
Subject Item
_:vb28707817
rdf:type
n3:Context
rdf:value
Sherry et al. observed that even transient STAT3 inhibition results in irreversible growth arrest and loss of self-renewal capacities in GBM stem cells [>>81<<]. STAT3 tyrosine (Y) phosphorylation has also been associated with more aggressive tumors. Increased expression of Y705-phosphorylated STAT3 in GBM samples correlated with significantly shorter overall survival [82]. Together, there is
n3:mentions
n2:19658181
Subject Item
_:vb28707818
rdf:type
n3:Context
rdf:value
Increased expression of Y705-phosphorylated STAT3 in GBM samples correlated with significantly shorter overall survival [>>82<<]. Together, there is consistent evidence that STAT3 is a key contributor to GBM pathogenesis by mediating cell survival, growth, and proliferation.
n3:mentions
n2:20455003
Subject Item
_:vb28707819
rdf:type
n3:Context
rdf:value
tumor cell migration preferentially occurs along white matter tracts, accounting for the characteristic “butterfly lesions” frequently observed crossing the corpus callosum, perineuronal satellitosis, and perivascular or subpial spread [>>83<<]. STAT3 inhibitors have been shown to decrease GBM invasion in human glioma cell line U251 [74].
n3:mentions
n2:17805551
Subject Item
_:vb28707820
rdf:type
n3:Context
rdf:value
STAT3 inhibitors have been shown to decrease GBM invasion in human glioma cell line U251 [>>74<<]. Using a JAK2 inhibitor and monolayer wound-healing assays, Senft et al. demonstrated decreased STAT3 activation and migratory behaviors across five different GBM cell lines in vitro [84]. Though the precise mechanisms remain unknown,
n3:mentions
n2:20069389
Subject Item
_:vb28707821
rdf:type
n3:Context
rdf:value
Using a JAK2 inhibitor and monolayer wound-healing assays, Senft et al. demonstrated decreased STAT3 activation and migratory behaviors across five different GBM cell lines in vitro [>>84<<]. Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [42,84,85]. Increased STAT3 and focal adhesion kinase
n3:mentions
n2:20589525
Subject Item
_:vb28707822
rdf:type
n3:Context
rdf:value
Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [>>42<<,84,85]. Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [40]. Further studies of the underlying signaling pathways are needed to more clearly
n3:mentions
n2:21906308
Subject Item
_:vb28707823
rdf:type
n3:Context
rdf:value
Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [42,>>84<<,85]. Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [40]. Further studies of the underlying signaling pathways are needed to more clearly
n3:mentions
n2:20589525
Subject Item
_:vb28707824
rdf:type
n3:Context
rdf:value
Though the precise mechanisms remain unknown, STAT3 may contribute to invasion by upregulating pro-invasive factors such as matrix metalloproteinase-2 (MMP-2), MMP-9, and fascin-1 [42,84,>>85<<]. Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [40]. Further studies of the underlying signaling pathways are needed to more clearly define
n3:mentions
n2:20361349
Subject Item
_:vb28707825
rdf:type
n3:Context
rdf:value
Increased STAT3 and focal adhesion kinase (FAK) has also been demonstrated in SOCS3 knockdown glioma cells leading to increased tumor invasion [>>40<<]. Further studies of the underlying signaling pathways are needed to more clearly define the relationship between STAT3 activation and GBM invasiveness.
n3:mentions
n2:21590492
Subject Item
_:vb28707826
rdf:type
n3:Context
rdf:value
VEGF-mediated angiogenesis is critical for the survival of most tumors, providing the requisite nutrients for accelerated growth and progression [>>24<<]. Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [86,87], and IL-6 receptor associated kinases in myeloma [88].
n3:mentions
n2:21283755
Subject Item
_:vb28707827
rdf:type
n3:Context
rdf:value
Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [>>86<<,87], and IL-6 receptor associated kinases in myeloma [88].
n3:mentions
n2:17374728
Subject Item
_:vb28707828
rdf:type
n3:Context
rdf:value
Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [86,>>87<<], and IL-6 receptor associated kinases in myeloma [88].
n3:mentions
n2:10635317
Subject Item
_:vb28707829
rdf:type
n3:Context
rdf:value
Constitutive tyrosine kinase activation is known to induce VEGF and has been observed in a wide range of cancers, including EGFR- and Src-induced VEGF in breast cancer [86,87], and IL-6 receptor associated kinases in myeloma [>>88<<]. Niu et al. noted that VEGF expression in several cancer cell lines correlated with constitutive STAT3 activity, and that STAT3 inhibition led to reduced Src-induced VEGF expression [89]. Results from promoter mutagenesis and chromatin
n3:mentions
n2:10753844
Subject Item
_:vb28707830
rdf:type
n3:Context
rdf:value
Niu et al. noted that VEGF expression in several cancer cell lines correlated with constitutive STAT3 activity, and that STAT3 inhibition led to reduced Src-induced VEGF expression [>>89<<]. Results from promoter mutagenesis and chromatin immunoprecipitation assays further indicated that the VEGF gene is directly regulated by STAT3, thereby suggesting that STAT3-targeted therapy could play a significant role in disrupting
n3:mentions
n2:11960372
Subject Item
_:vb28707831
rdf:type
n3:Context
rdf:value
More specifically, in vitro overexpression of the viral chemokine receptor US28 has been shown to activate several downstream transcription factors such as hypoxia inducible factor-1 and STAT3, resulting in VEGF promoter activation [>>90<<,91].
n3:mentions
n2:16924106
Subject Item
_:vb28707832
rdf:type
n3:Context
rdf:value
More specifically, in vitro overexpression of the viral chemokine receptor US28 has been shown to activate several downstream transcription factors such as hypoxia inducible factor-1 and STAT3, resulting in VEGF promoter activation [90,>>91<<].
n3:mentions
n2:21900396
Subject Item
_:vb28707833
rdf:type
n3:Context
rdf:value
VEGF is often overexpressed in GBM [>>10<<,92,93], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [11].
n3:mentions
n2:17075581
Subject Item
_:vb28707834
rdf:type
n3:Context
rdf:value
VEGF is often overexpressed in GBM [10,>>92<<,93], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [11].
n3:mentions
n2:10218626
Subject Item
_:vb28707835
rdf:type
n3:Context
rdf:value
VEGF is often overexpressed in GBM [10,92,>>93<<], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [11].
n3:mentions
n2:21321221
Subject Item
_:vb28707836
rdf:type
n3:Context
rdf:value
VEGF is often overexpressed in GBM [10,92,93], and pan-VEGF receptor tyrosine kinase inhibitors have been shown to normalize tumor vasculature and alleviate vasogenic brain edema [>>11<<]. Constitutively activated STAT3 and VEGF receptors can be coexpressed in glioma [58].
n3:mentions
n2:17222792
Subject Item
_:vb28707837
rdf:type
n3:Context
rdf:value
Constitutively activated STAT3 and VEGF receptors can be coexpressed in glioma [>>58<<]. In a study of the phenotypic, physiologic, and molecular tumor response to bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, Keunen et al. found that vascular remodeling and the creation of a more hypoxic tumor
n3:mentions
n2:11960378
Subject Item
_:vb28707838
rdf:type
n3:Context
rdf:value
recombinant humanized monoclonal anti-VEGF antibody, Keunen et al. found that vascular remodeling and the creation of a more hypoxic tumor microenvironment paradoxically resulted in a more invasive, glycolysis-dependent tumor phenotype [>>93<<]. De Groot et al. demonstrated that anti-VEGF therapy in glioma patients results in markedly elevated levels of STAT3 expression, and that STAT3 inhibitors could enhance the efficacy of antiangiogenic treatment strategies [94].
n3:mentions
n2:21321221
Subject Item
_:vb28707839
rdf:type
n3:Context
rdf:value
De Groot et al. demonstrated that anti-VEGF therapy in glioma patients results in markedly elevated levels of STAT3 expression, and that STAT3 inhibitors could enhance the efficacy of antiangiogenic treatment strategies [>>94<<]. Further study of the VEGF and STAT3 interactions will be required to better understand tumor escape and resistance patterns.
n3:mentions
n2:23013619
Subject Item
_:vb28707840
rdf:type
n3:Context
rdf:value
Tumor-mediated immune suppression at both the local and systemic levels has been well described in GBM patients [>>17<<]. T cell anergy, lymphodepletion, lymphosuppression, and impaired antibody synthesis are just some of the ways in which GBMs avoid antigen recognition and targeted destruction [39].
n3:mentions
n2:23096132
Subject Item
_:vb28707841
rdf:type
n3:Context
rdf:value
T cell anergy, lymphodepletion, lymphosuppression, and impaired antibody synthesis are just some of the ways in which GBMs avoid antigen recognition and targeted destruction [>>39<<].
n3:mentions
n2:22748651
Subject Item
_:vb28707842
rdf:type
n3:Context
rdf:value
Secreted factors include IL-10 (an inhibitor of Th1 activity), VEGF, and TGF-beta, which inhibit T cell, B cell, natural killer (NK) cell, and monocyte functions [>>49<<,95,96]. VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [97]. STAT3 hyperactivity can lead to abnormal DC
n3:mentions
n2:14964307
Subject Item
_:vb28707843
rdf:type
n3:Context
rdf:value
Secreted factors include IL-10 (an inhibitor of Th1 activity), VEGF, and TGF-beta, which inhibit T cell, B cell, natural killer (NK) cell, and monocyte functions [49,>>95<<,96]. VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [97]. STAT3 hyperactivity can lead to abnormal DC differentiation
n3:mentions
n2:19944963
Subject Item
_:vb28707844
rdf:type
n3:Context
rdf:value
Secreted factors include IL-10 (an inhibitor of Th1 activity), VEGF, and TGF-beta, which inhibit T cell, B cell, natural killer (NK) cell, and monocyte functions [49,95,>>96<<]. VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [97]. STAT3 hyperactivity can lead to abnormal DC differentiation via
n3:mentions
n2:20493562
Subject Item
_:vb28707845
rdf:type
n3:Context
rdf:value
VEGF not only promotes angiogenesis, as described previously, but also establishes a positive feedback for enhanced STAT3 activation in immature dendritic cells (DCs) [>>97<<]. STAT3 hyperactivity can lead to abnormal DC differentiation via constitutive JAK2/STAT3 activation [18] and decreased expression of major histocompatibility complex (MHC) class II, costimulatory CD40, and IL-12 molecules [98].
n3:mentions
n2:8837607
Subject Item
_:vb28707846
rdf:type
n3:Context
rdf:value
STAT3 hyperactivity can lead to abnormal DC differentiation via constitutive JAK2/STAT3 activation [>>18<<] and decreased expression of major histocompatibility complex (MHC) class II, costimulatory CD40, and IL-12 molecules [98].
n3:mentions
n2:16230418
Subject Item
_:vb28707847
rdf:type
n3:Context
rdf:value
STAT3 hyperactivity can lead to abnormal DC differentiation via constitutive JAK2/STAT3 activation [18] and decreased expression of major histocompatibility complex (MHC) class II, costimulatory CD40, and IL-12 molecules [>>98<<]. Conversely, STAT3 blockade in human GBM cell lines has been shown to alter pro-inflammatory cytokine and immune cell profiles. A study by See et al. demonstrated that siRNA-mediated STAT3 suppression triggered the release of soluble
n3:mentions
n2:14702634
Subject Item
_:vb28707848
rdf:type
n3:Context
rdf:value
such as interferon (IFN) gamma-inducible protein 10 (IP-10), Rantes, IL-8, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-β; furthermore, exposure to these paracrine signaling molecules induced DC maturation and activation [>>17<<].
n3:mentions
n2:23096132
Subject Item
_:vb28707849
rdf:type
n3:Context
rdf:value
However, relatively recent evidence suggests that exposure to glioma-derived chemokines induce constitutive STAT3 activation in MG, with consequent suppression of antitumor mechanisms or even tolerance to tumor antigens [>>99<<,100,101]. In contrast, a study by Komohara et al. demonstrated that direct interaction with glioma cells led to STAT3 activation in tumor infiltrating macrophages. In return, MG/macrophage-derived factors were shown to activate STAT3
n3:mentions
n2:19306372
Subject Item
_:vb28707850
rdf:type
n3:Context
rdf:value
However, relatively recent evidence suggests that exposure to glioma-derived chemokines induce constitutive STAT3 activation in MG, with consequent suppression of antitumor mechanisms or even tolerance to tumor antigens [99,>>100<<,101]. In contrast, a study by Komohara et al. demonstrated that direct interaction with glioma cells led to STAT3 activation in tumor infiltrating macrophages. In return, MG/macrophage-derived factors were shown to activate STAT3 signals
n3:mentions
n2:18832699
Subject Item
_:vb28707851
rdf:type
n3:Context
rdf:value
However, relatively recent evidence suggests that exposure to glioma-derived chemokines induce constitutive STAT3 activation in MG, with consequent suppression of antitumor mechanisms or even tolerance to tumor antigens [99,100,>>101<<]. In contrast, a study by Komohara et al. demonstrated that direct interaction with glioma cells led to STAT3 activation in tumor infiltrating macrophages.
n3:mentions
n2:16775224
Subject Item
_:vb28707852
rdf:type
n3:Context
rdf:value
In return, MG/macrophage-derived factors were shown to activate STAT3 signals in tumor cells, perpetuating glioma pathogenesis and progression [>>102<<].
n3:mentions
n2:22957741
Subject Item
_:vb28707853
rdf:type
n3:Context
rdf:value
STAT3 also recruits and promotes the proliferation of T regulatory cells (Tregs), which suppress effector lymphocyte activity within the tumor microenvironment [>>103<<,104]. Tregs are preferentially recruited to high-grade gliomas following tumor secretion of CCL2/22 chemokines [105].
n3:mentions
n2:15776005
Subject Item
_:vb28707854
rdf:type
n3:Context
rdf:value
STAT3 also recruits and promotes the proliferation of T regulatory cells (Tregs), which suppress effector lymphocyte activity within the tumor microenvironment [103,>>104<<]. Tregs are preferentially recruited to high-grade gliomas following tumor secretion of CCL2/22 chemokines [105].
n3:mentions
n2:16177085
Subject Item
_:vb28707855
rdf:type
n3:Context
rdf:value
Tregs are preferentially recruited to high-grade gliomas following tumor secretion of CCL2/22 chemokines [>>105<<]. Following direct interaction with local dendritic cells, Tregs secrete TGFb to inhibit activation of cytotoxic T cells [19,106]. STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of
n3:mentions
n2:20537408
Subject Item
_:vb28707856
rdf:type
n3:Context
rdf:value
Following direct interaction with local dendritic cells, Tregs secrete TGFb to inhibit activation of cytotoxic T cells [>>19<<,106]. STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of tumor-infiltrating Treg cells, as well as enhanced activity of DCs, natural killer (NK) cells, T cells, and neutrophils [107]. These
n3:mentions
n2:14499117
Subject Item
_:vb28707857
rdf:type
n3:Context
rdf:value
Following direct interaction with local dendritic cells, Tregs secrete TGFb to inhibit activation of cytotoxic T cells [19,>>106<<]. STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of tumor-infiltrating Treg cells, as well as enhanced activity of DCs, natural killer (NK) cells, T cells, and neutrophils [107]. These findings
n3:mentions
n2:20053772
Subject Item
_:vb28707858
rdf:type
n3:Context
rdf:value
STAT3 deletion in hematopoietic cells has been associated with a markedly decreased number of tumor-infiltrating Treg cells, as well as enhanced activity of DCs, natural killer (NK) cells, T cells, and neutrophils [>>107<<]. These findings further implicate STAT3 as a negative regulator of the host immune system.
n3:mentions
n2:16288283
Subject Item
_:vb28707859
rdf:type
n5:Section
dc:title
stat3 as a tumor suppressor
n5:contains
_:vb28707872 _:vb28707873 _:vb28707874 _:vb28707875 _:vb28707876 _:vb28707877 _:vb28707864 _:vb28707865 _:vb28707866 _:vb28707867 _:vb28707868 _:vb28707869 _:vb28707870 _:vb28707871 _:vb28707860 _:vb28707861 _:vb28707862 _:vb28707863
Subject Item
_:vb28707860
rdf:type
n3:Context
rdf:value
For example, the IL-6 growth-inhibitory and terminal differentiation signal has been correlated with STAT3 transcriptional activity in prostate cancer [>>108<<,109]. Similarly, IL-6 mediated growth arrest in melanoma is STAT3-dependent [110]. STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation
n3:mentions
n2:10639189
Subject Item
_:vb28707861
rdf:type
n3:Context
rdf:value
For example, the IL-6 growth-inhibitory and terminal differentiation signal has been correlated with STAT3 transcriptional activity in prostate cancer [108,>>109<<]. Similarly, IL-6 mediated growth arrest in melanoma is STAT3-dependent [110]. STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation
n3:mentions
n2:10617865
Subject Item
_:vb28707862
rdf:type
n3:Context
rdf:value
Similarly, IL-6 mediated growth arrest in melanoma is STAT3-dependent [>>110<<]. STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [111,112,113].
n3:mentions
n2:10391682
Subject Item
_:vb28707863
rdf:type
n3:Context
rdf:value
STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [>>111<<,112,113].
n3:mentions
n2:11239451
Subject Item
_:vb28707864
rdf:type
n3:Context
rdf:value
STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [111,>>112<<,113].
n3:mentions
n2:7521688
Subject Item
_:vb28707865
rdf:type
n3:Context
rdf:value
STAT3 is also involved in myeloid cell differentiation via granulocyte colony stimulating factor (G-CSF)-mediated JAK phosphorylation and p27 upregulation [111,112,>>113<<].
n3:mentions
n2:10918585
Subject Item
_:vb28707866
rdf:type
n3:Context
rdf:value
Inhibition of STAT3 via overexpression of the tumor suppressor PTEN promotes proliferation and tumorigenesis [>>114<<]. Moreover, STAT3 activation is implicated in epithelial cell apoptosis in the mammary gland, and STAT3 knockout in mammary gland tissue results in delayed involution suggesting an early role for STAT3 in initiation of apoptosis [115].
n3:mentions
n2:12865943
Subject Item
_:vb28707867
rdf:type
n3:Context
rdf:value
Moreover, STAT3 activation is implicated in epithelial cell apoptosis in the mammary gland, and STAT3 knockout in mammary gland tissue results in delayed involution suggesting an early role for STAT3 in initiation of apoptosis [>>115<<]. Keratinocyte differentiation involves STAT3 activation and its association with p27kip1 accumulation, while hepatocyte epithelial tubule differentiation relies on hepatocyte growth factor-mediated STAT3 activation and translocation to
n3:mentions
n2:8906870
Subject Item
_:vb28707868
rdf:type
n3:Context
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differentiation involves STAT3 activation and its association with p27kip1 accumulation, while hepatocyte epithelial tubule differentiation relies on hepatocyte growth factor-mediated STAT3 activation and translocation to the nucleus [>>116<<,117]. GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [118,119].
n3:mentions
n2:9790496
Subject Item
_:vb28707869
rdf:type
n3:Context
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involves STAT3 activation and its association with p27kip1 accumulation, while hepatocyte epithelial tubule differentiation relies on hepatocyte growth factor-mediated STAT3 activation and translocation to the nucleus [116,>>117<<]. GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [118,119].
n3:mentions
n2:9440692
Subject Item
_:vb28707870
rdf:type
n3:Context
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GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [>>118<<,119].
n3:mentions
n2:18524891
Subject Item
_:vb28707871
rdf:type
n3:Context
rdf:value
GBM is not precluded from such STAT3-mediated cell cycle regulation, and recent studies suggest that STAT3 activation actually prevents malignant transformation of glial cells in some systems [118,>>119<<].
n3:mentions
n2:19601808
Subject Item
_:vb28707872
rdf:type
n3:Context
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The role of the JAK-STAT pathway is well established in astrocyte differentiation [>>120<<,121,122,123,124].
n3:mentions
n2:9334309
Subject Item
_:vb28707873
rdf:type
n3:Context
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The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,>>121<<,122,123,124].
n3:mentions
n2:9570793
Subject Item
_:vb28707874
rdf:type
n3:Context
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The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,121,>>122<<,123,124]. While STAT3 activation has been associated with GBM evasion of immunosurveillance and enhancement of cell survival and proliferation, it is not surprising that STAT3 activation suppresses malignant transformation in certain GBM
n3:mentions
n2:18039109
Subject Item
_:vb28707875
rdf:type
n3:Context
rdf:value
The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,121,122,>>123<<,124]. While STAT3 activation has been associated with GBM evasion of immunosurveillance and enhancement of cell survival and proliferation, it is not surprising that STAT3 activation suppresses malignant transformation in certain GBM
n3:mentions
n2:12086863
Subject Item
_:vb28707876
rdf:type
n3:Context
rdf:value
The role of the JAK-STAT pathway is well established in astrocyte differentiation [120,121,122,123,>>124<<]. While STAT3 activation has been associated with GBM evasion of immunosurveillance and enhancement of cell survival and proliferation, it is not surprising that STAT3 activation suppresses malignant transformation in certain GBM
n3:mentions
n2:12359767
Subject Item
_:vb28707877
rdf:type
n3:Context
rdf:value
De la Iglesia et al. have shown that in PTEN-deficient GBM, endogenous STAT3 inhibition prevents STAT3-mediated transcriptional IL-8 repression, resulting in increased tumor proliferation and invasiveness [>>118<<]. Furthermore, they found that reactivation of STAT3 in PTEN-deficient GBM suppresses the invasive phenotype and GBM proliferation along myelin in white matter tracts. Thus, whether STAT3 behaves as a tumor suppressor or oncogene relies
n3:mentions
n2:18524891
Subject Item
_:vb28707878
rdf:type
n5:Section
dc:title
stat3 as a prognostic indicator
n5:contains
_:vb28707884 _:vb28707880 _:vb28707881 _:vb28707882 _:vb28707883 _:vb28707879
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_:vb28707879
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Jin et al. report that STAT3 expression in colorectal carcinoma is correlated with higher-grade tumors and poorer survival [>>125<<]. Conversely, Gordziel and colleagues found that strong STAT3 expression in colorectal carcinoma biopsies is associated with an improvement in median survival of about 30 months compared to STAT3 negative biopsies [126]. Such
n3:mentions
n2:23170117
Subject Item
_:vb28707880
rdf:type
n3:Context
rdf:value
Conversely, Gordziel and colleagues found that strong STAT3 expression in colorectal carcinoma biopsies is associated with an improvement in median survival of about 30 months compared to STAT3 negative biopsies [>>126<<]. Such discrepancies in study results may reflect the dependence of STAT3 tumorigenic versus tumor suppressor function on the tumor genetic background, potentially confounding the results.
n3:mentions
n2:23756862
Subject Item
_:vb28707881
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In GBM, survivin positivity has been suggested as a strong prognostic indicator of significantly poorer survival and higher malignant grade, owing to its anti-apoptotic activity [>>127<<,128]. Regarding STAT3, Abou-Ghazal and colleagues found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent
n3:mentions
n2:11844831
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_:vb28707882
rdf:type
n3:Context
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In GBM, survivin positivity has been suggested as a strong prognostic indicator of significantly poorer survival and higher malignant grade, owing to its anti-apoptotic activity [127,>>128<<]. Regarding STAT3, Abou-Ghazal and colleagues found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent
n3:mentions
n2:12569609
Subject Item
_:vb28707883
rdf:type
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found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent prognostic indicator of decreased survival [>>56<<,129]. Recent studies demonstrate that STAT3 could be a useful tumor marker of poor prognosis; however, given the tumor suppressive role of STAT3 in PTEN deficient tumors, it is important that future studies stratify GBM samples based on
n3:mentions
n2:19088040
Subject Item
_:vb28707884
rdf:type
n3:Context
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found that pSTAT3 expression in astrocytomas was correlated with poorer survival, and Tu et al. report that JAK/STAT activation correlates with higher-grade gliomas and is an independent prognostic indicator of decreased survival [56,>>129<<]. Recent studies demonstrate that STAT3 could be a useful tumor marker of poor prognosis; however, given the tumor suppressive role of STAT3 in PTEN deficient tumors, it is important that future studies stratify GBM samples based on
n3:mentions
n2:20135364
Subject Item
_:vb28707885
rdf:type
n5:Section
dc:title
stat3 as a therapeutic target
n5:contains
_:vb28707904 _:vb28707905 _:vb28707906 _:vb28707907 _:vb28707908 _:vb28707909 _:vb28707910 _:vb28707911 _:vb28707912 _:vb28707913 _:vb28707914 _:vb28707888 _:vb28707889 _:vb28707890 _:vb28707891 _:vb28707892 _:vb28707893 _:vb28707894 _:vb28707895 _:vb28707896 _:vb28707897 _:vb28707898 _:vb28707899 _:vb28707900 _:vb28707901 _:vb28707902 _:vb28707903 _:vb28707886 _:vb28707887
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_:vb28707886
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DrugMechanism of ActionOleanolic acidSuppresses IL-10 secretion which suppresses M2 polarization of tumor-associated macrophages [>>130<<]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells
n3:mentions
n2:21922144
Subject Item
_:vb28707887
rdf:type
n3:Context
rdf:value
DrugMechanism of ActionOleanolic acidSuppresses IL-10 secretion which suppresses M2 polarization of tumor-associated macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [>>26<<,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3
n3:mentions
n2:19127268
Subject Item
_:vb28707888
rdf:type
n3:Context
rdf:value
DrugMechanism of ActionOleanolic acidSuppresses IL-10 secretion which suppresses M2 polarization of tumor-associated macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,>>131<<]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific
n3:mentions
n2:21526200
Subject Item
_:vb28707889
rdf:type
n3:Context
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which suppresses M2 polarization of tumor-associated macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [>>132<<]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific cis elements [36]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream
n3:mentions
n2:22249692
Subject Item
_:vb28707890
rdf:type
n3:Context
rdf:value
macrophages [130]LLL12Suppress phosphorylation of STAT3; inhibit STAT3 DNA binding [26,131]LLL3WP1193Inhibitor of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [>>133<<]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific cis elements [36]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream decreased expression of MMP-2 and MMP-9 and inhibition
n3:mentions
n2:18839277
Subject Item
_:vb28707891
rdf:type
n3:Context
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of JAK2/STAT3 pathway in glioma-like stem cells resultin gin G1 arrest [132]RNAiDownregulation of cyclin D1 in glioma cells [133]OligodeoxynucleotidesInduce cell cycle arrest and apoptosis by mimicking STAT3 specific cis elements [>>36<<]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream decreased expression of MMP-2 and MMP-9 and inhibition of tumor cell invasiveness
n3:mentions
n2:11326271
Subject Item
_:vb28707892
rdf:type
n3:Context
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cycle arrest and apoptosis by mimicking STAT3 specific cis elements [36]AG490Inhibits JAK2, resulting in decreased activation of STAT3 and downstream decreased expression of MMP-2 and MMP-9 and inhibition of tumor cell invasiveness [>>84<<
n3:mentions
n2:20589525
Subject Item
_:vb28707893
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Potential drugs that directly inhibit STAT3 activation include the naturally occurring triterpenoid oleanolic acid, which also suppresses the M2 polarization of tumor-associated macrophages by suppressing IL-10 secretion [>>130<<]. Small molecule inhibitors are also candidates for suppressing STAT3 activity, as they produce a similar anti-tumor inflammatory microenvironment as siRNA-mediated knockdown of STAT3 [17].
n3:mentions
n2:21922144
Subject Item
_:vb28707894
rdf:type
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Small molecule inhibitors are also candidates for suppressing STAT3 activity, as they produce a similar anti-tumor inflammatory microenvironment as siRNA-mediated knockdown of STAT3 [>>17<<]. Other small molecule inhibitors, including LLL12 and LLL3, suppress phosphorylation of STAT3 and inhibit STAT3 DNA binding, resulting in decreased viability of tumor cells and resultant apoptosis. Moreover, treatment with LLL3 increased
n3:mentions
n2:23096132
Subject Item
_:vb28707895
rdf:type
n3:Context
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Moreover, treatment with LLL3 increased survival in GBM-bearing mice by 12.5 days [>>26<<,131]. Others have targeted the JAK2/STAT3 pathway in glioma stem-like cells (GSCs). WP1193 is a small molecule inhibitor of JAK2/STAT3, which promotes in vivo glioma inhibition in a dose-dependent manner and is partially associated with
n3:mentions
n2:19127268
Subject Item
_:vb28707896
rdf:type
n3:Context
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Moreover, treatment with LLL3 increased survival in GBM-bearing mice by 12.5 days [26,>>131<<]. Others have targeted the JAK2/STAT3 pathway in glioma stem-like cells (GSCs). WP1193 is a small molecule inhibitor of JAK2/STAT3, which promotes in vivo glioma inhibition in a dose-dependent manner and is partially associated with G1
n3:mentions
n2:21526200
Subject Item
_:vb28707897
rdf:type
n3:Context
rdf:value
WP1193 is a small molecule inhibitor of JAK2/STAT3, which promotes in vivo glioma inhibition in a dose-dependent manner and is partially associated with G1 arrest in GSCs [>>132<<]. STAT3 knockdown with interfering RNA, delivered by a lentivirus vector, resulted in down-regulation of cyclin D1 and inhibition of glioma cell proliferation [133]. Oligodeoxynucleotides may also serve as future therapeutic options as
n3:mentions
n2:22249692
Subject Item
_:vb28707898
rdf:type
n3:Context
rdf:value
STAT3 knockdown with interfering RNA, delivered by a lentivirus vector, resulted in down-regulation of cyclin D1 and inhibition of glioma cell proliferation [>>133<<]. Oligodeoxynucleotides may also serve as future therapeutic options as they induce cell-cycle arrest and apoptosis by mimicking STAT3 specific cis-elements [36]. Furthermore, STAT3’s role in Th17 T cell differentiation and cytokine
n3:mentions
n2:18839277
Subject Item
_:vb28707899
rdf:type
n3:Context
rdf:value
Oligodeoxynucleotides may also serve as future therapeutic options as they induce cell-cycle arrest and apoptosis by mimicking STAT3 specific cis-elements [>>36<<]. Furthermore, STAT3’s role in Th17 T cell differentiation and cytokine production renders it an attractive target for immunotherapy in autoimmune pathways, as ablation of STAT3 in CD4 cells results in increased Th1 responses rather than
n3:mentions
n2:11326271
Subject Item
_:vb28707900
rdf:type
n3:Context
rdf:value
role in Th17 T cell differentiation and cytokine production renders it an attractive target for immunotherapy in autoimmune pathways, as ablation of STAT3 in CD4 cells results in increased Th1 responses rather than Th17 responses [>>134<<].
n3:mentions
n2:17878325
Subject Item
_:vb28707901
rdf:type
n3:Context
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Other drug targets include STAT3 associated genes that inhibit tumor cell migration or invasion [>>135<<]. AG490 inhibits JAK2, the upstream activator of STAT3, which results in decreased expression of the STAT3 regulated genes MMP-2 and MMP-9 [84].
n3:mentions
n2:23891970
Subject Item
_:vb28707902
rdf:type
n3:Context
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AG490 inhibits JAK2, the upstream activator of STAT3, which results in decreased expression of the STAT3 regulated genes MMP-2 and MMP-9 [>>84<<].
n3:mentions
n2:20589525
Subject Item
_:vb28707903
rdf:type
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Resveratrol, a grape polyphenol, has been shown to enhance glioma radiosensitivity by inhibiting STAT3 signaling, rendering future promise for more effective radiotherapy [>>136<<]. Resistance to temozolomide has been shown to be associated with STAT3 activation and upregulation of the DNA repair enzyme MGMT [14]. Thus, STAT3 knockdown prior to temozolomide therapy may reduce the incidence of tumor resistance to
n3:mentions
n2:20371721
Subject Item
_:vb28707904
rdf:type
n3:Context
rdf:value
Resistance to temozolomide has been shown to be associated with STAT3 activation and upregulation of the DNA repair enzyme MGMT [>>14<<]. Thus, STAT3 knockdown prior to temozolomide therapy may reduce the incidence of tumor resistance to chemotherapy.
n3:mentions
n2:22532597
Subject Item
_:vb28707905
rdf:type
n3:Context
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is clearly an integral pathway to tumor growth and invasion, lifting the “brakes” on immune function through STAT3 checkpoint blockade combined with tumor-specific vaccine therapy may show promise for more robust anti-tumor responses [>>16<<]. Such checkpoint blockade combined with vaccine based immune activation has shown enhanced anti-tumor responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4)
n3:mentions
n2:17471161
Subject Item
_:vb28707906
rdf:type
n3:Context
rdf:value
anti-tumor responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [>>16<<,134,137,138,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134].
n3:mentions
n2:17471161
Subject Item
_:vb28707907
rdf:type
n3:Context
rdf:value
responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,>>134<<,137,138,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134].
n3:mentions
n2:17878325
Subject Item
_:vb28707908
rdf:type
n3:Context
rdf:value
responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,>>137<<,138,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134].
n3:mentions
n2:11560997
Subject Item
_:vb28707909
rdf:type
n3:Context
rdf:value
responses over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,>>138<<,139,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134].
n3:mentions
n2:12826605
Subject Item
_:vb28707910
rdf:type
n3:Context
rdf:value
over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,138,>>139<<,140,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134].
n3:mentions
n2:12682289
Subject Item
_:vb28707911
rdf:type
n3:Context
rdf:value
over vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,138,139,>>140<<,141]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134].
n3:mentions
n2:21527558
Subject Item
_:vb28707912
rdf:type
n3:Context
rdf:value
vaccine therapy alone in mouse models and clinical trials combining cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) blockade and granulocyte/macrophage-colony stimulating factor-secreting tumor vaccines [16,134,137,138,139,140,>>141<<]. Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [134].
n3:mentions
n2:10430624
Subject Item
_:vb28707913
rdf:type
n3:Context
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Combination blockade of STAT3 along with vaccine therapy has shown encouraging results in melanoma [>>134<<]. Thus, multi-modality therapy involving cancer vaccines may be the key to the role of STAT3 inhibition in curative immunotherapy by promoting CD4 and CD8 T cell mediated tumor-specific killing [140].
n3:mentions
n2:17878325
Subject Item
_:vb28707914
rdf:type
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Thus, multi-modality therapy involving cancer vaccines may be the key to the role of STAT3 inhibition in curative immunotherapy by promoting CD4 and CD8 T cell mediated tumor-specific killing [>>140<<].
n3:mentions
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