Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways

Xu, Qing; Briggs, Jon; Park, Sungman; Niu, Guilian; Kortylewski, Marcin; Zhang, Shumin; Gritsko, Tanya; Turkson, James; Kay, H. David; Semenza, Gregg L.; Cheng, Jin Q.; Jove, Richard; Yu, Hua

doi:10.1038/sj.onc.1208719

Cited by 524 publications

(477 citation statements)

References 40 publications

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“…Indeed, a recent study showed that the levels of HIF1, a factor involved in tumor proliferation, is upregulated by STAT3 (Xu et al, 2005). Consistent with this observation, inhibition of STAT3 activity by a siRNA or a small molecular inhibitor downregulated HIF-1 levels and tumor growth (Xu et al, 2005). As said earlier, HIF1 activity is controlled by the VHL gene product, whose loss leads to the development of RCC.…”

Section: Inactivation Of Grim-19 In Cancer I Alchanati Et Alsupporting

confidence: 53%

“…This effect, in part, is due to an increased expression of STAT3 regulated genes. Indeed, a recent study showed that the levels of HIF1, a factor involved in tumor proliferation, is upregulated by STAT3 (Xu et al, 2005). Consistent with this observation, inhibition of STAT3 activity by a siRNA or a small molecular inhibitor downregulated HIF-1 levels and tumor growth (Xu et al, 2005).…”

Section: Inactivation Of Grim-19 In Cancer I Alchanati Et Almentioning

confidence: 78%

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A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

et al. 2006

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Section: Inactivation Of Grim-19 In Cancer I Alchanati Et Alsupporting

confidence: 53%

Section: Inactivation Of Grim-19 In Cancer I Alchanati Et Almentioning

confidence: 78%

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

et al. 2006

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“…2) [24][25][26][27][28]. Interestingly, while these genes were overexpressed in JAK2 V617F patients relative to healthy controls, this was not the case in non-V617F patients.…”

Section: Resultsmentioning

confidence: 99%

JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

Schwemmers

Will

Waller

et al. 2007

Experimental Hematology

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Objective-Presence of the JAK2 V617F mutation in only 40-60% of patients with Essential Thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, Polycythemia vera (PV) and Idiopathic Myelofibrosis (IMF). Analogous to JAK2 V617F , these mutations cause constitutive JAK2 and STAT activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/ STAT signal transduction pathway, underlie a subset of JAK2 V617F -negative ET.Methods-cDNA microarrays and qRT-PCR were used to compare gene expression in 40 ET patients with and without the JAK2 V617F mutation.Results-Unsupervised clustering of gene expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2 V617F mutation. Patients lacking the JAK2 V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and SOCS2. In addition, JAK2 V617F -negative patients showed lower levels of STAT3 phosphorylation.Conclusions-These data demonstrate that a large proportion of JAK2 V617F -negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ETinducing changes will facilitate both a molecular classification of ET and the development of rationally designed therapies.

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“…Of interest, STAT3 activation is stimulated by inflammatory pathways (Hirano et al, 2000). Importantly, STAT3 has been shown to play a critical role in the process of HIF-1α activation and VEGF expression in multiple growth signaling pathways (Xu et al, 2005). In conditions of diabetes or high glucose treatment, STAT3 activation occurs in a redox-dependent manner involving NAD(P)H oxidase activity and peroxynitrite formation (Al-Shabrawey et al, submitted; Bartoli et al, submitted;Platt et al, 2005).…”

Section: Transcriptional Regulation Of Vegf Expression-tissuementioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

615

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways

Cited by 524 publications

References 40 publications

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

Vascular endothelial growth factor in eye disease

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