Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis

Wei, Daoyan; Xin, Le; Zheng, Leizhen; Wang, Liwei; Frey, Jennifer A.; Gao, Allen C.; Peng, Zhihai; Huang, Suyun; Xiong, Henry Q.; Abbruzzese, James L.; Xie, Keping

doi:10.1038/sj.onc.1206122

Cited by 502 publications

(416 citation statements)

References 51 publications

(60 reference statements)

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“…Forced expression of STAT3C (a construct constitutively activated by spontaneous dimmer formation) in immortalized fibroblasts induced cell transformation and tumor formation in nude mice (Bromberg et al, 1999). Blocking STAT3 activity with chemical reagents and dominant-negative forms inhibited the tumor cell growth in nude mice (Blaskovich et al, 2003;Wei et al, 2003). We showed suppression of the subcutaneous tumor-forming activity of T24 cells by overexpressing the dominant-negative STAT3.…”

Section: Discussionmentioning

confidence: 75%

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

et al. 2005

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Signal transducers and activators of transcription (STATs) are latent transcription factors that mediate cytokine-and growth factor-induced transcription. Constitutive activation of STAT3 has been shown in human cancers and transformed cell lines. We report that STAT3, but not STAT1 and STAT5, becomes phosphorylated in response to epidermal growth factor (EGF) and achieves maximal induction of collagenase-1 (MMP-1) transcription by interacting with c-JUN. Phosphorylation of STAT3 protein is biphasic: the first peak within 30 min and the second peak between 4 and 8 h. Association of STAT3 with c-JUN is detected and its constituting STAT3 is increasingly phosphorylated. The STAT and AP-1 elements are necessary for effective induction of MMP-1 promoter by EGF. Mutation of AP-1 element closely located at the STAT site abolishes the binding not only of c-JUN but also of STAT3 to MMP-1 promoter, resulting in the loss of the responsiveness to EGF. By blocking STAT3 activity with the dominant-negative form, we show the requirement of STAT3 for EGF induction of MMP-1 and MMP-10 (stromelysin-2). Furthermore, expression of the dominant-negative STAT3 is sufficient to inhibit the constitutive and EGF-inducible cell migration and invasion and the tumor formation in nude mice. These results demonstrate that STAT3 phosphorylation and its possible interaction with c-JUN are required for the strong responsiveness of MMP-1 to EGF, and STAT3 activation is crucial for exhibition of malignant characteristics in T24 bladder cancer cells.

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Section: Discussionmentioning

confidence: 75%

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

et al. 2005

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“…These results are in line with those of Wei et al 27 and others showing that constitutive STAT3 activity upregulates VEGF expression and tumor angiogenesis. 48,49 A putative upstream STAT binding element at nt À842 to À849 in the VEGF promoter was recently ascribed to be involved in STAT3-mediated VEGF expression. 48 However, in our progressive deletion analysis, IL-6 is still increasing VEGF transcription even in the absence of this upstream promoter region, indicating that IL-6-induced VEGF transcription is not dependent on the supposed STAT binding element at nt À842 to À849 in the VEGF promoter.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

Loeffler

Fayard

Weis

et al. 2005

Intl Journal of Cancer

189

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Interleukin-6 (IL-6) expression is strongly correlated with the degree of human glioma malignancy and necessary for tumor formation in a mouse model of spontaneous astrocytomas. Yet, exactly how IL-6 contributes to malignant progression of these brain tumors is still unclear. We have scrutinized the mechanism of transcriptional activation of vascular endothelial growth factor (VEGF) expression by IL-6 in the mouse brain and in glioblastoma cells. We demonstrate here that IL-6 drives transcriptional upregulation of VEGF in astrocytes in vivo using glial fibrillary acidic protein (GFAP)-IL-6/VEGF-green fluorescent protein (GFP) double transgenic mice. We further show that IL-6-induced VEGF transcription and VEGF secretion by human glioblastoma cells is dependent on signal transducer and activator of transcription 3 (STAT3). By progressive 5 0 -deletion analysis we defined the minimal VEGF promoter region for IL-6-responsiveness to nucleotides 288/250. Surprisingly, this promoter region is rich in GC-boxes and does not contain STAT3 binding elements. Electrophoretic mobility shift and supershift assays revealed binding of Sp1 and Sp3 to the 288/250 element upon IL-6 stimulation. Interestingly, preincubation with STAT3 antibody prevented the binding of Sp1 and Sp3 to the 288/250 element, indicating that STAT3 is involved in IL-6-driven Sp1/Sp3 protein-DNA complex formation. Physical interaction of STAT3 and Sp1 was demonstrated by coimmunoprecipitation. The functional relevance of the STAT3/ Sp1 association was corroborated by transient transfection experiments, which showed that overexpression of constitutively active STAT3 increased the minimal VEGF promoter activity. Taken together, our study suggests that IL-6 promotes tumor angiogenesis in gliomas and describes a novel transcriptional activation mechanism for STAT3 in the context of a STAT3 binding element (SBE)-free promoter. ' 2005 Wiley-Liss, Inc.

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“…68 To date, however, transkingdom RNAi has not been used to directly target angiogenesis, although some of the targets mentioned above (b-catenin, STAT3 and bcl-2) are known to augment angiogenesis through their effects on the expression of various proangiogenic factors. [69][70][71] Anti-tumor effects of knocking down these targets may, in part, be related to suppression of blood vessel formation. However, a number of studies using 'non-bacterial' application of siRNA against VEGF, 72,73 HIF-1a 74 and other angiogenesis-related molecules 75 indicates that inhibition of endothelial cell proliferation and new blood vessel formation are a viable target for RNAi-based treatment of cancer, as well as other diseases.…”

Section: Transkingdom Rnaimentioning

confidence: 99%

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

et al. 2011

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Several bacterial species have inherent ability to colonize solid tumors in vivo. However, their natural anti-tumor activity can be enhanced by genetic engineering that enables these bacteria express or transfer therapeutic molecules into target cells. In this review, we summarize latest research on cancer therapy using genetically modified bacteria with particular emphasis on blocking tumor angiogenesis. Despite recent progress, only a few recent studies on bacterial tumor therapy have focused on anti-angiogenesis. Bacteria-mediated anti-angiogenesis therapy for cancer, however, is an attractive approach given that solid tumors are often characterized by increased vascularization. Here, we discuss four different approaches for using modified bacteria as anti-cancer therapeutics-bactofection, DNA vaccination, alternative gene therapy and transkingdom RNA interference-with a specific focus on angiogenesis suppression. Critical areas and future directions for this field are also outlined.

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Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis

Cited by 502 publications

References 51 publications

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

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