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, Sébastien; Fayard, Bérengère; Weis, Joachim; Weissenberger, Jakob

doi:10.1002/ijc.20871

Cited by 191 publications

(154 citation statements)

References 48 publications

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“…3D). In agreement, IL6 has been shown to promote angiogenesis (Cohen et al 1996;Wei et al 2003;Huang et al 2004;Loeffler et al 2005;Nilsson et al 2005). However, endothelial cells typically do not express detectable levels of IL6R ( Supplementary Fig.…”

Section: Ras-induced Il6 Secretion Acts In a Paracrine Fashion To Prosupporting

confidence: 62%

Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis

Ancrile¹,

Lim²,

Counter³

2007

Genes Dev.

361

301

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Ras is mutated to remain in the active oncogenic state in many cancers. As Ras has proven difficult to target therapeutically, we searched for secreted, druggable proteins induced by Ras that are required for tumorigenesis. We found that Ras induces the secretion of cytokine IL6 in different cell types, and that knockdown of IL6, genetic ablation of the IL6 gene, or treatment with a neutralizing IL6 antibody retard Ras-driven tumorigenesis. IL6 appears to act in a paracrine fashion to promote angiogenesis and tumor growth. Inhibiting IL6 may therefore have therapeutic utility for treatment of cancers characterized by oncogenic Ras mutations.Supplemental material is available at http://www.genesdev.org.

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Section: Ras-induced Il6 Secretion Acts In a Paracrine Fashion To Prosupporting

confidence: 62%

Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis

Ancrile¹,

Lim²,

Counter³

2007

Genes Dev.

361

301

View full text Add to dashboard Cite

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“…[52][53][54] In this context, it is interesting to note that, in the present study, there was no increase in the amount of tumor necrosis in the MT-ret ϩ/Ϫ mice lacking IL-6. This observation suggests that blood supply to these tumors was not critically impaired because of the lack of IL-6.…”

Section: Discussionmentioning

confidence: 76%

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Felbert

Córdoba

Weissenberger

et al. 2005

The American Journal of Pathology

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Interleukin (IL)-6 is a pleiotropic cytokine that has been shown to inhibit the growth of early stage and to promote the proliferation of advanced stage melanoma cells in vitro. In patients with metastasizing melanomas, highly increased IL-6 blood levels correlate with a poor response to chemotherapy and a worse overall prognosis, suggesting that IL-6 promotes melanoma progression in vivo. Here, we analyzed the role of IL-6 in melanoma development and progression in a transgenic mouse model. We bred IL-6-deficient mice with MT-ret transgenic animals predisposed for melanomas. While MT-ret transgenic animals develop severe melanosis of the skin and subcutis and subsequent melanomas at an incidence of 80% during their first year of life, MT-ret mice devoid of IL-6 developed preneoplastic melanosis and consecutive melanomas significantly less frequently (47%; P < 0.05). Moreover, the tumors were significantly smaller in the groups of MT-ret mice lacking one (P < 0.05) or both (P < 0.01) copies of the IL-6 gene. Immunoblot analysis revealed that ret transgene expression was not reduced in the skin of mice lacking IL-6, indicating that the observed decrease of melanoma incidence and of tumor sizes was not because of a down-regulation of transgene expression. Interleukin (IL)-6 is a pleiotropic cytokine that induces the acute phase response, stimulates B-and T-lymphocytes, and regulates the growth, differentiation, and death of several cell populations including neurons and melanocytes. 1-3 IL-6 promotes the development and progression of plasmacytomas 4 and gliomas 4,5 in vivo. It is also a growth-promoting factor for human basal cell carcinoma, Kaposi's sarcoma, and prostate cancer cells in vitro. 3,6 The IL-6 receptor system consists of IL-6 receptor ␣ (IL-6R␣), the primary IL-6 receptor, and the ubiquitous gp130 signal-transducing receptor subunit. Binding of IL-6 to its receptor complex leads to the activation of janus kinases (Jaks) and subsequent phosphorylation, dimerization, and nuclear translocation of signal transducer and activator of transcription 3 (STAT3). 2,7 STAT3 promotes tumor progression by regulating the expression of genes involved in growth control such as c-myc, antiapoptosis [Bcl-x(L) and Mcl-1] and angiogenesis (vascular endothelial growth factor). 8 -11 In a recent study, STAT3 was found to be constitutively activated in some, but not all human melanoma cell lines and tumor specimens analyzed. 12 However, blocking experiments revealed that STAT3 activation in these cell lines was apparently mainly caused by Src tyrosine kinase activity and not by Jak activation. 12

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“…Although previous studies have confirmed that IL-6 is important in both physiological and pathological angiogenesis (Cohen et al, 1996;Mahnke et al, 2000), IL-6 has recently received more attention as a critical cytokine implicated in the angiogenesis of several human cancers, including cervical cancer, basal cell carcinoma, glioma, gastric carcinoma and mesothelioma (Wei et al, 2003;Huang et al, 2004;Jee et al, 2004;Loeffler et al, 2005;Adachi et al, 2006;Saidi et al, 2009). Strikingly, these investigations provide evidence that IL-6 may promote VEGF-induced tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 92%

“…siRNA-mediated targeting of IL-6 in vector or ILK-overexpressing cells inhibited the levels of phosphorylated STAT3 (Figure 6a). Because IL-6 is reported to upregulate VEGF to induce angiogenesis (Wei et al, 2003;Huang et al, 2004;Loeffler et al, 2005;Adachi et al, 2006), we used VEGF antibody to assay for differences in VEGF protein levels between the vector and ILK-overexpressing MMRU, and SK-mel-3 cells knocked down for IL-6 and STAT3 proteins. Control siRNA-transfected ILK-overexpressing melanoma cells exhibited a 1.4-to 1.5-fold increase in VEGF protein compared with the vector cells (Figure 6a).…”

Section: Ilk Expression In Melanoma Cells Induces Il-6-dependent Angimentioning

confidence: 99%

Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

et al. 2011

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Integrin-linked kinase (ILK) is a highly conserved serinethreonine protein kinase involved in cell-extracellular matrix interactions, cytoskeletal organization and cell signaling. Overexpression of ILK in epithelial cells leads to anchorage-independent growth with increased cell cycle progression. Previously, we have shown that ILK upregulation strongly correlates with melanoma progression, invasion and inversely correlates with 5-year survival of melanoma patients. However, the molecular mechanism by which ILK enhances melanoma progression is currently unknown. In the present study, we found that proangiogenic molecule interleukin-6 (IL-6) is the downstream target of ILK in melanoma cells. ILK overexpression increased IL-6, whereas silencing of ILK suppressed IL-6 expression at both messenger RNA and protein levels. ILK also altered the activity and subcellular localization of nuclear factor-kappaB (NF-jB) subunit p65. We further found that ILK enhanced the IL-6 gene transcription by promoting the binding of NF-kB p65 to IL-6 promoter. Moreover, ILK overexpression in melanoma cells enhanced the tube-forming ability of endothelial cells in vitro and microvessel formation in vivo. ILK-induced tube and blood vessel formation of endothelial cells was significantly reduced upon IL-6 inhibition in ILK-overexpressing melanoma cells. To delineate the mechanism by which ILK-induced IL-6 production can enhance angiogenesis, further analysis of the downstream targets of IL-6 signaling showed an increased activity of the signal transducer and activator of transcription 3 (STAT3) in ILK-overexpressing cells. As STAT3 binds to vascular endothelial growth factor (VEGF) promoter, we found that VEGF levels were elevated in ILK-overexpressing cells and declined upon transfection of IL-6 small interfering RNA, suggesting that ILK may regulate VEGF expression through IL-6 pathway by activating STAT3.

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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

Cited by 191 publications

References 48 publications

Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis

Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

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