Interleukin-6 Induced Basic Fibroblast Growth Factor-Dependent Angiogenesis in Basal Cell Carcinoma Cell Line via JAK/STAT3 and PI3-Kinase/Akt Pathways

Jee, Shiou‐Hwa; Chu, Chia-Yu; Hc, Chiu; Huang, Yamin; Tsai, Wei‐Ling; Liao, Yi‐Hua; Kuo, Min-Liang

doi:10.1111/j.0022-202x.2004.23497.x

Cited by 117 publications

(69 citation statements)

References 45 publications

(41 reference statements)

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“…Whether the protumorigenic effect of combined HH‐IL6 signaling is directly mediated by the HH‐IL6 targets EDN2, PLAT and NRP1 requires further functional studies. In this context, it is noteworthy that PLAT and NRP1 play a well‐documented role in angiogenesis, in line with previous reports about a putative angiogenic function of IL6 in BCC 45, 46, 47. However, as we did not detect a decrease in CD31 + endothelial cells in Il6ra‐deficient mouse BCC (data not shown), it appears rather unlikely that HH‐IL6 signal integration drives BCC growth by supporting tumor angiogenesis.…”

Section: Discussionsupporting

confidence: 90%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

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Section: Discussionsupporting

confidence: 90%

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Sternberg

Gruber

Eberl

et al. 2018

Intl Journal of Cancer

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“…Specifically, the IL-6/IL-6R complex initiates homodimerization of the ubiquitously expressed gp130 (h chain), activates a cytoplasmic tyrosine kinase bound to gp130, and then triggers Janus-activated kinase/signal transducers and activators of transcription (STAT), Ras/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt signaling (6,7). IL-6 signaling mediated via gp130 interferes with many cellular functions, such as cell growth and survival, differentiation, cell mobility, and angiogenesis, and is thereby critically involved in the pathogenesis of various human cancers (8)(9)(10). Therefore, blocking IL-6 activity may be of clinical benefit in the management of patients with malignant diseases.…”

Section: Introductionmentioning

confidence: 99%

A Novel Peptide Specifically Binding to Interleukin-6 Receptor (gp80) Inhibits Angiogenesis and Tumor Growth

Lai²,

Chen

et al. 2005

Cancer Research

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Experimental and clinical findings support the essential role of interleukin (IL)-6 in the pathogenesis of various human cancers and provide a rationale for targeted therapeutic investigations. A novel peptide, S7, which selectively binds to IL-6 receptor (IL-6R) A chain (gp80) and broadly inhibits IL-6-mediated events, was identified using phage display library screening. The synthetic S7 peptide specifically bound to soluble IL-6R as well as cognate human IL-6RA, resulting in a dose-dependent blockade of the interaction between IL-6 and IL-6RA. S7 peptide prevents IL-6-mediated survival signaling and sensitizes cervical cancer cells to chemotherapeutic compounds in vitro . The in vitro analysis of antiangiogenic activity showed that S7 peptide substantially inhibits IL-6-induced vascular endothelial growth factor-A expression and angiogenesis in different cancer cell lines. Furthermore, S7 peptide was bioavailable in vivo, leading to a significant suppression of IL-6-induced vascular endothelial growth factor-mediated cervical tumor growth in severe combined immunodeficient mice. These observations show the feasibility of targeting IL-6/IL-6R interaction using the small peptide and highlight its potential in the clinical applications. (Cancer Res 2005; 65(11): 4827-35)

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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%

“…IL-6 is known to regulate VEGF through STAT3 pathway in many cancers and thereby promotes angiogenesis (Wei et al, 2003;Huang et al, 2004;Jee et al, 2004;Saidi et al, 2009). We further examined whether silencing of IL-6 or its downstream target STAT3 in vector or ILK-overexpressing cells could affect VEGF expression.…”

Section: Discussionmentioning

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 Induced Basic Fibroblast Growth Factor-Dependent Angiogenesis in Basal Cell Carcinoma Cell Line via JAK/STAT3 and PI3-Kinase/Akt Pathways

Cited by 117 publications

References 45 publications

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

A Novel Peptide Specifically Binding to Interleukin-6 Receptor (gp80) Inhibits Angiogenesis and Tumor Growth

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

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