Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma

Huang, Shih-Pei; Wu, Ming–Shiang; Shun, Chia‐Tung; Wang, Hsiu‐Po; Lin∥, Ming–Tsan; Kuo, Min-Liang; Lin, Jaw–Town

doi:10.1007/bf02256101

Cited by 166 publications

(82 citation statements)

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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%

“…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%

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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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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

confidence: 99%

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

et al. 2011

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“…Endothelial cells form the connective and complete tube-like structures with branches when cultured in the appropriate media. The number of tubes was quantified in six different fields for each culture (24). Quantification of tube formation was shown as relative to the control.…”

Section: In Vitro Tube Formation Assaymentioning

confidence: 99%

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Chang¹,

Lin

et al. 2005

The Journal of Immunology

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138

113

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Cyclooxygenase-2 (COX-2) plays a crucial role in Helicobacter pylori-associated gastric cancer. In this study, we report that H. pylori-induced COX-2 expression enhances the cancer cell invasion and angiogenesis via TLR2 and TLR9, which can be attenuated by the specific COX-2 inhibitor NS398 or celecoxib. The cAMP response element (CRE) and AP1 sites, but not κB on the COX-2 promoter, are involved in MAPKs-regulated COX-2 expression. Differential bindings of the CREB-1, ATF-2, c-jun to the CRE site, and the c-fos, c-jun, ATF-2 to the AP1 site are demonstrated by DNA affinity protein-binding, supershift, and chromatin immunoprecipitation assays. Activations of these transcription factors were attenuated by different MAPKs inhibitors. The mutants of TLR2, TLR9, or MAPKs inhibited H. pylori-induced COX-2 promoter, CRE, and AP-1 activities. MAPKs inhibitors attenuated the H. pylori-induced COX-2 mRNA and protein expressions. These results indicate that H. pylori acts through TLR2 and TLR9 to activate MAPKs, especially p38, and their downstream transcription factors (CREB-1, ATF-2, c-jun, and c-fos), resulting in the activations of CRE and AP-1 on the COX-2 promoter. These intracellular networks drive the COX-2-dependent PGE2 release and contribute to cell invasion and angiogenesis.

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“…These molecules include interleukin 6 (IL-6) as well as its soluble receptor (sIL-6R) and urokinase-type plasminogen system members. IL-6 stimulates cell proliferation (5) and increases angiogenesis and invasion in tumor cells (6,7). The soluble form of the membrane IL-6 receptor (mIL-6R) binds the cytokine, and their complex is capable of activating the transmembrane protein, gp130, which promotes signal transduction in cells that do not express mIL-6R (IL-6 trans-signaling) (8).…”

Section: Introductionmentioning

confidence: 99%

Soluble interleukin-6 receptor to interleukin-6 (sIL‑6R/IL-6) ratio in serum as a predictor of high Gleason sum at radical prostatectomy

et al. 2011

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Abstract. Approximately 40% of males with low Gleason grade clinically localized prostate cancer (PCa) at biopsy were finally diagnosed with high Gleason grade PCa at radical prostatectomy (RP). Therefore, a more reliable assessment of the Gleason grade prior to RP is required. Readily available modalities such as circulating biomarkers may be useful for this purpose. The aim of this study was to evaluate the ability of preoperative interleukin 6 (IL-6) and its soluble receptor (sIL-6R), as well as urokinase-type plasminogen activator (u-PA), its receptor (u-PAR) and the inhibitor (PAI-1) to predict Gleason score upgrading. A total of 51 PCa patients with biopsy Gleason score ≤7 were studied. IL-6 and sIL-6R, uPA, uPAR and PAI-1 preoperative serum levels were determined. Differences in the median and mean values of the preoperative blood levels of all biomarkers between patients with and without Gleason score upgrading were tested. The prognostic performance of each biomarker was further assessed by means of receiver operating characteristic (ROC) curves. The results showed the sIL-6R and sIL-6R/IL-6 ratio median levels to be significantly higher in patients who had Gleason score upgrading from ≤7 at biopsy to >7 at RP (p=0.024 and p=0.011, respectively). The ROC curve revealed that sIL-6R and the sIL-6R/IL-6 ratio identified subjects at a high risk of upgrading [area under curve (AUC)=0.80 and AUC=0.83, respectively] with similar sensitivity and higher specificity for the ratio. The findings suggest that preoperative sIL-6R and sIL-6R/IL-6 ratio determination in serum are useful as prognostic biomarkers in PCa patients. IntroductionPatients with clinically localized PCa are classified as low, intermediate and high risk, according to prostate-specific antigen (PSA) levels, tumor clinical staging and Gleason score (GS). Patients with GS >7 belong to the high-class risk category (1,2). Treatment options depend on the recurrence risk. Although radical prostatectomy (RP) is recommended for the low to intermediate risk categories, a high-risk class category requires aggressive local radiation combined with 2-3 years of androgen-deprivation therapy (ADT) (1,2).GS upgrading from ≤6 at biopsy to ≥7 at RP has been reported to be approximately 40% (3,4). Thus factors predictive of GS upgrading at RP are required. A promising modality may be represented by molecules involved in PCa progression, which are detectable in blood. These molecules include interleukin 6 (IL-6) as well as its soluble receptor (sIL-6R) and urokinase-type plasminogen system members. IL-6 stimulates cell proliferation (5) and increases angiogenesis and invasion in tumor cells (6,7). The soluble form of the membrane IL-6 receptor (mIL-6R) binds the cytokine, and their complex is capable of activating the transmembrane protein, gp130, which promotes signal transduction in cells that do not express mIL-6R (IL-6 trans-signaling) (8). Certain authors observed a strong association between circulating sIL-6R levels prior to prostatectomy and the higher proba...

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Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma

Cited by 166 publications

References 50 publications

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

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

Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation

Soluble interleukin-6 receptor to interleukin-6 (sIL‑6R/IL-6) ratio in serum as a predictor of high Gleason sum at radical prostatectomy

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