scholarly journals CXCL11 mediates TWIST1-induced angiogenesis in epithelial ovarian cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770622 ◽  
Author(s):  
Yu-Jin Koo ◽  
Tae-Jin Kim ◽  
Kyung-Jin Min ◽  
Kyeong-A So ◽  
Un-Suk Jung ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Small Interfering Rna ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Angiogenic Factor ◽  
Cxc Chemokine ◽  
Chemokine Ligand ◽  
Cytokine Array ◽  
Interfering Rna

To investigate the role of TWIST1 in tumor angiogenesis in epithelial ovarian cancer and to identify key molecules involved in angiogenesis. TWIST1 small interfering RNA was transfected into A2780 cells, while a complementary DNA vector was transfected into non-malignant human ovarian surface epithelial cells to generate a TWIST1-overexpressing cell line. To evaluate how this affects angiogenesis, human umbilical vein endothelial cell tube formation assays were performed using the control and transfected cell lines. An antibody-based cytokine array was used to identify the molecules involved in TWIST1-mediated angiogenesis. After knockdown of TWIST1 via transfection of TWIST1 small interfering RNA into A2780 cells, the number of tubes formed by human umbilical vein endothelial cells significantly decreased in a tube formation assay. In a cytokine array, TWIST1 downregulation did not significantly decrease the secretion of the common pro-angiogenic factor, vascular endothelial growth factor, but instead inhibited the expression of the CXC chemokine ligand 11, which was confirmed by both an enzyme-linked immunosorbent assay and western blotting. In contrast, TWIST1 overexpression resulted in increased secretion of CXC chemokine ligand 11. Conversely, CXC chemokine ligand 11 downregulation did not inhibit the expression of TWIST1. Furthermore, the ability of TWIST1-expressing A2780 cells to induce angiogenesis was found to be inhibited after CXC chemokine ligand 11 knockdown in a tube formation assay. TWIST1 plays an important role in angiogenesis in epithelial ovarian cancer and is mediated by a novel pro-angiogenic factor, CXC chemokine ligand 11. Downregulation of CXC chemokine ligand 11 can inhibit tumor angiogenesis, suggesting that anti–CXC chemokine ligand 11 therapy may offer an alternative treatment strategy for TWIST1-positive ovarian cancer.

scholarly journals Switching the intracellular pathway and enhancing the therapeutic efficacy of small interfering RNA by auroliposome

2020 ◽  
Vol 6 (30) ◽  
pp. eaba5379 ◽  
Author(s):  
Md. Nazir Hossen ◽  
Lin Wang ◽  
Harisha R. Chinthalapally ◽  
Joe D. Robertson ◽  
Kar-Ming Fung ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gold Nanoparticles ◽  
Gene Silencing ◽  
Small Interfering Rna ◽  
Sirna Delivery ◽  
Delivery Systems ◽  
Ovarian Cancer Cells ◽  
Interfering Rna

Gene silencing using small-interfering RNA (siRNA) is a viable therapeutic approach; however, the lack of effective delivery systems limits its clinical translation. Herein, we doped conventional siRNA-liposomal formulations with gold nanoparticles to create “auroliposomes,” which significantly enhanced gene silencing. We targeted MICU1, a novel glycolytic switch in ovarian cancer, and delivered MICU1-siRNA using three delivery systems—commercial transfection agents, conventional liposomes, and auroliposomes. Low-dose siRNA via transfection or conventional liposomes was ineffective for MICU1 silencing; however, in auroliposomes, the same dose gave >85% gene silencing. Efficacy was evident from both in vitro growth assays of ovarian cancer cells and in vivo tumor growth in human ovarian cell line—and patient-derived xenograft models. Incorporation of gold nanoparticles shifted intracellular uptake pathways such that liposomes avoided degradation within lysosomes. Auroliposomes were nontoxic to vital organs. Therefore, auroliposomes represent a novel siRNA delivery system with superior efficacy for multiple therapeutic applications.

Association of Vascular Endothelial Growth Factor Gene Polymorphisms With Susceptibility to Epithelial Ovarian Cancer

2010 ◽  
Vol 20 (5) ◽  
pp. 717-723 ◽  
Author(s):  
Yan Li ◽  
Yan Wang ◽  
Shan Kang ◽  
Na Wang ◽  
Rong-Miao Zhou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Confidence Interval ◽  
Epithelial Ovarian Cancer ◽  
Odds Ratio ◽  
Gene Polymorphisms ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Background:Vascular endothelial growth factor (VEGF) is a major angiogenic factor involved in a number of pathological processes, including neovascularization, a crucial step in the development of solid malignancies. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with susceptibility to epithelial ovarian cancer (EOC).Methods:This case-control study included 303 EOC patients and 303 healthy controls. Genotyping of the VEGF gene polymorphisms at −460C/T, −1154G/A, −2578C/A, and +936C/T were performed by polymerase chain reaction and restriction fragment length polymorphism analysis.Results:No significant difference was found in allele and genotype distributions of the −460C/T, +936C/T, and −2578C/A polymorphisms between patients and controls. However, the frequencies of −1154G/A genotype and allele were significantly different between the two groups (P = 0.037, P = 0.013). Compared with the G/A + A/A genotype, the G/G genotype could significantly increase the risk of developing EOC (odds ratio, 1.64; 95% confidence interval, 1.12-2.39). The haplotype analysis suggested that the −460T/−1154A/−2578C haplotype exhibited a decrease in the risk of developing EOC compared with the −460T/−1154G/−2578C haplotype (odds ratio, 0.644; 95% confidence interval, 0.415-0.999).Conclusions:The study suggested a possible association between the VEGF −1154G/A polymorphism with susceptibility to EOC, but there is no support for an association of the VEGF −460C/T, +936C/T, and −2578C/A polymorphisms with the risk for EOC.

scholarly journals Characterization of Heparin Affin Regulatory Peptide Signaling in Human Endothelial Cells

2005 ◽  
Vol 280 (23) ◽  
pp. 22454-22461 ◽  
Author(s):  
Apostolos Polykratis ◽  
Panagiotis Katsoris ◽  
José Courty ◽  
Evangelia Papadimitriou
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Tyrosine Phosphatase ◽  
Neuronal Cell ◽  
Cell Types ◽  
Tube Formation ◽  
Regulatory Peptide ◽  
Intracellular Signals ◽  
Umbilical Vein Endothelial Cells ◽  
Interfering Rna

Heparin affin regulatory peptide (HARP) is an 18-kDa secreted growth factor that has a high affinity for heparin and a potent role on tumor growth and angiogenesis. We have previously reported that HARP is mitogenic for different types of endothelial cells and also affects cell migration and differentiation (12). In this study we examined the signaling pathways involved in the migration and tube formation on matrigel of human umbilical vein endothelial cells (HUVEC) induced by HARP. We report for the first time that receptor-type protein-tyrosine phosphatase β/ζ (RPTPβ/ζ), which is a receptor for HARP in neuronal cell types, is also expressed in HUVEC. We also document that HARP signaling through RPTPβ/ζ leads to activation of Src kinase, focal adhesion kinase, phosphatidylinositol 3-kinase, and Erk1/2. Sodium orthovanadate, chondroitin sulfate-C, PP1, wortmannin, LY294002, and U0126 inhibit HARP-mediated signaling and HUVEC migration and tube formation. In addition, RPTPβ/ζ suppression using small interfering RNA technology interrupts intracellular signals and HUVEC migration and tube formation induced by HARP. These results establish the role of RPTPβ/ζ as a receptor of HARP in HUVEC and elucidate the HARP signaling pathway in endothelial cells.

scholarly journals Reactive Nitrogen Species Induced by Hyperglycemia Suppresses Akt Signaling and Triggers Apoptosis by Upregulating Phosphatase PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) in an LKB1-Dependent Manner

Circulation ◽  
2007 ◽  
Vol 116 (14) ◽  
pp. 1585-1595 ◽  
Author(s):  
Ping Song ◽  
Yong Wu ◽  
Jian Xu ◽  
Zhonglin Xie ◽  
Yunzhou Dong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Small Interfering Rna ◽  
Umbilical Vein ◽  
Akt Signaling ◽  
Chromosome 10 ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells ◽  
Phosphatase And Tensin Homologue ◽  
Interfering Rna

Background— Oxidative stress plays a causal role in vascular injury in diabetes mellitus, but the mechanisms and targets remain poorly understood. Methods and Results— Exposure of cultured human umbilical vein endothelial cells to either peroxynitrite (ONOO − ) or high glucose significantly inhibited both basal and insulin-stimulated Akt phosphorylation at Ser473 and Akt activity in parallel with increased apoptosis, phosphorylation, and activity of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Furthermore, protein kinase B/Akt inhibition induced by ONOO − or high glucose and apoptosis triggered by high glucose could be abolished by transfection of PTEN-specific small interfering RNA, suggesting that PTEN mediated the Akt inhibition by ONOO − . In addition, exposure of human umbilical vein endothelial cells to ONOO − or high glucose remarkably increased Ser428 phosphorylation of LKB1, a tumor suppressor. Interestingly, the ONOO − -enhanced PTEN phosphorylation and Akt inhibition can be blocked by LKB1-specific small interfering RNA. Consistently, LKB1 phosphorylated PTEN at Ser380/Thr382/383 in vitro, suggesting that LKB1 might act as an upstream kinase for PTEN. Compared with nondiabetic mice, the levels of PTEN, LKB1-Ser428 phosphorylation, and 3-nitrotyrosine (a biomarker of ONOO − ) were significantly increased in the aortas of streptozotocin-induced diabetic mice, which was in parallel with a reduction in Akt-Ser473 phosphorylation and an increase in apoptosis. Furthermore, administration of PTEN-specific small interfering RNA suppressed diabetes-enhanced apoptosis and Akt inhibition. Finally, treatment with Tempol, a superoxide dismutase mimetic, and insulin, both of which reduced the ONOO − formation, markedly reduced diabetes-enhanced LKB1-Ser428 phosphorylation, PTEN, and apoptosis in the endothelium of mouse aortas. Conclusion— We conclude that hyperglycemia triggers apoptosis by inhibiting Akt signaling via ONOO − -mediated LKB1-dependent PTEN activation.

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