Stimulation of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increases the expression of CXCR4 on endothelial cells, rendering these cells more responsive to stromalderived factor 1 (SDF-1), an angiogenic CXC chemokine and unique ligand for CXCR4. Here, we show that prostaglandin E 2 (PGE 2 ) mediates the effects of bFGF and VEGF in up-regulating CXCR4 expression on human microvascular endothelial cells (HMECs). Forskolin or 3-isobutyl-1-methyl xanthine (IBMX), 2 inducers of adenylate cyclase, markedly enhanced, whereas cyclooxygenase (COX) inhibitors including aspirin, piroxicam, and NS398 markedly inhibited CXCR4 expression on HMECs. Furthermore, the ability of PGE 2 to augment in vitro tubular formation in SDF-1␣ containing matrigel was inhibited completely by blocking CXCR4. Treatment of bFGF-or VEGF-stimulated HMECs with COX inhibitors blocked tubular formation by about 50% to 70%. Prostaglandin-induced human endothelial cell organization and subsequent vascularization can be inhibited to a greater extent by a neutralizing antibody to human CXCR4 in severe combined immunodeficient mice. Additionally, VEGF-and bFGFinduced angiogenesis in vivo was also inhibited by about 50% by NS-398 or piroxicam, and this inhibitory effect was accompanied by decreased expression of CXCR4 on murine endothelial cells. IntroductionChemokines induce angiogenesis directly by binding their cognate receptors on endothelial cells or indirectly by promoting inflammatory cell infiltrates, which deliver other angiogenic stimuli. A number of proinflammatory chemokines including interleukin 8 (IL-8), growth-regulated oncogene ␣ (GRO-␣), stromal cell-derived factor 1 (SDF-1), monocyte chemotactic protein 1 (MCP-1), eotaxin 1, and I-309 have been shown to act as direct inducers of angiogenesis. [1][2][3] SDF-1 acts as a chemoattractant for leukocytes, 4 hematopoietic progenitor cells, 5 and endothelial cells. 6-8 SDF-1-deficient mice are grossly normal but die shortly after birth, lack B-cell lymphopoiesis during embryonic development, have defective bone marrow myelopoiesis, have a ventricular septal defect, 9 and have impaired vascularization of the gastrointestinal tract. 10 We previously reported that angiogenic factors, namely, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), can enhance the expression of CXCR4, but not other chemokine receptors on endothelial cells rendering endothelial cells more responsive to SDF-1. Conversely, SDF-1 enhances the production of VEGF and bFGF in a positive feedback loop, therefore, linking classical angiogenic factors to chemokine-induced angiogenesis. 11 In addition to inducing CXCR4, there is copious evidence in the literature that VEGF and bFGF are inducers of cyclooxygenase (COX) with subsequent induction of prostaglandin synthesis in endothelial cells. 12-17 Prostaglandin E 2 (PGE 2 ) is the major COX product of human microvascular endothelial cells (HMECs). [18][19][20][21] Prostaglandins participate in angiogenesis [22...
Purpose: To determine the prognostic significance of miR-663 in glioblastoma, its effect in tumor progression, and the underlying mechanism.Experimental Design: Specimens from 256 cases of patients with glioma, including 239 patients with follow-up information, were used to analyze the association between miR-663 and patients' prognosis by Kaplan-Meier and multivariate Cox regression analyses. The effects of miR-663 on glioblastoma cell proliferation and invasion were examined both in vitro and in vivo. Bioinformatics prediction and signal network analysis were applied to identify the putative targets of miR-663, which were further verified by luciferase reporter assay, rescue experiments as well as the immunohistochemistry (IHC) and Western blotting examination of downstream effectors. Quantitative reverse transcriptase PCR (qRT-PCR) and IHC were applied to investigate the clinical association between miR-663 and its target in human glioblastoma specimens.Results: miR-663 was inversely correlated with glioma grades but positively correlated with patients' survival. Furthermore, two distinct subgroups of patients with glioblastoma with different prognoses were identified on the basis of miR-663 expression in our specimens and that from The Cancer Genome Atlas (TCGA) database. Overexpression of miR-663 significantly suppressed the proliferation and invasion of glioblastoma cells in vitro and in vivo. Mechanistically, we discovered PIK3CD as a direct target of miR-663 and found that phosphorylated AKT and three key downstream effectors of PIK3CD, i.e., CCND1, MMP2, and MMP7, were downregulated by miR-663 overexpression. Moreover, PIK3CD was inversely correlated with miR-663 in glioblastoma specimens and predicted poor prognosis of patients with glioblastoma.Conclusion: miR-663 is a novel prognostic biomarker and a potential therapeutic candidate for glioblastoma. Clin Cancer Res; 20(7); 1803-13. Ó2014 AACR.
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