Yao Xiao-Hong, Ping Yi-Fang, Chen Jian-Hong, Chen Dai-Lun, Xu Cheng-Ping, Zheng Jiang, Wang Ji Ming, Bian Xiu-Wu
Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
J Neurooncol. 2008 Jan;86(1):47-53. doi: 10.1007/s11060-007-9443-y. Epub 2007 Jul 5.
Activation of the formylpeptide receptor (FPR), a G-protein-coupled receptor, by its chemotactic peptide ligand N-formylmethionyl-leucyl-phenylalanine (fMLF) promotes the directional migration and survival of human glioblastoma cells. fMLF also stimulates glioblastoma cells to produce biologically active VEGF, an important angiogenic factor involved in tumor progression. In this study, we examined the capacity of FPR to regulate the production of another angiogenic factor, the chemokine IL-8 (CXCL8), in addition to its demonstrated ability to induce VEGF secretion by malignant glioma cells. We showed that the human glioblastoma cell line U87 secreted considerable levels of IL-8 (CXCL8) upon stimulation by the FPR agonist peptide fMLF. Tumor cells transfected with small interference (si)RNA targeting FPR failed to produce IL-8 as well as VEGF in response to fMLF. Glioblastoma cells bearing FPR siRNA exhibited reduced rate of tumorigenicity in nude mice and tumors formed by such tumor cells showed less active angiogenesis and lower level expression of both IL-8 and VEGF. These results suggest that FPR plays an important role in the angiogenesis of human malignant gliomas through increasing the production of angiogenic factors by FPR positive tumor cells.
甲酰肽受体（FPR）是一种G蛋白偶联受体，其趋化肽配体N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLF）对FPR的激活可促进人胶质母细胞瘤细胞的定向迁移和存活。fMLF还刺激胶质母细胞瘤细胞产生具有生物活性的血管内皮生长因子（VEGF），VEGF是一种参与肿瘤进展的重要血管生成因子。在本研究中，我们除了研究FPR诱导恶性胶质瘤细胞分泌VEGF的能力外，还检测了FPR调节另一种血管生成因子趋化因子白细胞介素-8（IL-8，即CXCL8）产生的能力。我们发现，人胶质母细胞瘤细胞系U87在FPR激动剂肽fMLF刺激下分泌大量的IL-8（CXCL8）。用靶向FPR的小干扰（si）RNA转染的肿瘤细胞对fMLF无反应，无法产生IL-8和VEGF。携带FPR siRNA的胶质母细胞瘤细胞在裸鼠中的致瘤率降低，此类肿瘤细胞形成的肿瘤显示出较低的血管生成活性以及IL-8和VEGF的低水平表达。这些结果表明，FPR通过增加FPR阳性肿瘤细胞血管生成因子的产生，在人恶性胶质瘤的血管生成中发挥重要作用。
