Ahn So-Hee, Park Hyunju, Ahn Young-Ho, Kim Sewha, Cho Min-Sun, Kang Jihee Lee, Choi Youn-Hee
Department of Physiology, Ewha Womans University School of Medicine, Seoul 911-1, Korea.
Tissue Injury Defense Research Center , School of Medicine, Ewha Womans University, Seoul, Korea.
Sci Rep. 2016 Apr 14;6:24552. doi: 10.1038/srep24552.
Glioblastoma multiforme (GBM) is the most common primary intracranial tumor in adults and has poor prognosis. Diffuse infiltration into normal brain parenchyma, rapid growth, and the presence of necrosis are remarkable hallmarks of GBM. However, the effect of necrotic cells on GBM growth and metastasis is poorly understood at present. In this study, we examined the biological significance of necrotic tissues by exploring the molecular mechanisms underlying the signaling network between necrotic tissues and GBM cells. The migration and invasion of the GBM cell line CRT-MG was significantly enhanced by treatment with necrotic cells, as shown by assays for scratch wound healing and spheroid invasion. Incubation with necrotic cells induced IL-8 secretion in CRT-MG cells in a dose-dependent manner. In human GBM tissues, IL-8 positive cells were mainly distributed in the perinecrotic region, as seen in immunohistochemistry and immunofluorescence analysis. Necrotic cells induced NF-κB and AP-1 activation and their binding to the IL-8 promoter, leading to enhanced IL-8 production and secretion in GBM cells. Our data demonstrate that when GBM cells are exposed to and stimulated by necrotic cells, the migration and invasion of GBM cells are enhanced and facilitated via NF-κB/AP-1 mediated IL-8 upregulation.
多形性胶质母细胞瘤（GBM）是成人中最常见的原发性颅内肿瘤，预后较差。弥漫性浸润至正常脑实质、快速生长以及坏死的存在是GBM的显著特征。然而，目前坏死细胞对GBM生长和转移的影响尚不清楚。在本研究中，我们通过探索坏死组织与GBM细胞之间信号网络的分子机制，研究了坏死组织的生物学意义。划痕伤口愈合试验和球体侵袭试验表明，用坏死细胞处理可显著增强GBM细胞系CRT-MG的迁移和侵袭能力。用坏死细胞孵育以剂量依赖的方式诱导CRT-MG细胞分泌IL-8。在人GBM组织中，免疫组织化学和免疫荧光分析显示，IL-8阳性细胞主要分布在坏死周边区域。坏死细胞诱导NF-κB和AP-1活化及其与IL-8启动子的结合，导致GBM细胞中IL-8产生和分泌增加。我们的数据表明，当GBM细胞暴露于坏死细胞并受到其刺激时，GBM细胞的迁移和侵袭通过NF-κB/AP-1介导的IL-8上调而增强和促进。
