Abstract
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.
Highlights
The reason that increased necrosis is associated with decreased survival rate and contributes to poor prognosis is not clearly understood
To examine whether enhanced IL-8 directly mediated the migration of CRT-MG cells induced by necrotic cells, cells were treated with an anti-IL-8 neutralizing antibody or non-specific IgG in the presence of necrotic cells, and migration of CRT-MG cells was analyzed with the scratch wound healing assay (Fig. 1c)
To determine whether necrotic cells directly induced IL-8 secretion in glioblastoma cells, CRT-MG cells were incubated with different ratios of necrotic CRT-MG cells for 24 h, and IL-8 protein levels in culture media were analyzed by Enzyme-linked immunosorbent assay (ELISA), as described in the Methods section
Summary
The reason that increased necrosis is associated with decreased survival rate and contributes to poor prognosis is not clearly understood. We demonstrate that necrotic cells induce the expression of the CXC chemokine IL-8, and promote migration and invasion of human glioblastoma cells These responses were dependent on necrotic cell-induced activation of NF-κ B and AP-1 signaling pathways. To our knowledge, this is the first report to address the effect of necrotic cell/necrosis on the migration and invasion of human glioblastoma cells. This is the first report to address the effect of necrotic cell/necrosis on the migration and invasion of human glioblastoma cells These findings support the notion that necrotic tissues may play a role in tumor cell migration and invasion by activating intratumoral signaling pathways and inducing chemokine expression in glioblastoma
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