Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma.
Oxygen deprivation is an important biological feature of tumor growth. We previously showed that in glioma, anoxia increases expression of IL-8, a chemokine and angiogenic factor. Here, we analysed for the first time the biochemical mechanisms inducing the IL-8 gene upon anoxia in glioma cells, and showed that they differ from those inducing the VEGF gene. Both genes are induced in biologically and genetically heterogenous glioblastoma cell lines (LN-229, LN-Z308, U87MG, T98G), whereas, in gliosarcoma cells (D247MG), only the VEGF gene is induced. The kinetics of IL-8 and VEGF mRNA inductions differ in these cells and reoxygenation experiments showed that the induction is due to the anoxic stress per se. Furthermore, in LN-229 and LN-Z308 cell lines actinomycin D, DRB and nuclear run-on experiments showed that anoxia stimulates increased transcription of both genes. Electromobility shift assays show increased protein binding to the AP-1 site on the IL-8 promoter following anoxia treatment. Finally, in situ hybridization on glioblastoma sections shows that the in vivo expression patterns of IL-8 and VEGF genes overlap, but are not identical. Since intratumoral augmentation of IL-8 and VEGF secretion, following microenvironmental decreases in oxygen pressure, may promote angiogenesis, further definition of these pathways is essential to appropriately target them for antitumoral therapy.
Neurosurgery Department, University Hospital (CHUV), Lausanne, Switzerland.
I
I
Desbaillets
A C
AC
Diserens
N
N
de Tribolet
M F
MF
Hamou
E G
EG
Van Meir
D000818:Animals; D015687:Cell Hypoxia; D003035:Cobalt / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics; D005786:Gene Expression Regulation; D005909:Glioblastoma; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000502:physiology*; D012333:RNA, Messenger; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003609:Dactinomycin; D003035:Cobalt; D004004:Dichlororibofuranosylbenzimidazole; D010100:Oxygen