Abstract
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.
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Abbreviations
- Act.D:
-
actinomycin D
- DRB:
-
5,6-dichloro-1-D-ribofuranosylbenzimidazole
- HIF-1:
-
hypoxia-inducible factor-1
- IL-8:
-
interleukin-8
- MLTF:
-
adenovirus type 2 major late transcription factor
- VEGF:
-
vascular endothelial growth factor
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Acknowledgements
We would like to thank Drs D Bigner, WE Holmes, C Kunsch, H Marti, N Mukaida, G Semenza, and H Weich for plasmids and cell lines, Drs M Gassmann and H Marti for helpful advice, Drs G Barber, C Bonny, B Corthésy and R Kessler for reading the manuscript and L Paul for expert editorial assistance. This work was supported by grants from the Swiss National Science Foundation and the Swiss and Vaud Anti-Cancer Leagues.
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Desbaillets, I., Diserens, AC., de Tribolet, N. et al. Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. Oncogene 18, 1447–1456 (1999). https://doi.org/10.1038/sj.onc.1202424
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DOI: https://doi.org/10.1038/sj.onc.1202424
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