Journal
ONCOGENE
Volume 29, Issue 8, Pages 1123-1134Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.407
Keywords
hypoxia; metastasis; invasion; HIF-1 alpha; VHL; PHD
Funding
- Medical Student Research Fellowship (MSRF, NIH)
- Dorothy K Gerwin and the Maston Callison Bowld Cancer Research
- UTHSC Molecular Resource Center
- UTHSC Clinical and Translational Science Institute
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The role of the hypoxic response during metastasis was analysed in migrating border cells of the Drosophila ovary. Acute exposure to 1% O-2 delayed or blocked border cell migration (BCM), whereas prolonged exposure resulted in the first documented accelerated BCM phenotype. Similarly, manipulating the expression levels of sima, the Drosophila hypoxia-inducible factor (HIF)-1 alpha ortholog, revealed that Sima can either block or restore BCM in a dose-dependent manner. In contrast, overexpression of Vhl (Drosophila von Hippel-Lindau) generated a range of phenotypes, including blocked, delayed and accelerated BCM, whereas over-expression of hph (Drosophila HIF prolyl hydroxylase) only accelerated BCM. Mosaic clone analysis of sima or tango (HIF-1 beta ortholog) mutants revealed that cells lacking Hif-1 transcriptional activity were preferentially detected in the leading cell position of the cluster, resulting in either a delay or acceleration of BCM. Moreover, in sima mutant cell clones, there was reduced expression of nuclear slow border cells (Slbo) and basolateral DE-cadherin, proteins essential for proper BCM. These results show that Sima levels de. ne the rate of BCM in part through regulation of Slbo and DE-cadherin, and suggest that dynamic regulation of Hif-1 activity is necessary to maintain invasive potential of migrating epithelial cells. Oncogene (2010) 29, 1123-1134; doi: 10.1038/onc.2009.407; published online 7 December 2009
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