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Dose-dependent modulation of HIF-1α/sima controls the rate of cell migration and invasion in Drosophila ovary border cells

Oncogene volume 29, pages 1123–1134 (2010)Cite this article

Abstract

The role of the hypoxic response during metastasis was analysed in migrating border cells of the Drosophila ovary. Acute exposure to 1% O2 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)-1α ortholog, revealed that Sima can either block or restore BCM in a dose-dependent manner. In contrast, over-expression 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-1β 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 define 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.

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Acknowledgements

We thank Dr Eric Spana of the Duke Model Systems Genomics core facility for generating UAS–Vhl/VHL transgenic fly stocks. Drs Bruce Edgar, Denise Montell and Pernille Rorth generously shared reagents. Several stocks were obtained from the Bloomington Drosophila Stock Center. DE-cadherin antibodies were obtained from the Developmental Studies Hybridoma Bank. MN was supported by a Medical Student Research Fellowship (MSRF, NIH). All work was supported by the Dorothy K Gerwin and the Maston Callison Bowld Cancer Research funds at UTHSC (to TNS), the UTHSC Molecular Resource Center (to LTR) and the UTHSC Clinical and Translational Science Institute.

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Author notes

  1. L T Reiter and T N Seagroves: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA

    S Doronkin, I Djagaeva & L T Reiter

  2. College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    M E Nagle

  3. Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

    L T Reiter

  4. Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    T N Seagroves

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  1. S Doronkin
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Correspondence to S Doronkin.

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Doronkin, S., Djagaeva, I., Nagle, M. et al. Dose-dependent modulation of HIF-1α/sima controls the rate of cell migration and invasion in Drosophila ovary border cells. Oncogene 29, 1123–1134 (2010). https://doi.org/10.1038/onc.2009.407

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