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Notch signaling mediates hypoxia-induced tumor cell migration and invasion

PNAS, 29 April 2008
Vol. 105, Issue 17, p. 6392-6397
DOI: 10.1073/pnas.0802047105

Notch signaling mediates hypoxia-induced tumor cell migration and invasion

  1. Cecilia Sahlgren *,
  2. Maria V. Gustafsson,
  3. Shaobo Jin,
  4. Lorenz Poellinger, and
  5. Urban Lendahl
  1. Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, SE-171 77 Stockholm, Sweden
  1. Communicated by Tomas Hokfelt, Karolinska Institutet, Stockholm, Sweden, March 3, 2008 (received for review November 14, 2007)

Abstract

Tumor hypoxia is linked to increased metastatic potential, but the molecular mechanisms coupling hypoxia to metastasis are poorly understood. Here, we show that Notch signaling is required to convert the hypoxic stimulus into epithelial–mesenchymal transition (EMT), increased motility, and invasiveness. Inhibition of Notch signaling abrogated hypoxia-induced EMT and invasion, and, conversely, an activated form of Notch could substitute for hypoxia to induce these processes. Notch signaling deploys two distinct mechanisms that act in synergy to control the expression of Snail-1, a critical regulator of EMT. First, Notch directly up-regulated Snail-1 expression by recruitment of the Notch intracellular domain to the Snail-1 promoter, and second, Notch potentiated hypoxia-inducible factor 1α (HIF-1α) recruitment to the lysyl oxidase (LOX) promoter and elevated the hypoxia-induced up-regulation of LOX, which stabilizes the Snail-1 protein. In sum, these data demonstrate a complex integration of the hypoxia and Notch signaling pathways in regulation of EMT and open up perspectives for pharmacological intervention with hypoxiainduced EMT and cell invasiveness in tumors.

  • E-cadherin
  • lysyl oxidase
  • Snail

Footnotes

  • To whom correspondence should be addressed. E-mail: urban.lendahl{at}ki.se
  • Author contributions: C.S., L.P., and U.L. designed research; C.S., M.V.G., and S.J. performed research; C.S., M.V.G., S.J., L.P., and U.L. analyzed data; and C.S., L.P., and U.L. wrote the paper.

  • *Present address: Department of Biology, Åbo Akademi University, BioCity, FIN-20520, Turku, Finland.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0802047105/DCSupplemental.

Citation:

C. Sahlgren, M. V. Gustafsson, S. Jin, L. Poellinger, and U. Lendahl, Notch signaling mediates hypoxia-induced tumor cell migration and invasion. PNAS 105, 6392-6397 (2008).

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