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PNAS 105 (17): 6392-6397

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Notch signaling mediates hypoxia-induced tumor cell migration and invasion

Cecilia Sahlgren*, Maria V. Gustafsson, Shaobo Jin, Lorenz Poellinger, and Urban Lendahl{dagger}

Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Communicated by Tomas Hokfelt, Karolinska Institutet, Stockholm, Sweden, March 3, 2008

Received for publication 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 1{alpha} (HIF-1{alpha}) 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.

Key Words: E-cadherin • lysyl oxidase • Snail

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.

{dagger}To whom correspondence should be addressed. E-mail: urban.lendahl{at}ki.se

© 2008 by The National Academy of Sciences of the USA

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