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PNAS 105 (17): 6392-6397

Copyright © 2008 by the National Academy of 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

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

© 2008 by The National Academy of Sciences of the USA

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J. Cell Sci. 126, 3939-3947
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S.-P. Zheng, Y.-X. Chen, J.-L. Guo, D. Qi, S.-J. Zheng, S.-L. Zhang, and Z.-H. Weng (2013)
Experimental Biology and Medicine 238, 600-609
   Abstract »    Full Text »    PDF »
Wnt/{beta}-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1{alpha} signaling.
Q. Zhang, X. Bai, W. Chen, T. Ma, Q. Hu, C. Liang, S. Xie, C. Chen, L. Hu, S. Xu, et al. (2013)
Carcinogenesis 34, 962-973
   Abstract »    Full Text »    PDF »
Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia.
B. Diaz, A. Yuen, S. Iizuka, S. Higashiyama, and S. A. Courtneidge (2013)
J. Cell Biol. 201, 279-292
   Abstract »    Full Text »    PDF »
Hypoxia-Response Element (HRE)-Directed Transcriptional Regulation of the Rat Lysyl Oxidase Gene in Response to Cobalt and Cadmium.
S. Gao, J. Zhou, Y. Zhao, P. Toselli, and W. Li (2013)
Toxicol. Sci. 132, 379-389
   Abstract »    Full Text »    PDF »
Estrogen receptor {beta} sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription.
P. Mak, C. Chang, B. Pursell, and A. M. Mercurio (2013)
PNAS 110, 4708-4713
   Abstract »    Full Text »    PDF »
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H. Harrison, L. Rogerson, H. J. Gregson, K. R. Brennan, R. B. Clarke, and G. Landberg (2013)
Cancer Res. 73, 1420-1433
   Abstract »    Full Text »    PDF »
Evidence of functional cross talk between the Notch and NF-{kappa}B pathways in nonneoplastic hyperproliferating colonic epithelium.
I. Ahmed, B. Roy, P. Chandrakesan, A. Venugopal, L. Xia, R. Jensen, S. Anant, and S. Umar (2013)
Am J Physiol Gastrointest Liver Physiol 304, G356-G370
   Abstract »    Full Text »    PDF »
Combining Notch inhibition with current therapies for breast cancer treatment.
K. Brennan and R. B. Clarke (2013)
Therapeutic Advances in Medical Oncology 5, 17-24
   Abstract »    PDF »
Hypoxia promotes satellite cell self-renewal and enhances the efficiency of myoblast transplantation.
W. Liu, Y. Wen, P. Bi, X. Lai, X. S. Liu, X. Liu, and S. Kuang (2012)
Development 139, 2857-2865
   Abstract »    Full Text »    PDF »
The updated biology of hypoxia-inducible factor.
S. N. Greer, J. L. Metcalf, Y. Wang, and M. Ohh (2012)
EMBO J. 31, 2448-2460
   Abstract »    Full Text »    PDF »
Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma.
N. Cook, K. K. Frese, T. E. Bapiro, M. A. Jacobetz, A. Gopinathan, J. L. Miller, S. S. Rao, T. Demuth, W. J. Howat, D. I. Jodrell, et al. (2012)
J. Exp. Med. 209, 437-444
   Abstract »    Full Text »    PDF »
Multimodality Approaches to Treat Hypoxic Non-Small Cell Lung Cancer (NSCLC) Microenvironment.
S. Liang, P. Galluzzo, A. Sobol, S. Skucha, B. Rambo, and M. Bocchetta (2012)
Genes & Cancer 3, 141-151
   Abstract »    Full Text »    PDF »
E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2.
A. C. Ferreira, G. Suriano, N. Mendes, B. Gomes, X. Wen, F. Carneiro, R. Seruca, and J. C. Machado (2012)
Hum. Mol. Genet. 21, 334-343
   Abstract »    Full Text »    PDF »
Snail1 controls epithelial-mesenchymal lineage commitment in focal adhesion kinase-null embryonic cells.
X.-Y. Li, X. Zhou, R. G. Rowe, Y. Hu, D. D. Schlaepfer, D. Ilic, G. Dressler, A. Park, J.-L. Guan, and S. J. Weiss (2011)
J. Cell Biol. 195, 729-738
   Abstract »    Full Text »    PDF »
Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms.
S. K.- J. Landor, A. P. Mutvei, V. Mamaeva, S. Jin, M. Busk, R. Borra, T. J. Gronroos, P. Kronqvist, U. Lendahl, and C. M. Sahlgren (2011)
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   Abstract »    Full Text »    PDF »
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J. Cell Biol. 195, 417-433
   Abstract »    Full Text »    PDF »
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M. Hasmim, M. Z. Noman, J. Lauriol, H. Benlalam, A. Mallavialle, F. Rosselli, F. Mami-Chouaib, C. Alcaide-Loridan, and S. Chouaib (2011)
J. Immunol. 187, 4031-4039
   Abstract »    Full Text »    PDF »
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Development 138, 3593-3612
   Abstract »    Full Text »    PDF »
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J. Bajaj, T. T. Maliekal, E. Vivien, C. Pattabiraman, S. Srivastava, H. Krishnamurthy, V. Giri, D. Subramanyam, and S. Krishna (2011)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. Brabletz, K. Bajdak, S. Meidhof, U. Burk, G. Niedermann, E. Firat, U. Wellner, A. Dimmler, G. Faller, J. Schubert, et al. (2011)
EMBO J. 30, 770-782
   Abstract »    Full Text »    PDF »
Experimental selection of hypoxia-tolerant Drosophila melanogaster.
D. Zhou, N. Udpa, M. Gersten, D. W. Visk, A. Bashir, J. Xue, K. A. Frazer, J. W. Posakony, S. Subramaniam, V. Bafna, et al. (2011)
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   Abstract »    Full Text »    PDF »
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D. Luo, J. Wang, J. Li, and M. Post (2011)
Mol. Cancer Res. 9, 234-245
   Abstract »    Full Text »    PDF »
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F. Guan, L. Schaffer, K. Handa, and S.-i. Hakomori (2010)
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   Abstract »    Full Text »    PDF »
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G. Ferrari-Toninelli, S. A. Bonini, D. Uberti, L. Buizza, P. Bettinsoli, P. L. Poliani, F. Facchetti, and M. Memo (2010)
Neuro Oncology 12, 1231-1243
   Abstract »    Full Text »    PDF »
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P. K. Mazur, H. Einwachter, M. Lee, B. Sipos, H. Nakhai, R. Rad, U. Zimber-Strobl, L. J. Strobl, F. Radtke, G. Kloppel, et al. (2010)
PNAS 107, 13438-13443
   Abstract »    Full Text »    PDF »
Hypoxia stimulates CXCR4 signalling in ileal carcinoids.
Y. Arvidsson, A. Bergstrom, L. Arvidsson, E. Kristiansson, H. Ahlman, and O. Nilsson (2010)
Endocr. Relat. Cancer 17, 303-316
   Abstract »    Full Text »    PDF »
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R. Schietke, C. Warnecke, I. Wacker, J. Schodel, D. R. Mole, V. Campean, K. Amann, M. Goppelt-Struebe, J. Behrens, K.-U. Eckardt, et al. (2010)
J. Biol. Chem. 285, 6658-6669
   Abstract »    Full Text »    PDF »
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R. Vinas-Castells, M. Beltran, G. Valls, I. Gomez, J. M. Garcia, B. Montserrat-Sentis, J. Baulida, F. Bonilla, A. G. de Herreros, and V. M. Diaz (2010)
J. Biol. Chem. 285, 3794-3805
   Abstract »    Full Text »    PDF »
Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice.
D. Miniati, E. B. Jelin, J. Ng, J. Wu, T. R. Carlson, X. Wu, M. R. Looney, and R. A. Wang (2010)
Am J Physiol Lung Cell Mol Physiol 298, L169-L177
   Abstract »    Full Text »    PDF »
Receptor Channel TRPC6 Is a Key Mediator of Notch-Driven Glioblastoma Growth and Invasiveness.
S. Chigurupati, R. Venkataraman, D. Barrera, A. Naganathan, M. Madan, L. Paul, J. V. Pattisapu, G. A. Kyriazis, K. Sugaya, S. Bushnev, et al. (2010)
Cancer Res. 70, 418-427
   Abstract »    Full Text »    PDF »
Effect of Notch activation on the regenerative response to acute renal failure.
S. Gupta, S. Li, Md. J. Abedin, L. Wang, E. Schneider, B. Najafian, and M. Rosenberg (2010)
Am J Physiol Renal Physiol 298, F209-F215
   Abstract »    Full Text »    PDF »
Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1.
G. Zhou, L. A. Dada, M. Wu, A. Kelly, H. Trejo, Q. Zhou, J. Varga, and J. I. Sznajder (2009)
Am J Physiol Lung Cell Mol Physiol 297, L1120-L1130
   Abstract »    Full Text »    PDF »
Inflammation and EMT: an alliance towards organ fibrosis and cancer progression.
J. M. Lopez-Novoa and M. A. Nieto (2009)
EMBO Mol Med. 1, 303-314
   Abstract »    Full Text »    PDF »
Reversibility of Epithelial-Mesenchymal Transition (EMT) Induced in Breast Cancer Cells by Activation of Urokinase Receptor-dependent Cell Signaling.
M. Jo, R. D. Lester, V. Montel, B. Eastman, S. Takimoto, and S. L. Gonias (2009)
J. Biol. Chem. 284, 22825-22833
   Abstract »    Full Text »    PDF »
The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2.
T.-S. Yeh, C.-W. Wu, K.-W. Hsu, W.-J. Liao, M.-C. Yang, A. F.-Y. Li, A.-M. Wang, M.-L. Kuo, and C.-W. Chi (2009)
Cancer Res. 69, 5039-5048
   Abstract »    Full Text »    PDF »
Acquisition of Epithelial-Mesenchymal Transition Phenotype of Gemcitabine-Resistant Pancreatic Cancer Cells Is Linked with Activation of the Notch Signaling Pathway.
Z. Wang, Y. Li, D. Kong, S. Banerjee, A. Ahmad, A. S. Azmi, S. Ali, J. L. Abbruzzese, G. E. Gallick, and F. H. Sarkar (2009)
Cancer Res. 69, 2400-2407
   Abstract »    Full Text »    PDF »
Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin.
S. K. Harten, D. Shukla, R. Barod, A. Hergovich, M. S. Balda, K. Matter, M. A. Esteban, and P. H. Maxwell (2009)
Mol. Biol. Cell 20, 1089-1101
   Abstract »    Full Text »    PDF »
Tenascin-C Is a Novel RBPJ{kappa}-Induced Target Gene for Notch Signaling in Gliomas.
B. Sivasankaran, M. Degen, A. Ghaffari, M. E. Hegi, M.-F. Hamou, M.-C. S. Ionescu, C. Zweifel, M. Tolnay, M. Wasner, S. Mergenthaler, et al. (2009)
Cancer Res. 69, 458-465
   Abstract »    Full Text »    PDF »

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