JCB logo
Avanti Polar Lipids, Inc.
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online
doi:10.1083/jcb.200701092
The Journal of Cell Biology, Vol. 178, No. 3, 425-436
The Rockefeller University Press, 0021-9525 $30.00
© Lester et al.
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 3335K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lester, R. D.
Right arrow Articles by Gonias, S. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lester, R. D.
Right arrow Articles by Gonias, S. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Article

uPAR induces epithelial–mesenchymal transition in hypoxic breast cancer cells



Robin D. Lester, Minji Jo, Valérie Montel, Shinako Takimoto, and Steven L. Gonias

Department of Pathology, University of California, San Diego, La Jolla, CA 92093

Correspondence to Steven L. Gonias sgonias{at}ucsd.edu

Hypoxia activates genetic programs that facilitate cell survival; however, in cancer, it may promote invasion and metastasis. In this study, we show that breast cancer cells cultured in 1.0% O2 demonstrate changes consistent with epithelial–mesenchymal transition (EMT). Snail translocates to the nucleus, and E-cadherin is lost from plasma membranes. Vimentin expression, cell migration, Matrigel invasion, and collagen remodeling are increased. Hypoxia-induced EMT is accompanied by increased expression of the urokinase-type plasminogen activator receptor (uPAR) and activation of cell signaling factors downstream of uPAR, including Akt and Rac1. Glycogen synthase kinase-3ß is phosphorylated, and Snail expression is increased. Hypoxia-induced EMT is blocked by uPAR gene silencing and mimicked by uPAR overexpression in normoxia. Antagonizing Rac1 or phosphatidylinositol 3-kinase also inhibits development of cellular properties associated with EMT in hypoxia. Breast cancer cells implanted on chick chorioallantoic membranes and treated with CoCl2, to model hypoxia, demonstrate increased dissemination. We conclude that in hypoxia, uPAR activates diverse cell signaling pathways that cooperatively induce EMT and may promote cancer metastasis.

R.D. Lester and M. Jo contributed equally to this paper.

Abbreviations used in this paper: CAM, chorioallantoic membrane; DN, dominant-negative; EMT, epithelial–mesenchymal transition; EpoR, erythropoietin receptor; ERK, extracellular signal-regulated kinase; GSK-3ß, glycogen synthase kinase-3ß; HIF, hypoxia-inducible factor; HPRT-1, hypoxanthine phosphoribosyltransferase 1; PI3K, phosphatidylinositol 3-kinase; qPCR, quantitative PCR; sh, short hairpin; uPA, urokinase-type plasminogen activator; uPAR, uPA receptor; VEGF, vascular endothelial growth factor.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents