uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells.
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% O(2) 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-3beta 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 CoCl(2), 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.
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Robin D
RD
Lester
Minji
M
Jo
Valérie
V
Montel
Shinako
S
Takimoto
Steven L
SL
Gonias
D000818:Animals; D016587:Antimutagenic Agents / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D003035:Cobalt / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D004848:Epithelium / Q000502:physiology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D016587:Antimutagenic Agents; D015820:Cadherins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D003035:Cobalt; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; C018021:cobaltous chloride; D010100:Oxygen