The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3beta and c-Jun/AP-1 signaling.
Inappropriate activation of the Wnt/APC/beta-catenin signaling pathways plays a critical role at early stages in a variety of human cancers. However, their respective implication in tumor cell invasion is still hypothetical. Here, we show that two activators of the canonical Wnt/beta-catenin transcription pathway, namely Dvl-2, the Axin 501-560 fragment binding glycogen synthase kinase -3beta (GSK-3beta), and the negative Wnt regulator wt-Axin did not alter cell invasion into type I collagen. In addition, both Dvl-2 and Axin 501-560 exerted a permissive action on the proinvasive activity of HGF and intestinal trefoil factor. Upstream activation of Wnt signaling by the Wnt-2 and Wnt-3a ligands, stable overexpression of Wnt-2, as well as GSK-3beta inhibition by lithium, SB216763, and GSK-3beta dominant negative forms (K85R and R96E) conferred the invasive phenotype through several proinvasive pathways. Induction of the matrix metalloprotease MMP-7 (matrilysin) gene and protein by Wnt-2 was abolished by inactivation of the AP-1 binding site in the promoter. Accordingly, invasion induced by Wnt-2 was prevented by soluble FRP-3 and FRP-1, sequestration of Gbetagamma subunits, depletion of the GSK-3beta protein by RNA interference, the c-Jun dominant negative mutant TAM67 and was not reversed by wt-Axin. Thus, the proinvasive activity of Wnt-2 is mediated by a noncanonical Wnt pathway using GSK-3beta and the AP-1 oncogene. Our data provide a potential clue for our understanding of the action and crosstalk between Wnt activators and other proinvasive pathways, in relation with matrix substrates and proteases in human cancers.
Le Floch
Nathalie
N
INSERM U482, Signal transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, Paris Cedex, France.
Rivat
Christine
C
De Wever
Olivier
O
Bruyneel
Erik
E
Mareel
Marc
M
Dale
Trevor
T
Gespach
Christian
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D060466:Axin Protein; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D004285:Dogs; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism / Q000821:virology; D005822:Genetic Vectors / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006023:Glycoproteins / Q000494:pharmacology; D019073:HT29 Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000196:embryology / Q000378:metabolism / Q000821:virology; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008024:Ligands; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis; D009361:Neoplasm Invasiveness / Q000235:genetics*; D010446:Peptide Fragments / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000494:pharmacology; D012190:Retroviridae; D015398:Signal Transduction / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D051153:Wnt Proteins; D051154:Wnt2 Protein; D000099274:Frizzled-Related Proteins
D000911:Antibodies, Monoclonal; D060466:Axin Protein; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006023:Glycoproteins; D020962:Heterotrimeric GTP-Binding Proteins; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D018021:Lithium Chloride; D008301:Maleimides; D020783:Matrix Metalloproteinase 7; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D051153:Wnt Proteins; D051154:Wnt2 Protein; D000099274:Frizzled-Related Proteins; C417521:SB 216763; C000605506:GSK3B protein, human