The tandem PDZ domains of syntenin promote cell invasion.
Syntenin is a tandem PDZ protein that has recently been shown to be overexpressed in several cancer cells and tissues, and that might play an active role in tumor cell invasion and metastasis. Here we show that overexpression of the tandem PDZ domains of syntenin in non-invasive cells is necessary and sufficient to stimulate these cells to invade a collagen I matrix, and this effect can be regulated by ligand binding to the PDZ domains. Furthermore, we show that syntenin-induced invasion requires signaling through ras, rho and PI3K/MAPK signaling pathways and involves changes in cell-cell adhesion. Inversely, when we used RNA interference to inhibit syntenin expression in different invasive cancer cell lines, we observed a drastically decreased ability of these cells to migrate and invade into collagen type I or Matrigel. RNAi-treated cells also show increased cell aggregation, indicating that syntenin is important for cell-cell adhesion in epithelial cells. Together, these results suggest that downregulation of syntenin by RNA interference could provide a means of inhibiting tumor invasion and possibly metastasis in different cancers, and point to syntenin as a potential cancer biomarker and drug target.
Meerschaert
Kris
K
Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium. kris.meerschaert@ugent.be
Bruyneel
Erik
E
De Wever
Olivier
O
Vanloo
Berlinda
B
Boucherie
Ciska
C
Bracke
Marc
M
Vandekerckhove
Joël
J
Gettemans
Jan
J
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002449:Cell Aggregation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D053676:Syntenins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D053676:Syntenins; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D020741:rho GTP-Binding Proteins