Osteopontin--an important downstream effector of S100A4-mediated invasion and metastasis.
Substantial evidence has linked the small calcium-binding protein S100A4 to metastatic progression. S100A4-mediated effects include stimulation of angiogenesis, regulation of cell death and increased cell motility and invasion, but the exact molecular mechanisms by which the protein exerts these effects are incompletely elucidated. In the present study, we demonstrate that S100A4 induces NF-κB-dependent expression and secretion of osteopontin (OPN) in a selection of osteosarcoma cell lines. OPN is, as S100A4, known to result in a variety of cellular effects potentially leading to increased angiogenesis and metastasis, and several of the activated signaling pathways are common for the two proteins. In our study, extracellular S100A4 was found to upregulate enzymes of the plasminogen activator system and matrix metalloproteinase (MMP) family, especially urokinase plasminogen activator and MMP-13. Furthermore, increased motility and invasion was observed in vitro as a result of S100A4 treatment. OPN expression was inhibited by the use of siRNA molecules, and a partial blocking of S100A4-induced effects on protease expression and invasive capacity was detected. In conclusion, our results suggest regulation of OPN as a downstream molecular mechanism of S100A4 signaling. This novel finding adds more information to how S100A4 mediates tumor development and metastatic progression. The observation of a link between S100A4 and OPN, and also identification of common downstream effect molecules, highlights them, their receptors or downstream proteins, as targets for therapeutic approaches.
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. gisle.berge@rr-research.no
Gisle
G
Berge
Solveig
S
Pettersen
Ida
I
Grotterød
Ingrid J
IJ
Bettum
Kjetil
K
Boye
Gunhild M
GM
Mælandsmo
D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D053495:Osteopontin; C077591:S100A4 protein, human; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2