title: Lumican regulates osteosarcoma cell adhesion by modulating TGFβ2 activity.
abstract: Human osteosarcoma cell lines were recently shown to express and secrete the small leucine rich proteoglycan (SLRP) lumican, with the ability to regulate the growth and motility of these cells. In this study, lumican-deficient Saos 2 cells were demonstrated to have increased adhesive capability onto fibronectin (FN) (p≤0.01). Upon neutralization of endogenous transforming growth factor β2 (TGF-β2) activity, no difference in the ability of lumican siRNA-transfected and scramble siRNA-transfected Saos 2 cells to adhere onto FN was detected (p=NS). Exogenous TGF-β2 was shown to stimulate Saos 2 cell adhesion to FN (p≤0.01). These results therefore, suggest that the inverse correlation existing between lumican expression and Saos 2 cell adhesion is dependent on active TGF-β2 signaling. Furthermore, the significant increase in Smad 2 activation present in lumican-deficient cells (p≤0.01) was annulled in the presence of the anti-TGF-β2 peptide, demonstrating that lumican is an upstream regulator of the TGF-β2/Smad 2 signaling cascade. Crucial to FN-dependent adhesion, β1 integrin expression and pFAK activation were likewise identified as downstream TGF-β2 effectors regulated by lumican expression. In conclusion, this study demonstrates a novel out-in signaling circuit in human osteosarcoma cells: secreted to extracellular matrix lumican is an endogenous inhibitor of TGF-β2 activity, resulting in downstream effector modulation including pSmad 2, integrin β1 and pFAK to regulate osteosarcoma adhesion.
authors.affiliation: Department of Histology-Embryology, Medical School, University of Crete, Heraklion, Greece.
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikitovic
authors.forename: Georgia
authors.initials: G
authors.lastname: Chalkiadaki
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Berdiaki
authors.forename: John
authors.initials: J
authors.lastname: Aggelidakis
authors.forename: Pavlos
authors.initials: P
authors.lastname: Katonis
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D005353:Fibronectins / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007632:Keratan Sulfate / Q000235:genetics / Q000378:metabolism*; D000071234:Lumican; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D005353:Fibronectins; D019012:Integrin beta1; C000604306:LUM protein, human; D000071234:Lumican; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D053781:Transforming Growth Factor beta2; D007632:Keratan Sulfate; D051418:Focal Adhesion Kinase 2