title: Knockdown of S100A4 decreases tumorigenesis and metastasis in osteosarcoma cells by repression of matrix metalloproteinase-9.
abstract: Osteosarcoma (OS), the most frequent bone tumor in children and adolescents, is highly malignant. Metastases are the major cause of death, and patients with relapse have a poor prognosis. Given the associations of S100A4 with OS and tumor metastasis, we explored its potential roles in OS metastasis. Among 32 OS (16 metastatic and 16 non- metastatic) specimens examined, we found a significant increase of S100A4 mRNA in metastatic tissues, and more importantly, expression of S100A4 and MMP-9 to be strongly correlated in patients who had lymph node or distant metastasis. We observed that siRNA mediated suppression of the S100A4 gene significantly reduced the proliferative and invasive capability of highly invasive OS cells, with a reduced rate of tumor growth  and metastasis under in vivo conditions. Matrix metalloproteinase 9 (MMP-9) proved highly responsive to S100A4 gene suppression, demonstrating significant reduction in proteolytic activity, while overexpression of S100A4 increased the expression and proteolytic activity of MMP-9. Links of S100A4 with cell motility were confirmed by depletion which resulted in reduced cell migration. Moreover, loss of cell metastatic potential was completely rescued by overexpression of MMP-9. Collectively, our findings indicate that S100A4 contributes to OS metastasis by stimulating MMP-9 expression, suggesting potential as a novel diagnostic biomarker for OS progression as well as a therapeutic target.
authors.affiliation: Department of Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
authors.forename: Guoyou
authors.initials: G
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Yushu
authors.initials: Y
authors.lastname: Bai
authors.forename: Changwei
authors.initials: C
authors.lastname: Yang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D020780:Matrix Metalloproteinase 9