title: CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis.
abstract: Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and the poor survival rate for patients. We showed previously that the HMGCoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor statin exhibits antitumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify Cyr61 as a new target of statins. Transcriptome and molecular analyses revealed that statins downregulate Cyr61 expression in human and murine osteosarcoma cells. Cyr61 silencing in osteosarcoma cell lines enhanced cell death and reduced cell migration and cell invasion compared with parental cells, whereas Cyr61 overexpression had opposite effects. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients. Tissue microarray analysis revealed that Cyr61 protein expression was higher in human osteosarcoma than in normal bone tissue and was further increased in metastatic tissues. Finally, tumor behavior and metastasis occurrence were analyzed by intramuscular injection of modified osteosarcoma cells into BALB/c mice. Cyr61 overexpression enhanced lung metastasis development, whereas cyr61 silencing strongly reduced lung metastases in mice. The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma.
authors.affiliation: Laboratory of Osteoblast Biology and Pathology, INSERM, Paris, France. olivia.fromigue@inserm.fr
authors.forename: Olivia
authors.initials: O
authors.lastname: Fromigue
authors.forename: Zahia
authors.initials: Z
authors.lastname: Hamidouche
authors.forename: Pascal
authors.initials: P
authors.lastname: Vaudin
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
authors.forename: Ana
authors.initials: A
authors.lastname: Patino
authors.forename: Pascal
authors.initials: P
authors.lastname: Barbry
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055515:Cysteine-Rich Protein 61 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology*; D054876:Prenylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology
chemical_list: D055515:Cysteine-Rich Protein 61; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin