title: Caprin-1, a novel Cyr61-interacting protein, promotes osteosarcoma tumor growth and lung metastasis in mice.
abstract: Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. More than 30% of patients develop lung metastasis, which is the leading cause of mortality. Recently, the extracellular matrix protein Cyr61 has been recognized as a malignancy promoting protein in OS mouse model with prognostic potential in human OS. In this study, we aimed at the identification of novel Cyr61-interacting proteins. Here we report that Cyr61 associates with Caprin-1, and confocal microscopy showed that stable ectopic expression of Caprin-1 leads to the formation of stress granules containing Caprin-1 and Cyr61, confers resistance to cisplatin-induced apoptosis, and resulted in constitutive phosphorylation of Akt and ERK1/2. Importantly, ectopic expression of Caprin-1 dramatically enhanced primary tumor growth, remarkably increased lung metastatic load in a SCID intratibial OS mouse model, and decreased significantly (p<0.0018) the survival of the mice. Although Caprin-1 expression, evaluated with a tissue microarray including samples from 59 OS patients, failed to be an independent predictor for the patients' outcome in this limited cohort of patients, increased Caprin-1 expression indicated a tendency to shortened overall survival, and more strikingly, Cyr61/Caprin-1 co-expression was associated with worse survival than that observed for patients with tumors expressing either Cyr61 or Caprin-1 alone or none of these proteins. The findings imply that Caprin-1 may have a metastasis promoting role in OS and show that through resistance to apoptosis and via the activation of Akt and ERK1/2 pathways, Caprin-1 is significantly involved in the development of OS metastasis.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland. asabile@research.balgrist.ch
authors.forename: Adam A
authors.initials: AA
authors.lastname: Sabile
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Roman
authors.initials: R
authors.lastname: Muff
authors.forename: Knut
authors.initials: K
authors.lastname: Husmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Hess
authors.forename: Josefine
authors.initials: J
authors.lastname: Bertz
authors.forename: Bettina
authors.initials: B
authors.lastname: Langsam
authors.forename: Caroline
authors.initials: C
authors.lastname: Aemisegger
authors.forename: Urs
authors.initials: U
authors.lastname: Ziegler
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D020935:MAP Kinase Signaling System; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000235:genetics; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C486562:CAPRIN1 protein, human; C501848:CCN1 protein, human; D018797:Cell Cycle Proteins; D055515:Cysteine-Rich Protein 61; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin