title: Cyr61 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by Raf-1/MEK/ERK/Elk-1/TWIST-1 signaling pathway.
abstract: BACKGROUND
  Osteosarcoma is the most common primary malignant tumor in children and young adults, and its treatment requires effective therapeutic approaches because of a high mortality rate for lung metastasis. Epithelial to mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining the invasive and metastatic behavior during cancer progression. The cysteine-rich angiogenic inducer 61 (Cyr61) gene, a member of the CCN gene family, is responsible for the secretion of Cyr61, a matrix-associated protein that is involved in several cellular functions. A previous study showed that Cyr61 expression is related to osteosarcoma progression. In addition, Cyr61 could promote cell migration and metastasis in osteosarcoma. However, discussions on the molecular mechanism involved in Cyr61-regulated metastasis in osteosarcoma is poorly discussed.
  
  
  RESULTS
  We determined that the expression level of Cyr61 induced cell migration ability in osteosarcoma cells. The Cyr61 protein promoted the mesenchymal transition of osteosarcoma cells by upregulating mesenchymal markers (TWIST-1 and N-cadherin) and inhibiting the epithelial marker (E-cadherin). Moreover, the Cyr61-induced cell migration was mediated by EMT. The Cyr61 protein elicited a signaling cascade that included αvβ5 integrin, Raf-1, mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and Elk-1. The reagent or gene knockdown of these signaling proteins could inhibit Cyr61-promoted EMT in osteosarcoma. Finally, the knockdown of Cyr61 expression obviously inhibited cell migration and repressed mesenchymal phenotypes, reducing lung metastasis.
  
  
  CONCLUSIONS
  Our results indicate that Cyr61 promotes the EMT of osteosarcoma cells by regulating EMT markers via a signal transduction pathway that involves αvβ5 integrin, Raf-1, MEK, ERK, and Elk-1.
authors.forename: Chun-Han
authors.initials: CH
authors.lastname: Hou
authors.forename: Feng-Ling
authors.initials: FL
authors.lastname: Lin
authors.affiliation: Department of Orthopedic Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, NO, 95 Wen Chang Road, Taipei, Taiwan. shengmou@ms.skh.org.tw.
authors.forename: Sheng-Mon
authors.initials: SM
authors.lastname: Hou
authors.forename: Ju-Fang
authors.initials: JF
authors.lastname: Liu
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D019030:Receptors, Vitronectin / Q000378:metabolism; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D055515:Cysteine-Rich Protein 61; D019030:Receptors, Vitronectin; D051879:Twist-Related Protein 1; D050807:ets-Domain Protein Elk-1; C064660:integrin alphaVbeta5; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases