title: Suppression of osteosarcoma cell invasion by chemotherapy is mediated by urokinase plasminogen activator activity via up-regulation of EGR1.
abstract: BACKGROUND
  The cellular and molecular mechanisms of tumour response following chemotherapy are largely unknown. We found that low dose anti-tumour agents up-regulate early growth response 1 (EGR1) expression. EGR1 is a member of the immediate-early gene group of transcription factors which modulate transcription of multiple genes involved in cell proliferation, differentiation, and development. It has been reported that EGR1 act as either tumour promoting factor or suppressor. We therefore examined the expression and function of EGR1 in osteosarcoma.
  
  
  METHODS
  We investigated the expression of EGR1 in human osteosarcoma cell lines and biopsy specimens. We next examined the expression of EGR1 following anti-tumour agents treatment. To examine the function of EGR1 in osteosarcoma, we assessed the tumour growth and invasion in vitro and in vivo.
  
  
  RESULTS
  Real-time PCR revealed that EGR1 was down-regulated both in osteosarcoma cell lines and osteosarcoma patients' biopsy specimens. In addition, EGR1 was up-regulated both in osteosarcoma patient' specimens and osteosarcoma cell lines following anti-tumour agent treatment. Although forced expression of EGR1 did not prevent osteosarcoma growth, forced expression of EGR1 prevented osteosarcoma cell invasion in vitro. In addition, forced expression of EGR1 promoted down-regulation of urokinase plasminogen activator, urokinase receptor, and urokinase plasminogen activity. Xenograft mice models showed that forced expression of EGR1 prevents osteosarcoma cell migration into blood vessels.
  
  
  CONCLUSIONS
  These findings suggest that although chemotherapy could not prevent osteosarcoma growth in chemotherapy-resistant patients, it did prevent osteosarcoma cell invasion by down-regulation of urokinase plasminogen activity via up-regulation of EGR1 during chemotherapy periods.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Matsunoshita
authors.forename: Kosei
authors.initials: K
authors.lastname: Ijiri
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishidou
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagano
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagao
authors.forename: Setsuro
authors.initials: S
authors.lastname: Komiya
authors.forename: Takao
authors.initials: T
authors.lastname: Setoguchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001706:Biopsy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000032:analysis / Q000235:genetics*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D014568:Urokinase-Type Plasminogen Activator