Suppression of Osteosarcoma Cell Invasion by Chemotherapy Is Mediated by Urokinase Plasminogen Activator Activity via Up-Regulation of EGR1
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Background: The cellular and molecular mechanisms of tumour response following chemotherapy are largely unknown. Wefound that low dose anti-tumour agents up-regulate early growth response 1 (EGR1) expression. EGR1 is a member of theimmediate-early gene group of transcription factors which modulate transcription of multiple genes involved in cellproliferation, differentiation, and development. It has been reported that EGR1 act as either tumour promoting factor orsuppressor. 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 nextexamined the expression of EGR1 following anti-tumour agents treatment. To examine the function of EGR1 inosteosarcoma, 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 linesfollowing anti-tumour agent treatment. Although forced expression of EGR1 did not prevent osteosarcoma growth, forcedexpression of EGR1 prevented osteosarcoma cell invasion in vitro. In addition, forced expression of EGR1 promoted downregulationof urokinase plasminogen activator, urokinase receptor, and urokinase plasminogen activity. Xenograft micemodels 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 inchemotherapy-resistant patients, it did prevent osteosarcoma cell invasion by down-regulation of urokinase plasminogenactivity via up-regulation of EGR1 during chemotherapy periods.
- Public Library of Scienceの論文
- 2011-01-20
Public Library of Science | 論文
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