Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
PLoS One. 2011 Jan 20;6(1):e16234. doi: 10.1371/journal.pone.0016234.
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.
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.
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.
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.
肿瘤对化疗的反应的细胞和分子机制在很大程度上尚不清楚。我们发现低剂量抗肿瘤药物可上调早期生长反应 1（EGR1）的表达。EGR1 是转录因子即时早期基因家族的成员，可调节参与细胞增殖、分化和发育的多种基因的转录。据报道，EGR1 可作为肿瘤促进因子或抑制因子。因此，我们研究了 EGR1 在骨肉瘤中的表达和功能。
我们研究了 EGR1 在人骨肉瘤细胞系和活检标本中的表达。接下来，我们检查了抗肿瘤药物治疗后 EGR1 的表达。为了研究 EGR1 在骨肉瘤中的功能，我们评估了体外和体内的肿瘤生长和侵袭。
实时 PCR 显示，EGR1 在骨肉瘤细胞系和骨肉瘤患者的活检标本中均下调。此外，在抗肿瘤药物治疗后，EGR1 在骨肉瘤患者的标本和骨肉瘤细胞系中均上调。虽然强制表达 EGR1 不能阻止骨肉瘤的生长，但强制表达 EGR1 可防止骨肉瘤细胞的体外侵袭。此外，强制表达 EGR1 促进了尿激酶纤溶酶原激活物、尿激酶受体和尿激酶纤溶酶原活性的下调。异种移植小鼠模型表明，强制表达 EGR1 可防止骨肉瘤细胞在化疗期间通过上调 EGR1 进入血管的迁移。
这些发现表明，尽管化疗不能预防化疗耐药患者的骨肉瘤生长，但它通过上调 EGR1 可在化疗期间下调尿激酶纤溶酶原活性，从而防止骨肉瘤细胞侵袭。
