Early growth response gene-1 and hypoxia-inducible factor-1α affect tumor metastasis via regulation of tissue factor
Early growth response gene-1 and hypoxia-inducible factor-1α affect tumor metastasis via regulation of tissue factor
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DOI：
10.3109/0284186x.2013.705890
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发表时间：
2013-04
期刊：
影响因子：
3.1
通讯作者：
Li Sun;Yang Liu;Sen-sen Lin;Jing Shang;Jin Liu;Ji Li;S. Yuan;Luyong Zhang
中科院分区：
文献类型：
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作者：
Li Sun;Yang Liu;Sen-sen Lin;Jing Shang;Jin Liu;Ji Li;S. Yuan;Luyong Zhang
抽象背景。缺氧上调组织因子（TF）表达可能促进肿瘤细胞转移，但转录机制尚不清楚。材料和方法。为了验证Egr-1在缺氧诱导的乳腺癌细胞TF表达中的作用，进行定量PCR和Western blot分析。采用酶联免疫吸附试验（ELISA）检测缺氧条件下VEGF的分泌。将Egr-1和HIF-1α siRNA瞬时转染乳腺癌细胞以评价其特异性作用。结果低氧诱导的乳腺癌细胞Egr-1表达增加可上调TF表达，而刺激蛋白1（Sp1）与低氧诱导的TF表达无关。HIF-1α通过血管内皮生长因子（VEGF）介导低氧诱导的TF表达上调。Egr-1对缺氧条件下TF的调节作用不依赖于HIF-1α。Egr-1和HIF-1α均参与低氧诱导肿瘤细胞粘附。HIF-1α在人乳腺癌细胞侵袭中起关键作用，而Egr-1则无此作用。Egr-1和HIF-1α对MDA-MB-231和HUVEC共培养物中缺氧条件诱导的血管生成至关重要。Egr-1和HIF-1α小干扰RNA（siRNA）均能减少MDA-MB-435细胞尾静脉注射后的肺外渗。结论.缺氧诱导的人乳腺癌细胞TF表达依赖于Egr-1和HIF-1α，这两种蛋白可能直接或间接通过TF途径在乳腺癌转移中发挥重要作用。
Abstract Background. Hypoxia up-regulated expression of tissue factor (TF) may facilitate tumor cell metastasis, but transcriptional mechanisms remain undefined. Material and methods. To verify the role of Egr-1 in hypoxia-induced TF expression in breast cancer cells, quantitative PCR and Western blot analysis were performed. The secretion of VEGF under hypoxia was detected by enzyme-linked immunosorbent assay (ELISA). Egr-1 and HIF-1α siRNA were transiently transfected into breast cancer cells to evaluate their specific roles. Results. The increased Egr-1 expression occurring in hypoxic breast cancer cells can up-regulate TF expression and stimulating protein 1(Sp1) was not responsible for the hypoxia-induced expression of TF. HIF-1α mediated the hypoxia-induced up-regulation of TF expression through vascular endothelial growth factor (VEGF). The regulatory effects of Egr-1 on TF under hypoxia were independent of HIF-1α. Either Egr-1 or HIF-1α was responsible for hypoxic induction of tumor cells adhesion. HIF-1α, but not Egr-1, had a pivotal role in human breast cancer cells invasion. Both Egr-1 and HIF-1α were critical to angiogenesis induced by hypoxic conditions in MDA-MB-231 and HUVEC co-cultures. In nude mice, both Egr-1 and HIF-1α small interfering RNA (siRNA) could decrease extravasation of MDA-MB-435 cells in the lung after tail vein injection. Conclusions. Hypoxia-induced expression of TF in human breast cancer cells depends on Egr-1 and HIF-1α, and both of these proteins may play an important role in breast cancer metastasis, either directly or indirectly through the TF pathway.