title: Early growth response gene-1 and hypoxia-inducible factor-1α affect tumor metastasis via regulation of tissue factor.
abstract: BACKGROUND
  Hypoxia up-regulated expression of tissue factor (TF) may facilitate tumor cell metastasis, but transcriptional mechanisms remain undefined.
  
  
  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.
authors: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing, PR China.
authors: Li
authors: L
authors: Sun
authors: Yang
authors: Y
authors: Liu
authors: Sensen
authors: S
authors: Lin
authors: Jing
authors: J
authors: Shang
authors: Jin
authors: J
authors: Liu
authors: Ji
authors: J
authors: Li
authors: Shengtao
authors: S
authors: Yuan
authors: Luyong
authors: L
authors: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D013925:Thromboplastin / Q000235:genetics* / Q000378:metabolism
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013925:Thromboplastin