title: Regulation of vascular endothelial growth factor expression in human gastric cancer cells by interleukin-1beta.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF), a dominant angiogenic factor in gastric cancer, is upregulated by cytokines in the tumor microenvironment. Interleukin-1beta (IL-1beta), a proinflammatory cytokine, has been shown to be proangiogenic in vivo, despite its not demonstrating angiogenic activity in vitro. We hypothesized that IL-1beta regulates VEGF expression in human gastric cancer cells and investigated the mechanism by which this occurs.
  
  
  METHODS
  We treated the TMK-1 human gastric cancer cell line with IL-1beta for 1 to 24 hours, and then analyzed VEGF mRNA expression by Northern blotting and signaling intermediates by Western blotting. Signaling inhibitors were used to identify the dominant pathways involved in IL-1beta induction of VEGF. VEGF promoter-luciferase constructs and transcription blockers were used to investigate the transcriptional regulation of VEGF by IL-1beta.
  
  
  RESULTS
  Treating TMK-1 cells with IL-1beta increased VEGF mRNA levels and activated extracellular signal-regulated kinases 1 and 2 (Erk 1/2) and p38, but not Akt. Inhibitors of the Erk and p38 pathways blocked IL-1beta induction of VEGF mRNA. Treating TMK-1 cells with IL-1beta also increased VEGF promoter activity. VEGF transcriptional activity was found to depend on a 120-bp region just proximal to the transcription start site.
  
  
  CONCLUSIONS
  In human gastric cancer cells, IL-1beta induced VEGF through Erk- and p38-dependent pathways; this induction of VEGF was transcriptionally regulated.
authors.affiliation: Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Tex, USA.
authors.forename: Michiya
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Morihisa
authors.initials: M
authors.lastname: Akagi
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Gray
authors.forename: Wenbiao
authors.initials: W
authors.lastname: Liu
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
mesh_terms: D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000503:physiopathology*; D014158:Transcription, Genetic / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007375:Interleukin-1; D042442:Vascular Endothelial Growth Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases