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Clinical & Experimental Metastasis

, Volume 26, Issue 7, pp 685–692 | Cite as

Hepatocyte growth factor induced up-regulations of VEGF through Egr-1 in hepatocellular carcinoma cells

  • Kyung Hee Lee
  • Jae-Ryong Kim
Research Paper

Abstract

The potential role of hepatocyte growth factor (HGF) in the regulation of angiogenesis factors in hepatoma cells is not widely appreciated. We investigated the role of HGF-induced activation of a transcription factor, Egr-1, in the expression of pro-angiogenic factors. Genes associated with angiogenesis induced by HGF were screened by using cDNA microarray technology in hepatocellular carcinoma cell lines, HepG2 and Hep3B. Expression levels of Egr-1, vascular endothelial growth factor (VEGF), and interleukin (IL)-8 were further confirmed by real time RT-PCR and Western blot analysis. Roles of Egr-1 in the levels of HGF-induced up-regulations of VEGF and IL-8 were measured by knockdown of Egr-1 with Egr-1 shRNA and chromatin immunoprecipitation assay. The levels of Egr-1, VEGF and IL-8 were up-regulated in cells treated with HGF. HGF-induced up-regulations of Egr-1, VEGF, and IL-8 were inhibited by the pretreatment with an MEK inhibitor, PD098059. HGF-induced up-regulation of VEGF and IL-8 were repressed by Egr-1 knockdown. HGF enhanced the binding activity of Egr-1 to the VEGF promoter in control cells, but not in the Egr-1-shRNA cells. No constitutive and inducible Egr-1 binding activities to the IL-8 promoter were observed in control and Egr-1-shRNA cells. Egr-1 knockdown reduced the luciferase activities increased by HGF not in the IL-8 promoter, but in the VEGF promoter. Egr-1 might play an important role in the up-regulation of VEGF and IL-8 induced by HGF and contribute to HGF-mediated angiogenesis, which might be promising targets for hepatocellular carcinoma therapy.

Keywords

HGF Egr-1 VEGF IL-8 Angiogenesis 

Abbreviations

HGF

Hepatocyte growth factor

VEGF

Vascular endothelial growth factor

Egr-1

Early growth response gene-1

Notes

Acknowledgments

“This work was supported by the Korea Science and Engineering Foundation(KOSEF) NCRC grant funded by the Korea government(MEST) (No. R15-2004-033-05001-0)”

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Department of Hemato-Oncology, College of MedicineYeungnam UniversityDaeguRepublic of Korea
  2. 2.Department of Biochemistry and Molecular Biology, College of MedicineYeungnam UniversityDaeguRepublic of Korea
  3. 3.Aging-Associated Vascular Disease Research Center, College of MedicineYeungnam UniversityDaeguRepublic of Korea

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