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.