The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element

Abstract

We found that human melanoma SEKI and neuroepithelioma NAGAI cells, which are known to secrete high concentrations of leukemia inhibitory factor (LIF), also secrete high levels of hepatocyte growth factor (HGF). We therefore examined the role of LIF in HGF expression and examined the human HGF promoter. The expression of both LIF and HGF mRNA is very low in HEK293 cells. Treatment of these cells with LIF stimulated the expression of HGF mRNA. The cis-acting regulatory element of the HGF promoter in SEKI and 293 cells was analysed by means of a transient expression assay. By deletion analysis, we showed that the region comprising the -181 to -73 bp was required for full activity of the HGF promoter in SEKI cells and for LIF responsiveness of 293 cells. This region contains putative consensus sequences for the Stat and NF-IL6 (C/EBP beta) transcription factors. The activity of the HGF promoter was abolished by mutation of the Stat site at -99/-91, while the activity only slightly decreased on mutation of the NF-IL6 site. Treatment with anti-LIF antibodies or interruption of Stat3 signaling by dominant-negative Stat3 also reduced the HGF promoter activity. Stat3 activation was constitutive in SEKI cells and induced on treatment of 293 cells with LIF. These results suggest that cytokines, growth factors and oncogenes (v-Src, etc.) that activate Stat3 are important regulators of HGF expression.