The phyto-chemical (-)-epigallocatechin gallate suppresses gene expression of epidermal growth factor receptor in rat hepatic stellate cells in vitro by reducing the activity of Egr-1.
Hepatic stellate cells (HSC) are the major effectors in hepatic fibrogenesis. During liver injury, HSC become activated and proliferative. Platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) are the potent mitogens for many cell types. We previously demonstrated that (-)-epigallocatechin gallate (EGCG), the major and active component in green tea extracts, inhibited HSC growth, including reducing cell proliferation, and inducing apoptosis. We have reported that EGCG interrupts PDGF signaling by reducing receptor tyrosine phosphorylation and gene expression of PDGF-beta receptor. Additional experiments are necessary to elucidate the effect of EGCG on EGF signaling in activated HSC. The aims of this study are to evaluate the effect of EGCG on the expression of EGFR and to elucidate the underlying molecular mechanisms in activated HSC. We hypothesize that EGCG might interrupt EGF signaling by suppressing gene expression of EGF receptor (EGFR) in activated HSC, which, together with the interruption of PDGF signaling, might collectively result in the inhibition of HSC growth. The present report demonstrates that the phyto-chemical dose-dependently suppresses gene expression of EGFR in activated HSC in vitro. The Egr-1 binding site located in the egfr promoter is found to be cis-activating element in regulating the promoter activity of the gene. EGCG inhibits the trans-activation activity of Egr-1 in activated HSC by suppressing gene expression of the transcription factor. The interruption of the ERK signaling pathway by EGCG reduces the trans-activation activity of Egr-1 and the promoter activity of EGFR gene in HSC. Taken together, our results demonstrate that EGCG suppresses gene expression of EGFR in rat activated HSC in vitro mediated by reducing the trans-activation activity of Egr-1.
Fu
Yumei
Y
Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA 71130, United States.
Chen
Anping
A
D000818:Animals; D001483:Base Sequence; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D017931:DNA Primers; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation
D017931:DNA Primers; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D002392:Catechin; C045651:epigallocatechin gallate; D066246:ErbB Receptors