title: Sustained endoplasmic reticulum stress inhibits hepatocyte proliferation via downregulation of c-Met expression.
abstract: The molecular mechanisms of impaired liver regeneration in several liver diseases remain poorly understood. Endoplasmic reticulum (ER) stress has been observed in a variety of liver diseases. The aims of this study were to explore the impacts of ER stress on hepatocyte growth factor (HGF)-induced proliferation and c-Met expression in human hepatocyte L02 cells. Human hepatocyte L02 cells were incubated with thapsigargin (TG) to induce ER stress. 4-Phenylbutyric acid (PBA) was used to rescue ER stress. Activation of glucose-regulated protein 78, phosphorylation of PKR-like ER kinase and eukaryotic translation initiation factor-2α, and the expression of c-Met were determined by western blotting. The expression of c-Met mRNA was observed by reverse transcription polymerase chain reaction. L02 cell proliferation was determined by the MTS assay. L02 cell proliferation was significantly impaired in TG-treated L02 cells from 24 to 48 h, while PBA partly restored the proliferation of L02 cells. In addition, TG treatment significantly decreased the sensitivity of L02 cells to HGF-induced proliferation. PBA partly resumed the sensitivity of L02 cells to HGF-induced proliferation. The expression of c-Met protein in L02 cells was downregulated from 6 h after TG treatment, and PBA partly restored c-Met expression inhibited by TG. The expression of c-Met mRNA was also significantly downregulated from 24 to 48 h after TG treatment. Our results strongly suggest that sustained ER stress inhibits hepatocyte proliferation via downregulation of both c-Met mRNA and protein expression in human hepatocyte L02 cells.
authors.affiliation: Department of Infectious Diseases, Zunyi Medical College, 201 Dalian Street, Zunyi, 563003, Guizhou, China.
authors.forename: Yihuai
authors.initials: Y
authors.lastname: He
authors.forename: Jun
authors.initials: J
authors.lastname: Long
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhong
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Shide
authors.initials: S
authors.lastname: Lin
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; C018551:glucose-regulated proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met