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Sustained endoplasmic reticulum stress inhibits hepatocyte proliferation via downregulation of c-Met expression

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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.

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Acknowledgments

This work was partially supported by the Funds of the Chinese National Natural Science Foundation Project (81160067/H0318).

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  1. Department of Infectious Diseases, Zunyi Medical College, 201 Dalian Street, Zunyi, 563003, Guizhou, China

    Yihuai He, Jun Long, Weiwei Zhong, Yu Fu, Ying Li & Shide Lin

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  1. Yihuai He
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He, Y., Long, J., Zhong, W. et al. Sustained endoplasmic reticulum stress inhibits hepatocyte proliferation via downregulation of c-Met expression. Mol Cell Biochem 389, 151–158 (2014). https://doi.org/10.1007/s11010-013-1936-8

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