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SET mediates TCE-induced liver cell apoptosis through dephosphorylation and upregulation of nucleolin

Xiaohu Ren1,2, Xinfeng Huang1, Xifei Yang1

  • 1Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China.

Oncotarget
|April 14, 2017
PubMed

Insights

Trichloroethylene (TCE) causes liver damage. This study reveals TCE induces liver cell apoptosis by altering nucleolin protein levels via the SET protein, offering new therapeutic targets.

Area of Science:

  • Hepatotoxicity Research
  • Molecular Toxicology
  • Cellular Apoptosis Mechanisms

Background:

  • Trichloroethylene (TCE) is a prevalent occupational and environmental chemical linked to severe liver toxicity.
  • Previous research identified the phosphatase inhibitor SET as a key mediator in TCE-induced liver cell apoptosis.
  • The precise molecular pathways underlying TCE's hepatotoxicity remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TCE induces hepatocyte apoptosis.
  • To investigate the role of the SET protein and its downstream targets in TCE-induced liver injury.
  • To identify novel therapeutic targets for mitigating TCE-induced liver damage.

Main Methods:

  • Quantitative phosphoproteomic analysis was employed to identify SET-regulated proteins in TCE-treated human liver cells (HL-7702).
  • Functional assays were performed to assess the impact of SET on nucleolin phosphorylation and its interaction with c-myc.
  • Nucleolin expression was modulated using small interfering RNAs (siRNAs) to evaluate its role in TCE-induced apoptosis.
  • Hepatocyte apoptosis was quantified to determine the effect of nucleolin downregulation.

Main Results:

  • Quantitative phosphoproteomic analysis identified nucleolin as a novel SET-regulated phosphoprotein in TCE-exposed human liver cells.
  • SET was found to promote nucleolin dephosphorylation, reduce its binding to the transcriptional activator c-myc, and upregulate nucleolin expression in TCE-treated cells.
  • Downregulation of nucleolin using siRNAs significantly attenuated TCE-induced hepatocyte apoptosis.

Conclusions:

  • TCE may induce hepatocyte apoptosis through a pathway involving the phosphatase inhibitor SET.
  • SET mediates the dephosphorylation and subsequent overexpression of nucleolin, contributing to TCE-induced liver cell death.
  • Targeting the SET-nucleolin pathway presents a potential therapeutic strategy for preventing or treating TCE-induced hepatotoxicity.
Keywords:
SEThepatic cytotoxicitynucleolinproteomicstrichloroethylene

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