Mechanism underlying the targeted regulation of the SOD1 3'UTR by the AUF1/Dicer1/miR-155/SOD1 pathway in sodium arsenite-induced liver injury

Ecotoxicol Environ Saf. 2022 Sep 15:243:113990. doi: 10.1016/j.ecoenv.2022.113990. Epub 2022 Aug 20.

Abstract

Arsenic (As) is a natural hepatotoxicity inducer that is ubiquitous in water, soil, coal, and food. Studies have found that arsenite exposure elicits increased mRNA transcription and decreased protein expression of SOD1 in vivo and in vitro; however, the specific mechanisms remain unclear. Here, we established a model of arsenic-induced chronic liver injury by providing rats with drinking water containing different concentrations of sodium arsenite (NaAsO2) and found that NaAsO2 exposure decreased the mRNA and protein levels of AUF1 and the protein level of SOD1 and elevated the mRNA and protein levels of Dicer1 and miR-155 and the mRNA level of SOD1. Overexpression of AUF1 under NaAsO2 stress in vitro induced Dicer1 mRNA and protein expression and decreased miR-155 levels, which could be reversed by AUF1 siRNA. In addition, miR-155 overexpression downregulated SOD1 mRNA and protein levels, although this change was inhibited after transfection with an miR-155 inhibitor. Taken together, our findings showed that NaAsO2 could upregulate Dicer1 mRNA and protein, thereby increasing miR-155 expression by downregulating AUF1 mRNA and protein expression. A dual-luciferase reporter assay indicated that miR-155 decreased the mRNA and protein levels of SOD1 by targeting the SOD1 3'UTR, resulting in liver injury. This study provides an important research basis for further understanding the factors underlying arsenic-induced liver injury to improve the prevention and control strategies for arsenism.

Keywords: AU base enrichment element RNA binding protein 1; Arsenic; Liver injury; Oxidative stress; Ribonuclease III; Superoxide dismutase 1; miR-155.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Arsenic* / metabolism
  • Arsenic* / toxicity
  • Arsenites* / metabolism
  • Arsenites* / toxicity
  • Chemical and Drug Induced Liver Injury, Chronic*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Heterogeneous Nuclear Ribonucleoprotein D0
  • Heterogeneous-Nuclear Ribonucleoprotein D* / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein D* / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • Sodium Compounds
  • Superoxide Dismutase-1 / genetics

Substances

  • 3' Untranslated Regions
  • Arsenites
  • Heterogeneous Nuclear Ribonucleoprotein D0
  • Heterogeneous-Nuclear Ribonucleoprotein D
  • MIRN155 microRNA, rat
  • MicroRNAs
  • RNA, Messenger
  • Sodium Compounds
  • sodium arsenite
  • Sod1 protein, rat
  • Superoxide Dismutase-1
  • Dicer1 protein, rat
  • Ribonuclease III
  • DEAD-box RNA Helicases
  • Arsenic