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Deficiency of multidrug resistance 2 contributes to cell transformation through oxidative stress

Ali Tebbi, Florence Levillayer, Grégory Jouvion1

  • 1Unité d'Histopathologie humaine et modèles animaux.

Carcinogenesis
|November 7, 2015
PubMed

Insights

Multidrug resistance 2 (Mdr2) deficiency causes cellular damage and increases cancer susceptibility. This study reveals Mdr2's role beyond bile formation, impacting cellular functions and potentially other organs.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance 2 (Mdr2/ABCB4) transports phosphatidylcholine (PC) in hepatocytes, crucial for bile formation.
  • MDR3 mutations link to human liver diseases; Mdr2 knockout mice develop liver issues.
  • The direct cellular impact of Mdr2 deficiency beyond bile acid toxicity is understudied.

Purpose of the Study:

  • To investigate the intrinsic cellular functions of Mdr2 beyond its role in bile formation.
  • To explore the consequences of Mdr2 deficiency in non-hepatic cells and its link to tumorigenesis.

Main Methods:

  • Utilized Mdr2 knockout mouse embryonic fibroblasts (MEFs) to assess cellular functions.
  • Analyzed gene expression via microarray in MEFs and cap analysis in Mdr2 knockout HCCs.
  • Assessed susceptibility to chemical carcinogen-induced intestinal tumorigenesis in Mdr2 knockout mice.

Main Results:

  • Mdr2 deficiency in MEFs led to increased reactive oxygen species, lipid peroxidation, and DNA damage.
  • Mdr2 knockout MEFs exhibited spontaneous transformation; Mdr2 knockout mice showed heightened susceptibility to intestinal tumorigenesis.
  • Gene expression profiling revealed deregulation in oxidation-reduction, fatty acid metabolism, and lipid biosynthesis pathways.

Conclusions:

  • Mdr2 deficiency directly impairs cellular functions, contributing to DNA damage and transformation.
  • Perturbations in lipid and oxidation-reduction pathways are linked to Mdr2-associated tumorigenesis.
  • Mdr2/MDR3 may possess significant extrahepatic functions impacting cellular health and disease.

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