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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2018

The Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis

Ghjuvan Ghjacumu Shackleford
  • Fonction : Auteur
Nirmal Kumar Sampathkumar
  • Fonction : Auteur
Nicolas Ortonne
Frédérique Larousserie
  • Fonction : Auteur
Marc Herbin
  • Fonction : Auteur
  • PersonId : 847575
  • IdHAL : marc-herbin
Xavier Coumoul
Etienne-Emile Baulieu
  • Fonction : Auteur

Résumé

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in xenobiotic metabolism. Plexiform neurofibromas (PNFs) can transform into malignant peripheral nerve sheath tumors (MPNSTs) that are resistant to existing therapies. These tumors are primarily composed of Schwann cells. In addition to neurofibroma-tosis type 1 (NF1) gene inactivation, further genetic lesions are required for malignant transformation. We have quantified the mRNA expression levels of AHR and its associated genes in 38 human samples. We report that AHR and the biosynthetic enzymes of its en-dogenous ligand are overexpressed in human biopsies of PNFs and MPNSTs. We also detect a strong nuclear AHR staining in MPNSTs. The inhibition of AHR by siRNA or antagonists, CH-223191 and tri-methoxyflavone, induces apoptosis in human MPNST cells. Since AHR dysregulation is observed in these tumors, we investigate AHR involvement in Schwann cell physiology. Hence, we studied the role of AHR in myelin structure and myelin gene regulation in Ahr −/− mice during myelin development. AHR ablation leads to lo-comotion defects and provokes thinner myelin sheaths around the axons. We observe a dysregulation of myelin gene expression and myelin developmental markers in Ahr −/− mice. Interestingly, AHR does not directly bind to myelin gene promoters. The inhibition of AHR in vitro and in vivo increased β-catenin levels and stimulated the binding of β-catenin on myelin gene promoters. Taken together, our findings reveal an endogenous role of AHR in peripheral myeli-nation and in peripheral nerve sheath tumors. Finally, we suggest a potential therapeutic approach by targeting AHR in nerve tumors. AHR | myelin | nerve | MPNST | neurofibroma
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Dates et versions

hal-02110942 , version 1 (07-11-2019)

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Ghjuvan Ghjacumu Shackleford, Nirmal Kumar Sampathkumar, Mehdi Hichor, Laure Weill, Delphine Meffre, et al.. The Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (6), pp.E1319-E1328. ⟨10.1073/pnas.1715999115⟩. ⟨hal-02110942⟩
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