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Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1319-E1328. doi: 10.1073/pnas.1715999115. Epub 2018 Jan 19.

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

Author information

1
University Paris Descartes, INSERM UMR 1124, Faculty of Basic and Biomedical Sciences, 75270 Paris Cedex 6, France.
2
EA7331, Université Paris Descartes, Faculté de Pharmacie de Paris, 75270 Paris Cedex 6, France.
3
Department of Pathology, Henri Mondor Hospital, 94010 Créteil, France.
4
Department of Pathology, Cochin Hospital, 75014 Paris, France.
5
CNRS UMR 7179, Département Ecologie et Gestion de la Biodiversité, Muséum National d'Histoire Naturelle, 75231 Paris Cedex 5, France.
6
University Paris Descartes, CNRS UMR 8119, Faculty of Basic and Biomedical Sciences, 75270 Paris Cedex 6, France.
7
Paris-Saclay University, INSERM UMR-1195, 94276 Le Kremlin-Bicêtre Cedex, France etienne.baulieu@inserm.fr Charbel.massaad@parisdescartes.fr.
8
University Paris Descartes, INSERM UMR 1124, Faculty of Basic and Biomedical Sciences, 75270 Paris Cedex 6, France; etienne.baulieu@inserm.fr Charbel.massaad@parisdescartes.fr.

Abstract

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 neurofibromatosis 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 endogenous 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 trimethoxyflavone, 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 locomotion 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 myelination and in peripheral nerve sheath tumors. Finally, we suggest a potential therapeutic approach by targeting AHR in nerve tumors.

KEYWORDS:

AHR; MPNST; myelin; nerve; neurofibroma

PMID:
29351992
PMCID:
PMC5819423
DOI:
10.1073/pnas.1715999115
[Indexed for MEDLINE]
Free PMC Article

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