University Paris Descartes, INSERM UMR 1124, Faculty of Basic and Biomedical Sciences, 75270 Paris Cedex 6, France.
EA7331, Université Paris Descartes, Faculté de Pharmacie de Paris, 75270 Paris Cedex 6, France.
Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1319-E1328. doi: 10.1073/pnas.1715999115. Epub 2018 Jan 19.
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 () 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 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 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.
芳香烃受体 (AHR) 是一种配体激活的转录因子，参与外源性代谢物的代谢。丛状神经纤维瘤 (PNFs) 可转化为对现有治疗方法具有抗性的恶性外周神经鞘瘤 (MPNSTs)。这些肿瘤主要由雪旺细胞组成。除了 1 型神经纤维瘤病 () 基因失活外，恶性转化还需要进一步的遗传损伤。我们已经在 38 个人类样本中定量检测了 AHR 及其相关基因的 mRNA 表达水平。我们报告说，AHR 及其内源性配体的生物合成酶在 PNFs 和 MPNSTs 的人类活检中过度表达。我们还在 MPNSTs 中检测到强烈的核 AHR 染色。用 siRNA 或拮抗剂 CH-223191 和三甲氧基黄酮抑制 AHR 可诱导人 MPNST 细胞凋亡。由于在这些肿瘤中观察到 AHR 失调，我们研究了 AHR 参与雪旺细胞生理学的情况。因此，我们研究了 AHR 在髓鞘发育过程中对 小鼠髓鞘结构和髓鞘基因调节的作用。AHR 缺失会导致运动缺陷，并引起轴突周围更薄的髓鞘鞘。我们观察到 小鼠的髓鞘基因表达和髓鞘发育标记物失调。有趣的是，AHR 不会直接与髓鞘基因启动子结合。体外和体内抑制 AHR 会增加 β-连环蛋白水平，并刺激 β-连环蛋白在髓鞘基因启动子上的结合。总之，我们的研究结果揭示了 AHR 在周围髓鞘形成和周围神经鞘瘤中的内源性作用。最后，我们建议通过靶向神经肿瘤中的 AHR 来作为一种潜在的治疗方法。
