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The effect of estradiol, testosterone, and human chorionic gonadotropin on the proliferation of Schwann cells with NF1 +/− or NF1 −/− genotype derived from human cutaneous neurofibromas

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Abstract

Dermal neurofibromas are the hallmarks of neurofibromatosis type 1 (NF1). Neurofibromas harbor Schwann cells with two different genotypes: Schwann cells which carry the germline mutation and a healthy NF1 allele (NF1 +/−), and a subpopulation of Schwann cells which harbor the so-called second hit leading to inactivation of both NF1 alleles (NF1 −/−). The second hit in the NF1 gene of Schwann cells is considered to be the initial step in the development of neurofibromas. Dermal neurofibromas typically start to grow in puberty, and their number and size increase during pregnancy, indicating hormone responsiveness. This is the first study to address the effect of human chorionic gonadotropin (hCG) on the proliferation of human NF1 +/− and NF1 −/− Schwann cells in vitro. In addition, the effects of estradiol and testosterone were also investigated. The results showed that NF1 −/− Schwann cells were more sensitive to estradiol, testosterone, and human chorionic gonadotropin than NF1 +/− cells. Specifically, the proliferation of NF1 −/− Schwann cells was increased by up to 99, 110, and 170% compared to vehicle control when treated with estradiol, testosterone, and hCG, respectively. Interestingly, no effect of estradiol, testosterone, or hCG on the proliferation of the cells with NF1 +/− genotype was observed. To conclude, the somatic second hit in the NF1 gene sensitizes Schwann cells to sex hormones resulting in a highly increased proliferation. Our results highlight the significance of sex hormones in the regulation of neurofibroma growth.

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Abbreviations

NF1:

Neurofibromatosis type 1

NF1 :

Human NF1 gene

NF1 +/− :

Cells carrying the constitutional NF1 mutation only

NF1 −/− :

Cells with the NF1 second hit

NIH:

National Institutes of Health

MPNST:

Malignant peripheral nerve sheath tumor

hCG:

Human chorionic gonadotropin

FBS:

Fetal bovine serum

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Acknowledgements

We would like to thank Mr. Miso Immonen for technical support. This work was supported by The Turku University Foundation and The Jalmari and Rauha Ahokas Foundation.

Data availability

Raw data is available on request.

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Authors and Affiliations

  1. Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland

    Paula Pennanen, Roope A. Kallionpää & Juha Peltonen

  2. Department of Dermatology, University of Turku and Turku University Hospital, PO BOX 52, 20521, Turku, Finland

    Sirkku Peltonen

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  1. Paula Pennanen
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  2. Sirkku Peltonen
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Contributions

JP conceived the study. JP and SP made a significant contribution to writing the paper. SP collected the neurofibroma samples. RAK analyzed the data, drafted, and revised the paper. PP designed the experiments, cultured Schwann cells, performed the assays, analyzed the data, and wrote the paper. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Juha Peltonen.

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Conflict of interest

The authors declare no conflict of interest.

Ethical approval

This study has been performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Southwest Finland Hospital District, and patients gave their informed written consents. The study was carried out at Turku University Hospital and the University of Turku.

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Pennanen, P., Peltonen, S., Kallionpää, R.A. et al. The effect of estradiol, testosterone, and human chorionic gonadotropin on the proliferation of Schwann cells with NF1 +/− or NF1 −/− genotype derived from human cutaneous neurofibromas. Mol Cell Biochem 444, 27–33 (2018). https://doi.org/10.1007/s11010-017-3227-2

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