Impaired Pten Expression in Human Malignant Peripheral Nerve Sheath Tumours

PLoS One

Michael Baier¹  Andreas Kurtz¹  Su-Jin Park²  Victor-F Mautner³  Maren Bradtmöller⁴  Sebastian Jäschke⁴  Jan Zietsch⁴  Nikola Holtkamp⁴  Christian Hartmann⁵  Andreas von Deimling⁵  Frank L. Heppner⁵  David Reuss⁶  Anja Harder⁷ 

[1]Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany

[2]College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea

[3]Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany

[4]Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany

[5]Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, and Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany

[6]Institute of Neuropathology, University Hospital Münster, Münster, Germany

[7]Project Neurodegenerative Diseases, Robert-Koch-Institute, Berlin, Germany

关键词: DNA methylation;    Neurofibromatosis type 1;    Cultured fibroblasts;    Schwann cells;    Fibroblasts;    Polymerase chain reaction;    Metastasis;    Cell cultures;   

DOI  :  10.1371/journal.pone.0047595

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n = 16) than in neurofibromas (n = 16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n = 31) and PIK3CA (n = 38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1−/− and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.

【 授权许可】

CC BY