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Impaired Pten Expression in Human Malignant Peripheral Nerve Sheath Tumours

Cited 40 time in Web of Science Cited 44 time in Scopus
Authors

Bradtmoeller, Maren; Hartmann, Christian; Zietsch, Jan; Jaeschke, Sebastian; Mautner, Victor-F; Kurtz, Andreas; Park, Su-Jin; Baier, Michael; Harder, Anja; Reuss, David; von Deimling, Andreas; Heppner, Frank L.; Holtkamp, Nikola

Issue Date
2012-11
Publisher
Public Library of Science
Citation
PLoS ONE, Vol.7 No.11
Abstract
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.
ISSN
1932-6203
URI
https://hdl.handle.net/10371/192324
DOI
https://doi.org/10.1371/journal.pone.0047595
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