Impaired pten expression in human malignant peripheral nerve sheath tumours.
dc.contributor.author | Bradtmöller, Maren | |
dc.contributor.author | Hartmann, Christian | |
dc.contributor.author | Zietsch, Jan | |
dc.contributor.author | Jäschke, Sebastian | |
dc.contributor.author | Mautner, Victor-F. | |
dc.contributor.author | Kurtz, Andreas | |
dc.contributor.author | Park, Su-Jin | |
dc.contributor.author | Baier, Michael | |
dc.contributor.author | Harder, Anja | |
dc.contributor.author | Reuss, David | |
dc.contributor.author | Deimling, Andreas von | |
dc.contributor.author | Heppner, Frank L. | |
dc.contributor.author | Holtkamp, Nikola | |
dc.date.accessioned | 2018-05-07T16:07:28Z | |
dc.date.available | 2018-05-07T16:07:28Z | |
dc.date.created | 2012-11-27 | |
dc.date.issued | 2012-11-06 | none |
dc.identifier.other | http://edoc.rki.de/oa/articles/reIidj8gj3Br/PDF/25r27kyCePZ6.pdf | |
dc.identifier.uri | http://edoc.rki.de/176904/1371 | |
dc.description.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 downregulation 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 NF12/2 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. | eng |
dc.language.iso | eng | |
dc.publisher | Robert Koch-Institut | |
dc.subject | Animals | eng |
dc.subject | Humans | eng |
dc.subject | Mice | eng |
dc.subject | Blotting Western | eng |
dc.subject | Cell Line Tumor | eng |
dc.subject | Drug Synergism | eng |
dc.subject | Fibroblasts/drug effects | eng |
dc.subject | Fibroblasts/metabolism | eng |
dc.subject | Fibroblasts/pathology | eng |
dc.subject | Gene Expression Regulation Neoplastic/drug effects | eng |
dc.subject | Nerve Sheath Neoplasms/enzymology | eng |
dc.subject | Nerve Sheath Neoplasms/genetics | eng |
dc.subject | Nerve Sheath Neoplasms/pathology | eng |
dc.subject | Neurofibroma/enzymology | eng |
dc.subject | Neurofibroma/genetics | eng |
dc.subject | Neurofibroma/pathology | eng |
dc.subject | Neurofibromin 1/metabolism | eng |
dc.subject | PTEN Phosphohydrolase/genetics | eng |
dc.subject | PTEN Phosphohydrolase/metabolism | eng |
dc.subject | Ribosomal Protein S6 Kinases 70-kDa/metabolism | eng |
dc.subject | Simvastatin/pharmacology | eng |
dc.subject | Sirolimus/pharmacology | eng |
dc.subject.ddc | 610 Medizin | |
dc.title | Impaired pten expression in human malignant peripheral nerve sheath tumours. | |
dc.type | periodicalPart | |
dc.identifier.urn | urn:nbn:de:0257-10028668 | |
dc.identifier.doi | 10.1371/journal.pone.0047595 | |
dc.identifier.doi | http://dx.doi.org/10.25646/1296 | |
local.edoc.container-title | PLoS ONE | |
local.edoc.container-text | Bradtmöller M, Hartmann C, Zietsch J, Jäschke S, Mautner V-F, et al. (2012) Impaired Pten Expression in Human Malignant Peripheral Nerve Sheath Tumours. PLoS ONE 7(11): e47595. | |
local.edoc.fp-subtype | Artikel | |
local.edoc.type-name | Zeitschriftenartikel | |
local.edoc.container-type | periodical | |
local.edoc.container-type-name | Zeitschrift | |
local.edoc.container-url | http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047595 | |
local.edoc.container-publisher-name | Public Library of Science | |
local.edoc.container-volume | 7 | |
local.edoc.container-issue | 11 | |
local.edoc.container-year | 2012 |