Show simple item record

2012-11-06Zeitschriftenartikel DOI: 10.1371/journal.pone.0047595
Impaired pten expression in human malignant peripheral nerve sheath tumours.
dc.contributor.authorBradtmöller, Maren
dc.contributor.authorHartmann, Christian
dc.contributor.authorZietsch, Jan
dc.contributor.authorJäschke, Sebastian
dc.contributor.authorMautner, Victor-F.
dc.contributor.authorKurtz, Andreas
dc.contributor.authorPark, Su-Jin
dc.contributor.authorBaier, Michael
dc.contributor.authorHarder, Anja
dc.contributor.authorReuss, David
dc.contributor.authorDeimling, Andreas von
dc.contributor.authorHeppner, Frank L.
dc.contributor.authorHoltkamp, Nikola
dc.date.accessioned2018-05-07T16:07:28Z
dc.date.available2018-05-07T16:07:28Z
dc.date.created2012-11-27
dc.date.issued2012-11-06none
dc.identifier.otherhttp://edoc.rki.de/oa/articles/reIidj8gj3Br/PDF/25r27kyCePZ6.pdf
dc.identifier.urihttp://edoc.rki.de/176904/1371
dc.description.abstractMalignant 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.isoeng
dc.publisherRobert Koch-Institut
dc.subjectAnimalseng
dc.subjectHumanseng
dc.subjectMiceeng
dc.subjectBlotting Westerneng
dc.subjectCell Line Tumoreng
dc.subjectDrug Synergismeng
dc.subjectFibroblasts/drug effectseng
dc.subjectFibroblasts/metabolismeng
dc.subjectFibroblasts/pathologyeng
dc.subjectGene Expression Regulation Neoplastic/drug effectseng
dc.subjectNerve Sheath Neoplasms/enzymologyeng
dc.subjectNerve Sheath Neoplasms/geneticseng
dc.subjectNerve Sheath Neoplasms/pathologyeng
dc.subjectNeurofibroma/enzymologyeng
dc.subjectNeurofibroma/geneticseng
dc.subjectNeurofibroma/pathologyeng
dc.subjectNeurofibromin 1/metabolismeng
dc.subjectPTEN Phosphohydrolase/geneticseng
dc.subjectPTEN Phosphohydrolase/metabolismeng
dc.subjectRibosomal Protein S6 Kinases 70-kDa/metabolismeng
dc.subjectSimvastatin/pharmacologyeng
dc.subjectSirolimus/pharmacologyeng
dc.subject.ddc610 Medizin
dc.titleImpaired pten expression in human malignant peripheral nerve sheath tumours.
dc.typeperiodicalPart
dc.identifier.urnurn:nbn:de:0257-10028668
dc.identifier.doi10.1371/journal.pone.0047595
dc.identifier.doihttp://dx.doi.org/10.25646/1296
local.edoc.container-titlePLoS ONE
local.edoc.container-textBradtmöller 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-subtypeArtikel
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047595
local.edoc.container-publisher-namePublic Library of Science
local.edoc.container-volume7
local.edoc.container-issue11
local.edoc.container-year2012

Show simple item record