TY - JOUR
TI - Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development
AU - El-Habr, E.A.
AU - Levidou, G.
AU - Trigka, E.-A.
AU - Sakalidou, J.
AU - Piperi, C.
AU - Chatziandreou, I.
AU - Spyropoulou, A.
AU - Soldatos, R.
AU - Tomara, G.
AU - Petraki, K.
AU - Samaras, V.
AU - Zisakis, A.
AU - Varsos, V.
AU - Vrettakos, G.
AU - Boviatsis, E.
AU - Patsouris, E.
AU - Saetta, A.A.
AU - Korkolopoulou, P.
JO - Virchows Archiv
PY - 2014
VL - 465
TODO - 4
SP - 473-485
PB - Springer-Verlag
SN - 0945-6317, 1432-2307
TODO - 10.1007/s00428-014-1641-3
TODO - epithelial membrane antigen;  glial fibrillary acidic protein;  initiation factor 4E binding protein 1;  Janus kinase;  mammalian target of rapamycin;  mitogen activated protein kinase;  mitogen activated protein kinase 1;  mitogen activated protein kinase 3;  Notch1 receptor;  phosphatidylinositol 3 kinase;  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase;  protein;  protein akt1;  protein kinase B;  protein p110;  protein p110 gamma;  protein p85;  protein p85 alpha;  protein pik3ca;  protein S 100;  STAT3 protein;  unclassified drug;  Janus kinase;  mitogen activated protein kinase kinase;  MTOR protein, human;  NOTCH1 protein, human;  Notch1 receptor;  phosphatidylinositol 3 kinase;  protein kinase B;  STAT protein;  target of rapamycin kinase, adult;  Article;  cancer patient;  cancer radiotherapy;  cancer surgery;  cancer survival;  controlled study;  exon;  female;  gene mutation;  human;  human tissue;  immunoreactivity;  major clinical study;  male;  meningioma;  multimodality cancer therapy;  overall survival;  protein expression;  protein phosphorylation;  protein protein interaction;  retrospective study;  signal transduction;  brain tumor;  disease course;  immunohistochemistry;  meningioma;  metabolism;  mortality;  mutation;  pathology;  physiology;  prognosis;  tumor cell line;  Western blotting, Blotting, Western;  Brain Neoplasms;  Cell Line, Tumor;  Disease Progression;  Female;  Humans;  Immunohistochemistry;  Janus Kinases;  Male;  Meningioma;  Mitogen-Activated Protein Kinase Kinases;  Mutation;  Phosphatidylinositol 3-Kinases;  Prognosis;  Proto-Oncogene Proteins c-akt;  Receptor, Notch1;  Signal Transduction;  STAT Transcription Factors;  TOR Serine-Threonine Kinases
TODO - We investigated the significance of PI3K/AKT/mTOR pathway and its interactions with MAPK, JAK/STAT and Notch pathways in meningioma progression. Paraffin-embedded tissue from 108 meningioma patients was analysed for the presence of mutations in PIK3CA and AKT1. These were correlated with the expression status of components of the PI3K/AKT/mTOR pathway, including p85α and p110γ subunits of PI3K, phosphorylated (p)-AKT, p-mTOR, p-p70S6K and p-4E-BP1, as well as of p-ERK1/2, p-STAT3 and Notch-1, clinicopathological data and patient survival. A mutation in PIK3CA or AKT1 was found in around 9 % of the cases. Higher grade meningiomas displayed higher nuclear expression of p-p70S6K; higher nuclear and cytoplasmic expression of p-4E-BP1 and of Notch-1; lower cytoplasmic expression of p85αPI3K, p-p70S6K and p-ERK1/2; and lower PTEN Histo-scores (H-scores). PTEN H-score was inversely correlated with recurrence probability. In univariate survival analysis, nuclear expression of p-4E-BP1 and absence of p-ERK1/2 expression portended adverse prognosis, whereas in multivariate survival analysis, p-ERK1/2 expression emerged as an independent favourable prognostic factor. Treatment of the human meningioma cell line HBL-52 with the PI3K inhibitor LY294002 resulted in reduction of p-AKT, p-p70S6K and p-ERK1/2 protein levels. The complex interactions established between components of the PI3K/AKT/mTOR pathway, or with components of the MAPK, JAK/STAT and Notch-1 pathways, appear to be essential for facilitating and fuelling meningioma progression. © 2014, Springer-Verlag Berlin Heidelberg.
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