Τίτλος:
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
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
El-Habr, E.A.
Levidou, G.
Trigka, E.-A.
Sakalidou, J.
Piperi, C.
Chatziandreou, I.
Spyropoulou, A.
Soldatos, R.
Tomara, G.
Petraki, K.
Samaras, V.
Zisakis, A.
Varsos, V.
Vrettakos, G.
Boviatsis, E.
Patsouris, E.
Saetta, A.A.
Korkolopoulou, P.
Περιοδικό:
Virchows Archiv
Λέξεις-κλειδιά:
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
DOI:
10.1007/s00428-014-1641-3
