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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

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Abstract

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.

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Authors and Affiliations

  1. First Department of Pathology, Laikon General Hospital, Athens University Medical School, 115 27, Athens, Greece

    Elias A. El-Habr, Georgia Levidou, Eleni-Andriana Trigka, Joanna Sakalidou, Ilenia Chatziandreou, Rigas Soldatos, Georgia Tomara, Efstratios Patsouris, Angelica A. Saetta & Penelope Korkolopoulou

  2. CNRS UMR 8246, INSERM, UMR 1130, Neuroscience Paris Seine, Sorbonne Universités, UPMC Univ Paris 06, 75005, Paris, France

    Elias A. El-Habr

  3. Department of Biological Chemistry, Athens University Medical School, 115 27, Athens, Greece

    Christina Piperi & Anastasia Spyropoulou

  4. Department of Pathology, Metropolitan Hospital, 185 47, Athens, Greece

    Kalliopi Petraki

  5. Department of Pathology, Red Cross Hospital, 115 26, Athens, Greece

    Vassilis Samaras

  6. Department of Neurosurgery, Red Cross Hospital, 115 26, Athens, Greece

    Athanasios Zisakis & Vassilis Varsos

  7. Department of Neurosurgery, Metropolitan Hospital, 185 47, Athens, Greece

    George Vrettakos

  8. Department of Neurosurgery, Medical School, Evangelismos Hospital, National and Kapodistrian University of Athens, 106 76, Athens, Greece

    Efstathios Boviatsis

  9. First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 115 27, Athens, Greece

    Elias A. El-Habr

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  1. Elias A. El-Habr
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  2. Georgia Levidou
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Correspondence to Elias A. El-Habr.

Additional information

Elias A. El-Habr, Georgia Levidou, Eleni-Andriana Trigka and Joanna Sakalidou have equally contributed to this manuscript.

Angelica A. Saetta and Penelope Korkolopoulou are senior authors.

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Fig. S1

p-AKT, p-p70S6K, and p-ERK1/2 protein levels in fresh frozen tissue specimens by Western blot and immunohistochemical expression of p-AKT, p-p70S6K and p-ERK1/2 in formalin-fixed tissue from the same five specimens. (A) Detection of p-AKT in the five cases. Tumours #2, 5 showed the highest p-AKT levels in frozen and paraffin-embedded samples. (B) Detection of p-p70S6K in the five cases. Tumours #1, 3, 5 showed the highest p-p70S6K levels in frozen and paraffin-embedded samples. (C) Detection of p-ERK1/2 in the five cases. Tumours #1, 2, 5 showed the highest p-ERK1/2 levels in frozen and paraffin-embedded samples (GIF 257 kb)

High resolution (TIFF 11559 kb)

Fig. S2

Detection of p-AKT, p-p70S6K and p-ERK1/2 protein levels in the meningioma cell line HBL-52 before and after 3 h treatment with PI3K inhibitor LY294002 (100 μM). Actin was used as an internal control for Western blot analysis in all experiment (GIF 24 kb)

High resolution (TIFF 5907 kb)

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El-Habr, E.A., Levidou, G., Trigka, EA. et al. 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. Virchows Arch 465, 473–485 (2014). https://doi.org/10.1007/s00428-014-1641-3

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