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Open AccessArticle

Mir-34a-5p Mediates Cross-Talk between M2 Muscarinic Receptors and Notch-1/EGFR Pathways in U87MG Glioblastoma Cells: Implication in Cell Proliferation

1
Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, P.le Aldo Moro, 5, 00185 Rome, Italy
2
Institute of Molecular Biology and Pathology, National Research Council of Italy, c/o Sapienza University of Rome, P.le Aldo Moro, 5, 00185 Rome, Italy
3
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 291, 00161 Rome, Italy
4
Research Center of Neurobiology “Daniel Bovet”, Sapienza University of Rome, P.le Aldo Moro, 5, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
Current Address: National Institute of Molecular Genetics INGM “Romeo ed Enrica Invernizzi”, via Francesco Sforza, 35, 20132 Milan, Italy.
Int. J. Mol. Sci. 2018, 19(6), 1631; https://doi.org/10.3390/ijms19061631
Received: 21 May 2018 / Accepted: 25 May 2018 / Published: 31 May 2018
(This article belongs to the Special Issue The Role of MicroRNAs in Human Diseases)
Glioblastoma (GBM) is the most aggressive human brain tumor. The high growth potential and decreased susceptibility to apoptosis of the glioma cells is mainly dependent on genetic amplifications or mutations of oncogenic or pro-apoptotic genes, respectively. We have previously shown that the activation of the M2 acetylcholine muscarinic receptors inhibited cell proliferation and induced apoptosis in two GBM cell lines and cancer stem cells. The aim of this study was to delve into the molecular mechanisms underlying the M2-mediated cell proliferation arrest. Exploiting U87MG and U251MG cell lines as model systems, we evaluated the ability of M2 receptors to interfere with Notch-1 and EGFR pathways, whose activation promotes GBM proliferation. We demonstrated that the activation of M2 receptors, by agonist treatment, counteracted Notch and EGFR signaling, through different regulatory cascades depending, at least in part, on p53 status. Only in U87MG cells, which mimic p53-wild type GBMs, did M2 activation trigger a molecular circuitry involving p53, Notch-1, and the tumor suppressor mir-34a-5p. This regulatory module negatively controls Notch-1, which affects cell proliferation mainly through the Notch-1/EGFR axis. Our data highlighted, for the first time, a molecular circuitry that is deregulated in the p53 wild type GBM, based on the cross-talk between M2 receptor and the Notch-1/EGFR pathways, mediated by mir-34a-5p. View Full-Text
Keywords: M2 muscarinic receptors; glioblastoma; Notch-1; EGFR; mir-34a-5p; p53 M2 muscarinic receptors; glioblastoma; Notch-1; EGFR; mir-34a-5p; p53
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MDPI and ACS Style

Di Bari, M.; Bevilacqua, V.; De Jaco, A.; Laneve, P.; Piovesana, R.; Trobiani, L.; Talora, C.; Caffarelli, E.; Tata, A.M. Mir-34a-5p Mediates Cross-Talk between M2 Muscarinic Receptors and Notch-1/EGFR Pathways in U87MG Glioblastoma Cells: Implication in Cell Proliferation. Int. J. Mol. Sci. 2018, 19, 1631.

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