G Catanzaro1, Z M Besharat2, E Miele3, M Chiacchiarini2,3, A Po2, A Carai4, C E Marras4, M Antonelli5, M Badiali6, A Raso7, S Mascelli7, D Schrimpf8,9, D Stichel9, M Tartaglia10, D Capper8,9,11, A von Deimling8,9, F Giangaspero5,12, A Mastronuzzi13, F Locatelli13,14, E Ferretti1,12. 1. Department of Experimental Medicine, Sapienza University, Rome, Italy. 2. Department of Molecular Medicine, Sapienza University, Rome, Italy. 3. Center for Life NanoScience@Sapienza, IIT, Rome, Italy. 4. Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 5. Department of Radiological, Oncological and Pathological Science, Sapienza University, Rome, Italy. 6. Bone Marrow Transplantation Unit, Microcitemico Children's Hospital, Cagliari, Italy. 7. Giannina Gaslini Institute, Genoa, Italy. 8. Department of Neuropathology, Heidelberg University, Heidelberg, Germany. 9. German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, Heidelberg, Germany. 10. Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, Italy. 11. Department of Neuropathology, Charité Universitätsmedizin Berlin, Berlin, Germany. 12. IRCCS Neuromed, Pozzilli, Italy. 13. Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 14. University of Pavia, Pavia, Italy.
Abstract
AIMS: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. METHODS: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. RESULTS: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. CONCLUSIONS: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.
AIMS: Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. METHODS: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. RESULTS: One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. CONCLUSIONS: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.
Authors: Elisabetta Flex; Simone Martinelli; Anke Van Dijck; Andrea Ciolfi; Serena Cecchetti; Elisa Coluzzi; Luca Pannone; Cristina Andreoli; Francesca Clementina Radio; Simone Pizzi; Giovanna Carpentieri; Alessandro Bruselles; Giuseppina Catanzaro; Lucia Pedace; Evelina Miele; Elena Carcarino; Xiaoyan Ge; Chieko Chijiwa; M E Suzanne Lewis; Marije Meuwissen; Sandra Kenis; Nathalie Van der Aa; Austin Larson; Kathleen Brown; Melissa P Wasserstein; Brian G Skotko; Amber Begtrup; Richard Person; Maria Karayiorgou; J Louw Roos; Koen L Van Gassen; Marije Koopmans; Emilia K Bijlsma; Gijs W E Santen; Daniela Q C M Barge-Schaapveld; Claudia A L Ruivenkamp; Mariette J V Hoffer; Seema R Lalani; Haley Streff; William J Craigen; Brett H Graham; Annette P M van den Elzen; Daan J Kamphuis; Katrin Õunap; Karit Reinson; Sander Pajusalu; Monica H Wojcik; Clara Viberti; Cornelia Di Gaetano; Enrico Bertini; Simona Petrucci; Alessandro De Luca; Rossella Rota; Elisabetta Ferretti; Giuseppe Matullo; Bruno Dallapiccola; Antonella Sgura; Magdalena Walkiewicz; R Frank Kooy; Marco Tartaglia Journal: Am J Hum Genet Date: 2019-08-22 Impact factor: 11.025
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