Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2014-12

AUTHORS

V Kumar, R Palermo, C Talora, A F Campese, S Checquolo, D Bellavia, L Tottone, G Testa, E Miele, S Indraccolo, A Amadori, E Ferretti, A Gulino, A Vacca, I Screpanti

ABSTRACT

Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols. More... »

PAGES

2324

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2014.133

DOI

http://dx.doi.org/10.1038/leu.2014.133

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1023644735

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24727676


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456 Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
457 Neuromed Institute, Pozzilli, Italy
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460 schema:name Istituto Oncologico Veneto-IRCCS-Padova, Padua, Italy
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463 schema:name Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
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467 schema:name Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
468 Department of Experimental Medicine, Sapienza University, Rome, Italy
469 Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy
470 Institute Pasteur-Foundation Cenci Bolognetti, Sapienza University, Rome, Italy
471 Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
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