title: Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia.
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.
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Palermo
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Talora
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: A F
authors.initials: AF
authors.lastname: Campese
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Checquolo
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Bellavia
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Tottone
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Testa
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: E
authors.identifier: 0000000247471032
authors.initials: E
authors.lastname: Miele
authors.affiliation: Istituto Oncologico Veneto-IRCCS-Padova, Padua, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Indraccolo
authors.affiliation: 1] Istituto Oncologico Veneto-IRCCS-Padova, Padua, Italy [2] Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Amadori
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ferretti
authors.affiliation: 1] Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy [2] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy [3] Neuromed Institute, Pozzilli, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vacca
authors.affiliation: 1] Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy [2] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy [3] Institute Pasteur-Foundation Cenci Bolognetti, Sapienza University, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Screpanti
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D053829:Amyloid Precursor Protein Secretases; D018797:Cell Cycle Proteins; D004151:Dipeptides; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D035683:MicroRNAs; D016328:NF-kappa B; D051880:Receptors, Notch; D044767:Ubiquitin-Protein Ligases; C513273:FBXW7 protein, human; C525067:MIR223, human; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
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