title: miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth.
abstract: The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 3' untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c-MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 3' UTR shortening at different stages of tumorigenesis.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Marija
authors.initials: M
authors.lastname: Mihailovich
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Michael
authors.initials: M
authors.lastname: Bremang
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Spadotto
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Musiani
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Vitale
authors.affiliation: Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varano
authors.affiliation: Department of Biosciences, Milan University, Milan 20133, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zambelli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Mancuso
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: David A
authors.initials: DA
authors.lastname: Cairns
authors.affiliation: Department of Biosciences, Milan University, Milan 20133, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pavesi
authors.affiliation: Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Casola
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Tiziana
authors.identifier: http://orcid.org/0000-0003-3556-1265
authors.initials: T
authors.lastname: Bonaldi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020543:Proteome; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: D000067780:ELAV-Like Protein 1; C000593997:Elavl1 protein, mouse; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C532375:Mirn20 microRNA, mouse; C489428:Myc protein, mouse; D020543:Proteome; D016271:Proto-Oncogene Proteins c-myc; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse