title: Reprogramming of miRNA networks in cancer and leukemia.
abstract: We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Nonmalignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs. hsa-miR-103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150 kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR-204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network.
authors.affiliation: Data Mining for Analysis of Microarrays, Department of Morphology and Embryology, Università degli Studi, Ferrara 44100, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Marco
authors.initials: M
authors.lastname: Galasso
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.forename: Luca
authors.initials: L
authors.lastname: Tagliavini
authors.forename: Giacomo
authors.initials: G
authors.lastname: Gamberoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Drusco
authors.forename: Jlenia
authors.initials: J
authors.lastname: Marchesini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Mascellani
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Sana
authors.forename: Ramzey
authors.initials: R
authors.lastname: Abu Jarour
authors.forename: Caroline
authors.initials: C
authors.lastname: Desponts
authors.forename: Michael
authors.initials: M
authors.lastname: Teitell
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.forename: Rami
authors.initials: R
authors.lastname: Aqeilan
authors.forename: Marilena V
authors.initials: MV
authors.lastname: Iorio
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Di Leva
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: Marco
authors.initials: M
authors.lastname: Catozzi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Previati
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.forename: Tiziana
authors.initials: T
authors.lastname: Palumbo
authors.forename: Michela
authors.initials: M
authors.lastname: Garofalo
authors.forename: Angelo
authors.initials: A
authors.lastname: Veronese
authors.forename: Arianna
authors.initials: A
authors.lastname: Bottoni
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.forename: Rosa
authors.initials: R
authors.lastname: Visone
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pekarsky
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.forename: Mary
authors.initials: M
authors.lastname: Dillhoff
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.forename: Marie-Annick
authors.initials: MA
authors.lastname: Buendia
authors.forename: Pascal
authors.initials: P
authors.lastname: Pineau
authors.forename: Anne
authors.initials: A
authors.lastname: Dejean
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.forename: Simona
authors.initials: S
authors.lastname: Rossi
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Jeff
authors.initials: J
authors.lastname: Palatini
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.forename: Anne
authors.initials: A
authors.lastname: Rosenberg
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics
chemical_list: D035683:MicroRNAs