Michael A. Teitell, Anne Dejean, Angelo Veronese, Rosa Visone, Dido Lenze, Yuri Pekarsky, Luca Tagliavini, Mary Dillhoff, Chang Gong Liu, Giacomo Gamberoni, Flavia Pichiorri, Jlenia Marchesini, George A. Calin, Alessandra Drusco, Anne L. Rosenberg, Marie Annick Buendia, Pascal Pineau, Maurizio Previati, Michela Garofalo, Stefan Costinean, Marco Galasso, Maria Elena Sana, Arianna Bottoni, Stefano Volinia, Thomas J. Kipps, Albert de la Chapelle, Ramzey Abu Jarour, Gianpiero Di Leva, Marco Catozzi, Simona Rossi, Nicola Zanesi, Raffaele Baffa, Marilena V. Iorio, Cristian Taccioli, Tiziana Palumbo, Massimo Negrini, Caroline Desponts, Jeff Palatini, Stefan Ambs, Carlo M. Croce, Stefano Cairo, Andrea Vecchione, Rami I. Aqeilan, Kay Huebner, Nicoletta Mascellani, Curtis C. Harris, Muller Fabbri, Laura Z. Rassenti, Pierluigi Gasparini, Mark Bloomston, Ramiro Garzon, Università degli Studi di Ferrara = University of Ferrara (UniFE), Ohio State University [Columbus] (OSU), The Scripps Research Institute [La Jolla, San Diego], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Jefferson (Philadelphia University + Thomas Jefferson University), Istituto Tumori 'Giovanni Paolo II' [Bari], National Institutes of Health [Bethesda] (NIH), University of California [San Diego] (UC San Diego), University of California (UC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Oncogenèse et Virologie Moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Università degli Studi di Salerno = University of Salerno (UNISA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Istituto per l'Ambiente Marino Costiero, C.N.R., Organisation Nucléaire et Oncogenèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Evolution et Diversité Biologique (EDB), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Università degli Studi di Salerno (UNISA)
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.