Reprogramming of miRNA networks in cancer and leukemia

Stefano Volinia, Marco Galasso, Stefan Costinean, Luca Tagliavini, Giacomo Gamberoni, Alessandra Drusco, Jlenia Marchesini, Nicoletta Mascellani, Maria Elena Sana, Ramzey Abu Jarour, Caroline Desponts, Michael Teitell, Raffaele Baffa, Rami Aqeilan, Marilena V. Iorio, Cristian Taccioli, Ramiro Garzon, Gianpiero Di Leva, Muller Fabbri, Marco CatozziMaurizio Previati, Stefan Ambs, Tiziana Palumbo, Michela Garofalo, Angelo Veronese, Arianna Bottoni, Pierluigi Gasparini, Curtis C. Harris, Rosa Visone, Yuri Pekarsky, Albert De La Chapelle, Mark Bloomston, Mary Dillhoff, Laura Z. Rassenti, Thomas J. Kipps, Kay Huebner, Flavia Pichiorri, Dido Lenze, Stefano Cairo, Marie Annick Buendia, Pascal Pineau, Anne Dejean, Nicola Zanesi, Simona Rossi, George A. Calin, Chang Gong Liu, Jeff Palatini, Massimo Negrini, Andrea Vecchione, Anne Rosenberg, Carlo M. Croce

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)589-599
Number of pages11
JournalGenome Research
Volume20
Issue number5
DOIs
Publication statusPublished - May 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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