Reprogramming of miRNA networks in cancer and leukemia.
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.
Volinia
Stefano
S
Data Mining for Analysis of Microarrays, Department of Morphology and Embryology, Università degli Studi, Ferrara 44100, Italy.
Galasso
Marco
M
Costinean
Stefan
S
Tagliavini
Luca
L
Gamberoni
Giacomo
G
Drusco
Alessandra
A
Marchesini
Jlenia
J
Mascellani
Nicoletta
N
Sana
Maria Elena
ME
Abu Jarour
Ramzey
R
Desponts
Caroline
C
Teitell
Michael
M
Baffa
Raffaele
R
Aqeilan
Rami
R
Iorio
Marilena V
MV
Taccioli
Cristian
C
Garzon
Ramiro
R
Di Leva
Gianpiero
G
Fabbri
Muller
M
Catozzi
Marco
M
Previati
Maurizio
M
Ambs
Stefan
S
Palumbo
Tiziana
T
Garofalo
Michela
M
Veronese
Angelo
A
Bottoni
Arianna
A
Gasparini
Pierluigi
P
Harris
Curtis C
CC
Visone
Rosa
R
Pekarsky
Yuri
Y
de la Chapelle
Albert
A
Bloomston
Mark
M
Dillhoff
Mary
M
Rassenti
Laura Z
LZ
Kipps
Thomas J
TJ
Huebner
Kay
K
Pichiorri
Flavia
F
Lenze
Dido
D
Cairo
Stefano
S
Buendia
Marie-Annick
MA
Pineau
Pascal
P
Dejean
Anne
A
Zanesi
Nicola
N
Rossi
Simona
S
Calin
George A
GA
Liu
Chang-Gong
CG
Palatini
Jeff
J
Negrini
Massimo
M
Vecchione
Andrea
A
Rosenberg
Anne
A
Croce
Carlo M
CM
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
D035683:MicroRNAs