TY - JOUR
T1 - Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM
AU - Fontana, Laura
AU - Fiori, Micol E.
AU - Albini, Sonia
AU - Cifaldi, Loredana
AU - Giovinazzi, Serena
AU - Forloni, Matteo
AU - Boldrini, Renata
AU - Donfrancesco, Alberto
AU - Federici, Valentina
AU - Giacomini, Patrizio
AU - Peschle, Cesare
AU - Fruci, Doriana
PY - 2008/5/21
Y1 - 2008/5/21
N2 - We identified a key oncogenic pathway underlying neuroblastoma progression: specifically, MYCN, expressed at elevated level, transactivates the miRNA 17-5p-92 cluster, which inhibits p21 and BIM translocation by interaction with their mRNA 3′ UTRs. Overexpression of miRNA 17-5p-92 cluster in MYCN-not-amplified neuroblastoma cells strongly augments their in vitro and in vivo tumorigenesis. In vitro or in vivo treatment with antagonis 17-5p abolishes the growth of MYCN amplified and therapy resistant neuroblastoma through p21 and BIM upmodulation, leading to cell cycling blockade and activation of apoptosis, respectively. In primary neuroblastoma, the majority of cases show a rise of miR-17-5p level leading to p21 downmodulation, which is particularly severe in patients with MYCN amplification and poor prognosis. Altogether, our studies demonstrate for the first time that antagomir treatment can abolish tumor growth in vivo, specifically in therapy resistant neuroblastoma.
AB - We identified a key oncogenic pathway underlying neuroblastoma progression: specifically, MYCN, expressed at elevated level, transactivates the miRNA 17-5p-92 cluster, which inhibits p21 and BIM translocation by interaction with their mRNA 3′ UTRs. Overexpression of miRNA 17-5p-92 cluster in MYCN-not-amplified neuroblastoma cells strongly augments their in vitro and in vivo tumorigenesis. In vitro or in vivo treatment with antagonis 17-5p abolishes the growth of MYCN amplified and therapy resistant neuroblastoma through p21 and BIM upmodulation, leading to cell cycling blockade and activation of apoptosis, respectively. In primary neuroblastoma, the majority of cases show a rise of miR-17-5p level leading to p21 downmodulation, which is particularly severe in patients with MYCN amplification and poor prognosis. Altogether, our studies demonstrate for the first time that antagomir treatment can abolish tumor growth in vivo, specifically in therapy resistant neuroblastoma.
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U2 - 10.1371/journal.pone.0002236
DO - 10.1371/journal.pone.0002236
M3 - Article
C2 - 18493594
AN - SCOPUS:48249098902
VL - 3
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 5
M1 - e2236
ER -