Letter abstract
Nature Medicine 14, 1271 - 1277 (2008)
Published online: 19 October 2008 | doi:10.1038/nm.1880
The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities
Désirée Bonci1, Valeria Coppola1, Maria Musumeci1, Antonio Addario1, Raffaella Giuffrida2, Lorenzo Memeo2, Leonardo D'Urso3, Alfredo Pagliuca1, Mauro Biffoni1, Catherine Labbaye1, Monica Bartucci1, Giovanni Muto3, Cesare Peschle1,4 & Ruggero De Maria1,2
MicroRNAs (miRNAs) are noncoding small RNAs that repress protein translation by targeting specific messenger RNAs. miR-15a and miR-16-1 act as putative tumor suppressors by targeting the oncogene BCL2. These miRNAs form a cluster at the chromosomal region 13q14, which is frequently deleted in cancer. Here, we report that the miR-15a and miR-16-1 cluster targets CCND1 (encoding cyclin D1) and WNT3A, which promotes several tumorigenic features such as survival, proliferation and invasion. In cancer cells of advanced prostate tumors, the miR-15a and miR-16 level is significantly decreased, whereas the expression of BCL2, CCND1 and WNT3A is inversely upregulated. Delivery of antagomirs specific for miR-15a and miR-16 to normal mouse prostate results in marked hyperplasia, and knockdown of miR-15a and miR-16 promotes survival, proliferation and invasiveness of untransformed prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice. Conversely, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of prostate tumor xenografts. Altogether, we propose that miR-15a and miR-16 act as tumor suppressor genes in prostate cancer through the control of cell survival, proliferation and invasion. These findings have therapeutic implications and may be exploited for future treatment of prostate cancer.
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, viale Regina Elena 299, 00161 Rome, Italy.
- Department of Experimental Oncology, Mediterranean Institute of Oncology, via Penninazzo 7, 95029 Viagrande, Catania, Italy.
- Department of Urology, San Giovanni Bosco Hospital, piazza Donatori del sangue 3, 10154 Turin, Italy.
- Istituto di Ricovero e Cura a Carattere Scientifico, MultiMedica, via Fantoli 16/15, 20138 Milan, Italy.
Correspondence to: Ruggero De Maria1,2 e-mail: demaria@iss.it
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