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The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities

Nature Medicine volume 14, pages 1271–1277 (2008)Cite this article

Abstract

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.

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Figure 1: miR-15a and miR-16 downregulation is associated with oncogenic activities.
Figure 2: Restoration of miR-15a and miR-16 induces growth arrest and apoptosis in defective prostate cancer cells.
Figure 3: miR-15a and miR-16 target CCND1 and WNT3A.
Figure 4: In vivo effect of miR-15a–miR-16 modulation.

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Acknowledgements

We thank G. Loreto, A. Di Virgilio and M. Blasi for technical assistance and E. Palio and M. Gulisano for valuable discussion and suggestions. This work was supported by the Italian Health Ministry, the Italian Ministry of University and Research (project number RBIP06ZJ78), and the Italian Association for Cancer Research. M. Bartucci is a recipient of a fellowship from the Italian Association for Cancer Research.

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Authors and Affiliations

  1. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, viale Regina Elena 299, Rome, 00161, Italy

    Désirée Bonci, Valeria Coppola, Maria Musumeci, Antonio Addario, Alfredo Pagliuca, Mauro Biffoni, Catherine Labbaye, Monica Bartucci, Cesare Peschle & Ruggero De Maria

  2. Department of Experimental Oncology, Mediterranean Institute of Oncology, via Penninazzo 7, Viagrande, Catania, 95029, Italy

    Raffaella Giuffrida, Lorenzo Memeo & Ruggero De Maria

  3. Department of Urology, San Giovanni Bosco Hospital, piazza Donatori del sangue 3, 10154, Turin, Italy

    Leonardo D'Urso & Giovanni Muto

  4. Istituto di Ricovero e Cura a Carattere Scientifico, MultiMedica, via Fantoli 16/15, Milan, 20138, Italy

    Cesare Peschle

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  1. Désirée Bonci
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Contributions

D.B., V.C., M.M., A.A., R.G., L.M., L.D., A.P., M. Biffoni, C.L. and M. Bartucci conducted the in vitro and in vivo experiments. G.M., D.B. and R.D.M. planned the experiments. L.D. provided human samples. G.M. and C.P. discussed the results and commented on the manuscript. R.D.M. wrote the manuscript and was responsible for research coordination and strategy.

Corresponding author

Correspondence to Ruggero De Maria.

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Bonci, D., Coppola, V., Musumeci, M. et al. The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14, 1271–1277 (2008). https://doi.org/10.1038/nm.1880

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