Journal Article

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

Giuffrida, Raffaella, Biffoni, Mauro, Labbaye, Catherine, Memeo, Lorenzo, D'Urso, Leonardo, Pagliuca, Alfredo, Peschle, Cesare, Bonci, Désirée, Muto, Giovanni, Bartucci, Monica, De Maria, Ruggero, Addario, Antonio, Coppola, Valeria, Musumeci, Maria

2008

Overview

Two microRNAs, miR-15a and miR-16, localize to a chromosome region that is frequently deleted in cancer. Bonci et al . now show that these microRNAs have tumor suppressive effects in prostate cancer cells and regulate the expression of crucial oncogenic targets. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Line, Tumor / Cellular biology / Control / Cyclin D1 - genetics / Cyclin D1 - metabolism / Gene expression / Genetic aspects / Humans / Immunohistochemistry / Infectious Diseases / Invasiveness / letter / Male / Metabolic Diseases / Methods / Mice / MicroRNAs - genetics / Molecular Medicine / Multigene Family - genetics / Neurosciences / Oncogene Proteins - genetics / Oncogene Proteins - metabolism / Oncology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Ribonucleic acid / Risk factors / RNA / Survival / Tumors / Wnt Proteins - genetics / Wnt Proteins - metabolism / Wnt3 Protein / Wnt3A Protein