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

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.

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

“…However, the influence of miRNAs on tumor microenvironment and CAFs is still largely unexplored. In a previous report, our group demonstrated that miR-15a (miR-15) and miR-16-1 (miR-16) reduction in tumor cells promotes prostate cancer progression, whereas their reconstitution impairs tumor growth (Bonci et al, 2008). Here, we extended our study to the prostate stromal compartment, demonstrating a fundamental role of miR-15 and miR-16 in tumor-stroma interaction.…”

Cyclin T2: A novel miR‐15a target gene involved in early spermatogenesis

“…miR-15a downregulation has been associated with various cancers [32,33]. Few studies have suggested that miR-15a is involved in cell differentiation, although it has been thought to be associated with development and differentiation [34,35].…”

Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs

“…This downregulation is due at least in part to impairment of the microprocessor function (Thomson et al, 2006). Among these downregulated micro-RNAs, several have been shown to be bona fide tumor suppressors (Calin et al, 2002;Mayr et al, 2007;Welch et al, 2007;Bonci et al, 2008;Cole et al, 2008;Esquela-Kerscher et al, 2008;Chen et al, 2009;Trang et al, 2010). On the other hand, certain micro-RNAs are overexpressed in cancer.…”