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Novel therapeutic targets for prostate cancer

Researchers at our institute have characterized several microRNAs that modulate the activity of androgens and their receptors in prostate cancers, including hormone-castration-resistant prostate cancer.

Published on 9 July 2019
MicroRNAs (miRNAs or mIRs) are very short single-stranded ribonucleic acids (usually 21 to 24 nucleotides), capable of inhibiting the expression of a target gene by pairing to a complementary sequence of its messenger RNA leading to its translational repression or degradation. Research on mIRs has highlighted their multiple roles in regulating (negatively and sometimes positively) gene expression. Aberrant expression of mIRs is also reported to be involved in many diseases, and mIRs-based therapies are currently under study.

In a close collaboration with Dr. Charlotte Bevan's team at Imperial College of London, and more specifically Dr. Claire Fletcher who spent 6 months in this team, researchers at the IRIG have participated in the characterization of several miRs that play a role in prostate carcinogenesis.
Androgens and their receptor (AR) play a major role in prostate cancer. In order to systematically identify miRs that may modulate AR activity in prostate cancers, a cell line expressing the AR gene fused to luciferase (a luminescent protein that tracks AR gene expression in cells) was transfected in the presence of a collection of inhibitors of all known miRs in the human genome. Seventy-eight inhibitors led to modulation of AR expression. Of these, three significantly reduced the transcription of the AR gene as well asmRNA and protein levels.
In summary, this study identified miRs that modulate AR activity in prostate cancers, including hormone castration-resistant prostate cancer. These observations are based on new mechanisms that could open up new therapeutic avenues.
The results of this study in detail:
Of the 78 miR inhibitors, miR-346, miR-361-3p and miR-197 inhibitors significantly reduced RNA gene transcription, mRNA and protein levels, while inducing apoptosis and inhibiting proliferation, epithelial-mesenchymal transition, migration and invasion of transfected prostate cells. Conversely, the corresponding miR mimics increased AR activity through a new anti-dogmatic mechanism uncovered by this study, direct association with the 3' UTR region of the AR gene and stabilization of transcription. Analysis of the miR targets identified by AGO-PAR-CLIP revealed roles in DNA replication and repair, cell cycle, signal transduction and immune function. As expected, silencing these targets, including tumor suppressors ARHGDIA and TAGLN2, phenocopied miR effects, demonstrating physiological relevance.
Transfection is the process of gene transfer, i.e. the introduction of exogenous genetic material into eukaryotic cells.

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