Abstract
With approx. 30,000 deaths annually in the United States, prostate cancer
(PCa) is a major oncologic disease. Here we show that the
microRNAs miR-130a, miR-203 and miR-205 jointly interfere with the
two major oncogenic pathways in prostate carcinoma and are
downregulated in cancer tissue. Using transcriptomics we show that
the microRNAs repress several gene products known to be
overexpressed in this cancer. Argonaute 2 (AGO2)
co-immunoprecipitation, reporter assays and western blot analysis
demonstrate that the microRNAs directly target several components
of the mitogen-activated protein kinase (MAPK) and androgen
receptor (AR) signaling pathways, among those several AR
coregulators and HRAS (Harvey rat sarcoma viral oncogene homolog),
and repress signaling activity. Both pathways are central for the
development of the primary tumor and in particular the progression
to its incurable castration-resistant form. Reconstitution of the
microRNAs in LNCaP PCa cells induce morphological changes, which
resemble the effect of androgen deprivation, and jointly impair
tumor cell growth by induction of apoptosis and cell cycle
arrest. We therefore propose that these microRNAs jointly act as
tumor suppressors in prostate carcinoma and might interfere with
progression to castration resistance.
Oncogene. 2012 Mar 5. doi: 10.1038/onc.2012.55