Control of gene expression in prostate epithelial cell differentiation hierarchy

The aim of present investigation is to elucidate the complex stem cell (SC) dynamics within prostate cancer, which can be exploited to design novel diagnostic and therapeutic strategies for the management of prostate cancer. In order to determine the precise transcriptional and microRNA regulatory mechanisms modulating SC self-renewal and differentiation, unique cellular assays have been developed in our lab. These assays utilise homogeneous cell sub-populations enriched from patient-derived prostate cultures. Occasionally, cell line models and patient-derived mouse prostate cancer xenografts were also employed.
Using a prospective bioinformatic analysis of gene expression data from Birnie et. al., 2008, we have identified LCN2, CEACAM6, and S100p as candidate genes for regulation of prostate SC differentiation. These genes are over-expressed in differentiated cells, compared to SC, and have a more similar expression pattern with each other than with any other gene. Since their promoters have binding sites for 32 common transcription factors, the genes may therefore form a co-regulated network and/or have similar functions. Retinoic acid treatment can also induce the expression of all these genes, suggesting that LCN2, CEACAM6, and S100p may play an important role in retinoic acid-mediated prostate epithelial SC differentiation. The genes could also be so-regulated by miR-128, miR-188, and miR-548c, based on an analysis of the miRNA expression by microarray generated in this work. Patient-derived prostate epithelial sub-populations enriched from PrEC, BPH, PCa, and CRPC were profiled for the expression of 766 miRNAs. This analysis identified a very specific prostate cancer SC miRNA signature, and showed that miRNA expression can distinguish between PCa and CRPC. The integration of this miRNA microarray data with gene expression microarray data showed that pathways regulating both the cell cycle (SC quiescence) and cell-cell interaction (SC-stromal niche interaction) could be significantly influenced by miRNAs during differentiation. A lack of telomerase expression/activity in prostate cancer SCs, in contrast to their differentiated progeny also points towards the quiescent nature of these cells. The telomerase studies further revealed that BPH is a disease sustained by progenitor proliferation and that inhibition of telomerase in BPH derived SCs can suppress their self-renewal; while cancer SC self-renewal is not affected by telomerase inhibition.
We anticipate that these results, with further functional studies, will comprehensively establish a detailed knowledge base for regulatory mechanisms active in prostate SC and prostate cancer SC differentiation. This data will be invaluable in formulating efficient management strategies for prostate cancer.