ASCO GU 2008 - The Role Of MicroRNA In Prostate Tumor Biology

Main Category: Prostate / Prostate Cancer
Also Included In: Biology / Biochemistry;  Urology / Nephrology;  Men's health
Article Date: 17 Feb 2008 - 0:00 PDT

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UroToday.com - Dr. Nelson discussed that androgen-independent CaP progression is not really independent of androgens. Using microarray based expression profiling in LNCaP cells, gene expression following androgen deprivation therapy was performed. They sought to identify the regulatory cascade governing the progression to androgen-independence. This was correlated with human CaP tumor microarrays, and they found concordance with the LNCaP findings.

Neoadjuvant ADT in patients was found to both increase and decrease certain gene expression by microarray profiling. Identified genes were then reapplied to an androgen regulated gene network and then studied with siRNA to understand biological implications of each gene. MicroRNA is a non-coding RNA that is a hairpin loop structure that is moved to the cytoplasm and becomes involved in a risk complex. It can result in cleavage of mRNA and an increase in a protein or translational repression, depending on the cytoplamic events. MicroRNA profiling through microarray profiling was performed to look at mRNA expression and integrate it into androgen regulated network analysis to understand the biological implications of microRNA. RT-PCR is used and targets of the amplified microRNA are identified. Then anti-sense is used to block these targets and the fate of the microRNA is studied. They found that this can relieve the microRNA repression, thus validating this approach.

Dr. Nelson then cited several examples they derived from this approach. They found the transcription factor SREBP gave rise to miR-33a, an androgen-regulated microRNA. This was more highly expressed in AICAP. It is a transcriptional regulator involved in fatty acid, cholesterol and steroid biosynthesis. Targets of SREBP were confirmed by androgen receptor siRNA experiments. Relaxin was identified as repressed by androgens and increased with NHT duration. miR-33a affects relaxin expression and downstream events. In another example, GADD45G mRNA is also increased with androgens and GADD45G protein levels are decreased with androgens. GADD45G siRNA downregulated GADD45G and reduces the phosphorylation of p38 kinase pathways and affects cell stress and survival response. Other miRNAs were found in the introns of androgen regulated genes and correlate with their microarray profiles. Proof of principle is done by blocking the microRNA and finding reversal of the androgen repression.

Presented by Colleen C. Nelson at the American Society of Clinical Oncology (ASCO) - 2008 Genitourinary Cancers Symposium - A Multidisciplinary Approach - February 14-16, 2008 San Francisco, California, USA

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS Professor & Chairman Department of Urology University of California, Davis, School of Medicine Sacramento, CA

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