Non-coding RNAs as Prognostic and Diagnostic Markers in Prostate Cancer

Division Of Basic Sciences - Nci

Investigators

Abstract

MicroRNA expression is commonly altered in solid human tumors. Multiple microRNAs have been shown to have oncogenic properties, or act like tumor suppressor genes. These microRNAs have been termed oncomiRs. An alteration in their expression is causatively linked to cancer development and can predict disease outcome. Recently, the Croce group (Carlo Croce, M.D., Ohio State University) reported that expression of RNAs encoded by ultraconserved genomic regions (ucRNA) is altered in human cancer. At this time, 481 of these ultraconserved elements have been annotated and defined as segments greater than 200 bp with perfect conservation among human, rat, and, mouse genomes. In collaboration with Dr. Croce, we are investigating microRNA and ucRNA expression profiles of prostate tumors. This teamwork led to the first study that applied large-scale gene expression profiling to identify alterations in microRNA function in tumors from African-American and European-American patients. We determined genome-wide expression of microRNAs and mRNAs in 60 primary prostate tumors and 16 non-tumor prostate tissues. The mRNA analysis revealed that key components of microRNA processing and several microRNA host genes, e.g., MCM7 and C9orf5, were significantly up-regulated in prostate tumors. Consistent with these findings, tumors expressed the miR-106b-25 cluster, which maps to intron 13 of MCM7, and miR-32, which maps to intron 14 of C9orf5, at significantly higher levels than non-tumor prostate. The expression levels of other microRNAs, including a number of miR-106b-25 cluster homologues, were also altered in prostate tumors. Additional differences in microRNA abundance were found between organ-confined tumors and those with extraprostatic disease extension. Lastly, we found evidence that some microRNAs are androgen-responsive and that tumor microRNAs influence transcript abundance of protein-coding target genes in the cancerous prostate. In cell culture, E2F1 and p21/WAF1 were identified as targets of miR-106b, Bim of miR-32, and exportin-6 and protein tyrosine kinase 9 of miR-1. In summary, microRNA expression becomes altered with the development and progression of prostate cancer. Some of these microRNAs regulate the expression of cancer-related genes in prostate cancer cells. We also compared the tumor microRNA signatures between African-Americans and European-Americans, but only a few microRNAs were differentially expressed. miR-129, miR-196b, and miR-342 were found to be less abundant in tumors of African-Americans than in tumors of European-Americans. From the analysis, it did not appear that tumor microRNAs are differentially expressed to any major degree by race/ethnicity. Currently, we are analyzing the expression profiles for ucRNA in these samples. Preliminary results indicate that numerous ucRNAs are differentially expressed between tumor and surrounding normal tissue, by Gleason grade, and between organ-confined tumors and those with extraprostatic disease extension. The chip data are in the process of being validated by other methods. A recent publication (Proc Natl Acad Sci USA 105:10513-18, 2008) found that circulating microRNAs, which are only 17-25 bp in size, are stable blood-based markers that could be useful for cancer detection. We have begun evaluating the technology for analyzing microRNA abundance in serum samples from prostate cancer cases and controls to examine whether the microRNA expression profile of blood samples can be used to predict the presence of tumor. In a pilot study, we will evaluate the relative abundance of several candidate microRNAs in serum samples from cancer patients and population-based controls. These microRNAs will be selected from the tumor microRNA expression profile that we identified. Samples for the study will be drawn from our ongoing case-control of prostate cancer in the greater Baltimore, Maryland area.