Abstract 4003: Serum miRNAs associated with prostate cancer: correlation to deregulated signaling pathways

Abstract

Abstract Introduction and Objective: MicroRNAs (miRNA) are well documented to regulate cancer cell activity by targeting tumor suppressors and oncogenes, modulating signaling pathways to promote tumor progression and metastasis. Given the recent knowledge that miRNAs are secreted from normal and prostate cancer cells and circulate at measureable levels, the goal of this study was to identify circulating miRNAs (c-miRNA) in patient serum predictive of prostate cancer risk, prognosis and response to current standards of therapy. Methods: Blood samples were collected from 35 consented men (27 with Prostate Cancer (PCa) and 8 cancer−free age matched individuals) at the University of Vermont Medical Center. A standardized protocol for archived and freshly drawn sample analyses is detailed in Farina et al J Cell Biochem 2014. Serum samples were divided into 1 ml aliquots and frozen only once prior to RNA isolation using the miRNeasy Serum/Plasma kit (QIAGEN). Global profiling was performed with Affymetrix microRNA v4.0 microarray, having over 2500 mature human miRNAs. Three outlier samples (due to secondary complications) were removed prior to data analyses including Principal Component Analyses (PCA), hierarchical clustering, and differential expression. MicroRNAs detected in either all PCa patients or controls were analyzed for putative biological activity by Gene Ontology and Biological Pathway analyses of their predicted gene targets. Results: The PCA generally grouped PCa patients and cancer−free individuals separately. Two miRNAs are consistently elevated in serum of all men screened and may serve as novel endogenous control genes. Four miRNAs are detected in all PCa patients but not in all cancer−free men, while 42 miRNAs are expressed in all cancer−free individuals but not in all men with cancer. Thus, there is a greater loss of c-miRNAs in PCa patients than gain. Enriched KEGG pathways targeted by these miRNAs include Prostate Cancer as well as ErbB, Wnt, TGF-beta, and MAPK signaling pathways. In addition, 12 of the 29 most significantly deregulated c-miRNAs between patients with PCa and cancer-free individuals are differentially secreted in normal prostate epithelial cells (RWPE-1) as compared to PCa cell lines (LNCaP and PC-3). Conclusion: Together, these data suggest that c-miRNAs secreted from PCa cells promote cancer progression through known signaling pathways. While we consider these findings preliminary until a larger sample set is screened, we conclude that the measurement of circulating miRNAs will become valuable biomarkers. Citation Format: Nicholas H. Farina, Jon E. Ramsey, Areg Zingiryan, Steven Ades, Mark K. Plante, Gary S. Stein, Janet L. Stein, Jane B. Lian, Scott D. Perrapato. Serum miRNAs associated with prostate cancer: correlation to deregulated signaling pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4003. doi:10.1158/1538-7445.AM2015-4003