Abstract 2523: Key cluster for prostate cancer diagnosis and therapy; miR-888 cluster
Authors: Tsuyoshi Hasegawa, Aurora Kerscher
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the 2nd leading cause of cancer death among men in the U.S. No accurate biomarkers exist and therapeutic options are limited for advanced PCa. MicroRNAs (miRNAs), small non-coding RNAs, act as negative regulators of gene expression. MiRNAs have recently emerged as promising therapeutic tools for cancers. It is poorly understood how they function to promote cancer progression. We found miR-888 was involved with PCa progression. miR-888 belongs to a genomic cluster on human chromosome Xq27.3, linked to hereditary PCa. I hypothesized additional members of this cluster (miR-892c, -890, -892a, -892b, -891b, -891a) function to promote PCa progression. Our lab profiled miR-888 cluster expression in paired syngenic human PCa cell lines (RWPE1 &amp; WPE1-NB26, LNCaP &amp; C4-2, PC3-N &amp; PC3-ML) differing in metastatic status and androgen response. We noted that the miR-888 cluster was preferentially elevated in metastatic PC3-ML and under-expressed in non-aggressive PC3-N cells. I examined miR-888 cluster function in vitro and found that forced expression (via miRNA mimics) of certain miR-888 cluster members, notably miR-888 and miR-891a, promoted cell proliferation, colony formation, migration and invasion in PC3-N cells. Conversely, other cluster members inhibited these activities. Experiments with hormone sensitive LNCaP cells showed similar results in these assays. PC3-ML transfected with miRNA inhibitors exhibited reciprocal effects. In mouse xenograft studies, I used lentiviral vectors to individually overexpress miR-888 and miR-891a in PC3-N cells and injected them subcutaneously into flanks of NOD/SCID mice. The miRNAs accelerated tumor formation and increased tumor size compared to controls. miR-888 may promote tumorigenesis by suppressing the tumor suppressors TIMP2 and SMAD4, which our lab validated as miR-888 targets using luciferase reporter assays. I confirmed by western blot that xenograft tumors overexpressing miR-888 had decreased protein levels for these targets. Studies reveal miRNAs exist in exosomes, small membrane bound vesicles involved in cell-to-cell communication. I postulated that aggressive tumors secrete exosomes with the miR-888 cluster as cargo and promote PCa progression. Indeed, I noted that miR-888 cluster expression is elevated in exosomes isolated from aggressive PC3-ML compared to PC3-N cells as well as in EPS urine exosomes from high-grade PCa patients versus those with low-grade disease. My work indicates miR-888 and miR-891a are novel oncogenic factors in the prostate and may use exosomes to exert their effects. This is the first report to explore the functional role of the miR-888 cluster in any tissue and may lead to promising clinical strategies for PCa. Citation Format: Tsuyoshi Hasegawa, Aurora Kerscher. Key cluster for prostate cancer diagnosis and therapy; miR-888 cluster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2523. doi:10.1158/1538-7445.AM2017-2523