Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the U.S. No accurate biomarkers exists that can discriminate for aggressive PCa and therapeutic options are limited for metastatic disease. MicroRNAs (MiRNAs) have emerged as promising clinical tools for cancers. These small non-coding RNAs negatively regulate gene expression post-transcriptionally. Widespread miRNA dysregulation has been noted in PCa. However, it is poorly understood how they function in the prostate to promote cancer progression and metastasis. Our lab recently identified miR-888 as a novel oncogenic miRNA up-regulated in specimens from patients with advanced PCa and acts to increase prostate cell proliferation, migration, & colony formation in vitro (Lewis et al, Cell Cycle 2014). MiR-888 belongs to a genomic cluster of seven miRNAs on human chromosome Xq27.3, an area linked to hereditary prostate cancer (HPCX1). We hypothesize additional members of miR-888 cluster (miR-892c, -890, -892a, -892b, -891b, -891a) function to promote PCa progression. Our studies employed paired syngenic human PCa cell lines differing in their metastatic status and response to androgen (i.e., androgen-sensitive, non-malignant RWPE-1 & aggressive WPE1-NB26; androgen-sensitive LNCaP & aggressive C4-2; hormone-refractory PC3-N & aggressive PC3-ML) to examine the miR-888 cluster's ability to modulate prostate cell proliferation (WST-1 assays), colony formation (Soft agar assays), migration, and invasion (Boyden chamber assays). Profiling miRNA expression in these cancer lines, we found that all miR-888 cluster members were preferentially elevated in highly aggressive PC3-ML and extensively down-regulated in non-aggressive PC3-N cells. Furthermore, we noted certain members of the miR-888 cluster, most notably miR-891a, acted in vitro to promote prostate cell proliferation, colony formation, migration & invasion activities. Interestingly, our results also suggested that other miR-888 cluster members act conversely to inhibit these activities - implying the miR-888 cluster functions as a unit to fine tune and coordinate prostate cancer pathways. Xenograft experiments are currently ongoing to evaluate in vivo effects of the miR-888 cluster during tumorigenesis. Preliminary data indicated that miR-888 could accelerate tumor formation of PC3-N cells subcutaneously implanted into flanks of NOD/SCID male mice. MiR-888 cluster members are now being evaluated for their non-cell autonomous effects in the prostate by exosomal transport. We have successfully isolated exosomes from human PCa cell lines and are working towards developing these secreted membrane-bound vesicles as novel miRNA delivery vehicles for PCa. Taken together, this study offers a more detailed understanding of PCa and insight into the complexity of miRNA networks involved in cancer progression.

Citation Format: Tsuyoshi Hasegawa, Mary Pahuski, Garrison Glavich, Holly B. Lewis, Aurora Esquela-Kerscher. The miR-888 cluster: a new oncogenic cluster involved in aggressive prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1933.