Abstract
Abstract Prostate cancer remains the second leading cause of cancer-related deaths among men in the United States despite the widespread use of prostate specific antigen (PSA) as a diagnostic marker for prostate cancer and as a predictor of treatment outcome. MicroRNAs (MiRNAs) belong to a growing class of small non-coding RNAs that are often abnormally expressed in fluid and tissue specimens from prostate cancer patients compared to non-cancer individuals. These miRNAs are hypothesized to play a direct role in promoting disease progression and metastasis in the prostate and are intensely studied for both their diagnostic and therapeutic potential for human cancer. Our laboratory profiled candidate prostate-cancer associated miRNAs in an innovative prostatic fluid biomarker source called expressed prostatic secretions in urine (EPS urine) to determine their utility as discriminating biomarkers for advanced forms of prostate cancer. 10 out of 50 miRNA tested showed statistically significant differences in expression between cancer and non-cancer patient groups within the supernatant but not pellet fractions of whole EPS urine. We are investigating if differential miRNA expression in EPS supernatant is due to exosomal populations and how miRNA-loaded exosomes modulate prostate tumorigenesis in mice. Our profiling studies identified miR-888 as a novel factor that correlates with advanced prostate cancer in human prostate cancer cell lines, EPS urine, and primary tumors. Functional assays revealed that miR-888 promotes proliferation, migration, and colony formation of hormone-refractory and androgen-sensitive human prostate cancer cells. Our working model is that miR-888 overexpression in the diseased prostate suppresses SMAD4, RBL1, and TIMP2 targets leading to tumor progression and metastasis. Human miR-888 belongs to a genomic cluster of seven miRNAs on human chromosome Xq27.3. We are currently testing how this miR-888 cluster interacts within a growing network of coding and non-coding genes to regulate prostate tumor progression. This research will provide a better understanding how prostate tumor cells progress to a more metastatic, aggressive state and facilitate the development of more effective diagnostic and therapeutic strategies for this prevalent and deadly disease. Citation Format: Holly Lewis, Tsuyoshi Hasegawa, Garrison Glavich, Raymond Lance, O. John Semmes, Hind Beydoun, Richard Drake, Aurora Esquela-Kerscher. From profiling to function: A role for microRNA miR-888 in promoting prostate cancer progression. [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 3086. doi:10.1158/1538-7445.AM2015-3086
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