Abstract 128: Exosomal miRNAs contribute to prostatic zinc homeostasis

Abstract A high level of zinc accumulation is required for normal prostatic function and secretion of prostatic fluid, and loss of zinc is a consistent marker of malignancy. We have recently shown that the reduction in expression of a major zinc transport protein, hZIP1, is due, in part, to aberrantly expressed microRNAs (miRs). MiR-183, 96 and 182, of the miR-183 family, target hZIP1 and other zinc transporters through binding the 3′ untranslated region (UTR) leading to decreased intracellular zinc in prostatic cells. Overexpression of miRs-183, 96 and 182 in prostate cancer is accompanied by decreased zinc concentration. African American men, as compared to Caucasian men, are at a higher risk of diagnosis and death from prostate cancer. African American men typically present with prostate tumors with higher Gleason grades at an earlier age than Caucasian men. This suggests that the prostatic tumors African American men suffer from are more aggressive and faster growing than the prostate tumors of Caucasian men and that there may be a strong biological component to this disparity. It has been previously shown that the prostatic lesions of African American men have a consistently lower zinc concentration than the lesions of their Caucasian peers and have comparatively reduced prostatic expression of hZIP1. We hypothesize that increased expression and exosomal secretion of miRs-183, 96 and 182 may be responsible for the greater degree of zinc depletion in the cancerous prostatic lesions of African American men, as compared to Caucasian men. Exosomes are small vesicles secreted from most cell types that have been repeatedly shown to be capable of carrying miRs to neighboring cells or the circulation. Our preliminary data shows that miRs-183, 96 and 182 are secreted in exosomes from primary prostate epithelial cells in culture, indicating a possible regulation of zinc via cell-to-cell transfer of exosomal miRs. Additionally, we found that the miR-183 family is more highly expressed in the prostatic tissues of African American men, which may contribute to the prostatic zinc disparity. Ongoing work will measure exosomal levels and activity of miR-183, 96 and 182 in primary prostatic epithelial cells from African American and Caucasian men and we have data to suggest that exosomes from African American men contain higher levels of miRs-183, 96 and 182. We will further determine the ability of exosomally derived miR-183, 96 and 182 to regulate zinc homeostasis in primary prostate epithelial cells. The identification of these miRNAs have important implications for patient care, in that African American men may benefit more from zinc supplementation than their Caucasian peers. As miRNA-targeted therapies emerge, these miRNAs may be targeted for prostate cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 128. doi:1538-7445.AM2012-128