The microRNA (miR)183 cluster, which is comprised of miRs-183, -96 and -182, is also a miR family with sequence homology. Despite the strong similarity in the sequences of these miRs, minute differences in their seed sequences result in both overlapping and distinct messenger RNA targets, which are often within the same pathway. These miRs have tightly synchronized expression during development and are required for maturation of sensory organs. In comparison to their defined role in normal development, the miR-183 family is frequently highly expressed in a variety of non-sensory diseases, including cancer, neurological and auto-immune disorders. Here, we discuss the conservation of the miR-183 cluster and the functional role of this miR family in normal development and diseases. We also describe the regulation of vital cellular pathways by coordinated expression of these miR siblings. This comprehensive review sheds light on the likely reasons why the genomic organization and seeming redundancy of the miR-183 family cluster was conserved through 600 million years of evolution.

Background: Zinc is vital to normal prostate function and uniquely concentrates in healthy prostate. A hallmark of prostate cancers is diminished zinc levels. Results: The miR-183 family is overexpressed in prostate cancer and regulates intracellular zinc via suppression of zinc transporters. Conclusion: Prostatic zinc homeostasis is regulated by microRNAs. Significance: The miR-183 family regulates zinc and may contribute to prostate carcinogenesis.

To reduce treatment of indolent prostate cancer (PCa), biomarkers are needed to improve identification of patients with a low-risk of having aggressive disease. Over-treatment of these patients occurs because of uncertainty in the aggressiveness of the entire tumor based on the biopsies, which do not accurately sample multifocal tumors. Circulating microRNAs (miRNAs) are stable serum markers and differential miRNA levels occur in men with PCa. The goal of this study was to identify circulating miRNAs that were associated with aggressive or indolent PCa. We measured circulating miRNAs in 150 patients prior to surgery and compared the miRNA levels to the pathology of the entire radical prostatectomy specimen. For this study we used an exceptionally well-characterized cohort of patients who had benign prostatic hyperplasia (BPH), low-grade or high-grade PCa. Low-grade was defined as patients with 100% Gleason grade 3 tumor as determined by step-wise sectioning. High-grade PCa patients had 30-90% Gleason grade 4+5 in the tumor. BPH patients had at least two biopsies negative for PCa. Twenty one miRNAs were selected for analysis. The miRNAs were quantified by RT-qPCR and analyzed by logistic regression. High levels of 14 miRNAs were exclusively present in the serum from patients with low-grade PCa or BPH, compared to men with high-grade PCa who had consistently low levels. The expression levels of the 14 miRNAs were combined into a “miR Score” which had a negative predictive value (NPV) of 0.939 to predict absence of high-grade PCa among PCa and BPH patients. Biochemical recurrence (BCR) was known for the PCa patients and a combined “miR Risk Score” accurately classified a subset of patients with low risk of BCR (NPV 0.941). In summary, measurement of serum miRNAs may have pre-surgical utility in combination with clinical risk calculators to identify patients with low risk of harboring aggressive PCa.

Members of the microRNA (miR)-183 family are expressed at high levels in the majority of cancer types, including breast and prostate, and are considered ‘oncomiRs’. The purpose of the present study was to investigate the role of exosomes in cell-to-cell transfer of the miR-183 family, which includes miRs-96, −182 and −183. Despite highly detectable levels of these three miRs within prostate and breast cells in vitro, only miR-182 was detectable in exosomes isolated from cell culture supernatant. Similar to the in vitro results, miR-182 was the only miR detected in exosomes isolated from fresh human serum. The packaging of miR-182 into exosomes was examined in MDA-MB-231 (MDA-182) breast cancer cells with miR-182 overexpression. Levels of mature miR-182 increased in exosomes in a dose-dependent manner compared to intracellular expression. Furthermore, co-culture of MDA-182 cells with naïve MDA-MB-231 cells resulted in an increase in mature miR-182 in the naïve cells, which was blocked by a chemical inhibitor of microvesicle formation. In summary, the present study demonstrates that of the miR-183 family members, miR-182 is preferentially packaged in exosomes, detectable in exosomes from human sera and may be transferred between cells via a microvesicle-dependent mechanism.

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