Abstract 2066: Role of miR-182/miR-96 cluster in prostatic zinc homeostasis

Abstract

Abstract Zinc has been shown to have a defensive action against the development of prostate cancer (PCa). Zinc is an essential element that is required for the activity of more than 300 enzymes, structure of proteins, and control of genetic expression. It plays an important role in cellular processes such as cell division, growth, differentiation, development, aging, and synthesis and repair of DNA, RNA, and protein. Prostatic secretary epithelial cells accumulate large amounts of zinc and have a high expression of human Zinc transporter 1 (hZIP1), the major zinc transporter in the prostate. PCa tissue exhibits lower levels of zinc and hZIP1 compared with surrounding normal-appearing areas. Furthermore, compared to Caucasian men, the prostates of African American men, a population with a disproportionately high risk of developing PCa, have decreased zinc and hZIP1. Previously, we examined several miRNAs in formalin-fixed paraffin-embedded prostate tissue from African American and Caucasian patients, of which miR-182/96 levels were higher in PCa samples and had inverse correlation with hZIP1 mRNA in Caucasian patients (Spearman rho = −0.77, p=0.009). No correlation between hZIP1 and miR-182 was found in the African-American specimens, suggesting a different mechanism for hZIP1 regulation in African-Americans. Based on previous studies, we hypothesize that miR-182/96 cluster is responsible for regulation of hZIP1 levels in PCa and prostate tissue. In this study, we examined the relationship between the levels of miR-182/96 and hZIP1 in more detail using cell culture models. We observed an inverse correlation between hZIP1 and miR-182 levels in several prostate cell cultures; primary normal epithelial cells, normal stromal cells, and prostate cancer cells (PC3 and LNCaP). MiR-182 is transcribed in a cluster with miR-96 and the miRNAs have an overlapping mRNA target sequence. As expected, miR-96 expression was identical to that of miR-182, thus also inversely correlated with hZIP1 in prostate cell cultures. Overexpression of miR-182 in both normal and LNCaP cells decreased hZIP1 mRNA levels, further implicating miR-182 as a regulator of zinc transport. Ongoing experiments focus on validating the two putative miR-182/96 binding sites in the 3′UTR of hZIP1 and the effect of miR-182 and miR-96 overexpression on zinc transport. Our results may establish a role for miR-182 in prostatic zinc homeostasis. Because zinc levels are linked to PCa risk, these miRNAs may be useful as a prognostic or diagnostic marker in prostate biopsies to identify patients with high risk of PCa recurrence and for identifying individuals for zinc replacement. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2066.