br From the Department of Pathology College of Medicine Univ
From the Department of Pathology,* College of Medicine, University of Illinois at Chicago, Chicago; and the Department of Urology,y Feinberg College of Medicine, Northwestern University, Chicago, Illinois
Accepted for publication December 20, 2018.
A subset of men with prostate cancer develops aggressive disease. We sought to determine whether miR-182, an miRNA with reported oncogenic functions in the prostate, is associated with biochemical recurrence and aggressive disease. Prostate epithelial miR-182 Galactose 1-phosphate was quantified via in situ hybridization of two prostate tissue microarrays and by laser-capture microdissection of prostate epithelium. miR-182 was significantly higher in cancer epithelium than adjacent benign epithelium (P < 0.0001). The ratio of cancer to benign miR-182 expression per patient was inversely associated with recurrence in a multivariate logistic regression model (odds ratio Z 0.18; 95% CI, 0.03e0.89; P Z 0.044). Correlation of miR-182 with mRNA expression in laser-capture microdissected benign prostate epithelium was used to predict prostatic miR-182 targets. Genes that were negatively corre-lated with miR-182 were enriched for its predicted targets and for genes previously identified as up-regulated in prostate cancer metastases. miR-182 expression was also negatively correlated with genes previously identified as up-regulated in primary prostate tumors from African American patients, who are at an increased risk of developing aggressive prostate cancer. Taken together, these results suggest that although miR-182 is expressed at higher levels in localized prostate cancer, its levels are lower in aggressive cancers, suggesting a biphasic role for this miRNA that may be exploited for prognostic and/or therapeutic purposes to reduce prostate cancer progression. (Am J Pathol 2019, 189: 911e923; https://doi.org/10.1016/j.ajpath.2018.12.014)
Prostate cancer (PCa) has the highest incidence of any cancer in men, and although most patients have organ-confined disease, approximately 1 in 10 patients will die of their cancer.1 Classifying prostate tumors as indolent or aggressive remains a challenge both biologically and clini-cally. For localized or regional PCa, radical prostatectomy and radiation therapy are potentially curative. However, these treatments often cause morbidities.2 Tissue-based biomarker panels can be used to complement clinical no-mograms to guide treatment decisions3,4 and have shown utility for predicting disease recurrence after prostatectomy.5e7 The expression of miRNAs, small non-coding RNAs that regulate mRNA translation,8 is dysre-gulated in many cancers, including PCa.9 Currently, no miRNA biomarker test for PCa is used clinically, although several studies have described promising results that tissue or serum miRNAs have diagnostic and/or prognostic utility
for PCa.10e13 Thus, miRNAs may augment existing PCa prognostic tools and provide insight into cellular pathways that differentiate indolent and aggressive PCa.
miR-182, a member of the miR-183 family, is considered an oncomiR and is consistently present at high levels in PCa.14e18 miR-182 regulates genes involved in proliferation and the Wnt and PI3K pathways, which are known drivers of PCa.14,17e22 miR-182 and other miRNAs in the miR-183
family regulate prostate zinc homeostasis through direct translational inhibition of SLC39A1, which encodes a key zinc transporter.14 Zinc depletion has been implicated in prostate carcinogenesis,23 and patients with biochemical recurrence were found in a retrospective study to have 21% lower levels of zinc in tumor-adjacent benign tissue than
Disclosures: None declared.
Copyright ª 2019 American Society for Investigative Pathology. Published by Elsevier Inc.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0).
Baumann et al
patients with nonrecurrent disease.24 In light of these find-ings with recurrence and the high level of miR-182 in PCa, we hypothesized that miR-182 may associate with biochemical recurrence and that miR-182 in benign tissue may regulate pathways that prime the tissue for aggressive disease.
We examined the expression of miR-182 in relation to clinical markers of aggressive PCa, such as high Gleason grade and biochemical recurrence. miR-182 expression was quantified in tissues from patients with PCa through in situ hybridization (ISH) of a prostate tissue microarray (TMA), and quantitative RT-PCR (RT-qPCR) of laser-captured microdissected (LCM) prostate epithelium. Correlation of miR-182 with gene expression in LCM-collected prostate epithelium was used to predict tissue-specific targets. These approaches facilitated investigation of prostate epithelium and avoided analyzing the more prevalent stroma, which can bias results for this epithelial-specific miRNA. Our results suggest that miR-182 is a complex oncomiR that is higher in PCa compared with benign tissues, but within patients with PCa, the levels of the miRNA associated with aggressive tumor characteristics and PCa recurrence are lower.