The miR-183 family cluster alters zinc homeostasis in benign prostate cells, organoids and prostate cancer xenografts

• Published in: Scientific reports Vol. 7; no. 1; pp. 7704 - 13
• Main Authors: Dambal, Shweta, Baumann, Bethany, McCray, Tara, Williams, LaTanya, Richards, Zachary, Deaton, Ryan, Prins, Gail S, Nonn, Larisa
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.08.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adenocarcinoma; Animals; Benign; Biomarkers, Tumor; Cancer; Cation Transport Proteins - genetics; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; DNA microarrays; Gene Expression Regulation, Neoplastic; Heterografts; Homeostasis; Humans; Male; Mice; MicroRNAs - genetics; Multigene Family; Organoids; Prostate; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Science & Technology - Other Topics; Signal Transduction; Transcription; Transcriptional Activation; Tumor Burden; Tumors; Wound healing; Xenografts; Zinc; Zinc - metabolism; Zinc transporter
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-07979-y

The miR-183 cluster, which is comprised of paralogous miRs-183, -96 and -182, is overexpressed in many cancers, including prostate adenocarcinoma (PCa). Prior studies showed that overexpression of individual pre-miRs-182, -96 and -183 in prostate cells decreased zinc import, which is a characteristic feature of PCa tumours. Zinc is concentrated in healthy prostate 10-fold higher than any other tissue, and an >80% decrease in zinc is observed in PCa specimens. Here, we studied the effect of overexpression of the entire 4.8 kb miR-183 family cluster, including the intergenic region which contains highly conserved genomic regions, in prostate cells. This resulted in overexpression of mature miR-183 family miRs at levels that mimic cancer-related changes. Overexpression of the miR-183 cluster reduced zinc transporter and intracellular zinc levels in benign prostate cells, PCa xenografts and fresh prostate epithelial organoids. Microarray analysis of miR-183 family cluster overexpression in prostate cells showed an enrichment for cancer-related pathways including adhesion, migration and wound healing. An active secondary transcription start site was identified within the intergenic region of the miR-183 cluster, which may regulate expression of miR-182. Taken together, this study shows that physiologically relevant expression of the miR-183 family regulates zinc levels and carcinogenic pathways in prostate cells.