microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma

•The active hormone 1,25(OH)2D regulates miRs in prostate stroma.•Inflammation-related pathways were enriched in the putative targets for the 1,25(OH)2D-regulated miRs.•The miR-processing enzyme DICER1 positively correlated with 1,25(OH)2D in the stroma.•A high epithelial:stromal ratio of DICER1 pro...

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Published in:The Journal of steroid biochemistry and molecular biology 2017-03, Vol.167, p.192-202
Main Authors: Dambal, Shweta, Giangreco, Angeline A., Acosta, Andres M., Fairchild, Andrew, Richards, Zachary, Deaton, Ryan, Wagner, Dennis, Vieth, Reinhold, Gann, Peter H., Kajdacsy-Balla, Andre, Van der Kwast, Theodorus, Nonn, Larisa
Format: Article
Language:English
Subjects:
Aged
Cancer
Carcinogenesis
Cell Differentiation
Cholecalciferol - metabolism
DEAD-box RNA Helicases - metabolism
DNA microarrays
Epithelium
Epithelium - metabolism
Gene expression
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Inflammation
Lasers
Male
microRNA
MicroRNAs
MicroRNAs - metabolism
Middle Aged
miRNA
Prostate
Prostate - metabolism
Prostate cancer
Prostate stroma
Prostatectomy
Prostatic Neoplasms - metabolism
Recurrence
Ribonuclease
Ribonuclease III - metabolism
Stromal cells
Studies
Vitamin D
Vitamin D - analogs & derivatives
Vitamin D - metabolism
Vitamin D receptors
Vitamin D3
Vitamin deficiency
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Summary:•The active hormone 1,25(OH)2D regulates miRs in prostate stroma.•Inflammation-related pathways were enriched in the putative targets for the 1,25(OH)2D-regulated miRs.•The miR-processing enzyme DICER1 positively correlated with 1,25(OH)2D in the stroma.•A high epithelial:stromal ratio of DICER1 protein levels associated with future biochemical recurrence. Vitamin D deficiency increases the risk of lethal prostate adenocarcinomas (PCa) and the majority of older men are deficient. Although PCa arises from the epithelium, the surrounding stroma has hormonal regulatory control over the epithelium and contributes to carcinogenesis. Herein, we describe regulation of microRNAs (miRs) by the active hormone dihydroxyvitamin D (1,25(OH)2D) in human prostate stroma. 1,25(OH)2D binds the vitamin D receptor (VDR) transcription factor to regulate gene expression, including miRs, which have emerged as potent regulators of protein expression. 1,25(OH)2D–regulated miRs were identified by profiling in primary human prostatic stromal cells (PrS) and three miRs, miR-126-3p, miR 154-5p and miR-21-5p were subsequently validated in laser-capture micro-dissected prostate stromal tissue from a vitamin D3 clinical trial (N=45). Regulation of these miRs by 1,25(OH)2D was VDR-dependent. Network analysis of known and putative mRNA targets of these miRs was enriched with cancer and inflammation pathways, consistent with known roles of stroma and of vitamin D in carcinogenesis. Expression of the miR processing ribonuclease, DICER1, positively correlated with vitamin D metabolite levels in the clinical trial specimens. High epithelial/stromal ratios of DICER1 were significantly associated biochemical recurrence (OR 3.1, p=0.03) in a tissue microarray of 170 matched PCa patients. In summary, these results underscore the role of the prostate stroma in regulating responses to the hormone 1,25(OH)2D and identified miRs and DICER1 as being regulated in human prostate stroma. Regulation of stromal DICER1 by 1,25(OH)2D may also have clinical relevance in protection against aggressive PCa.
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2017.01.004