title: microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma.
abstract: 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.
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Shweta
authors.initials: S
authors.lastname: Dambal
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Angeline A
authors.initials: AA
authors.lastname: Giangreco
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Acosta
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Fairchild
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Richards
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Deaton
authors.affiliation: Department of Nutritional Sciences, Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wagner
authors.affiliation: Department of Nutritional Sciences, Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Vieth
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States; University of Illinois Cancer Center, Chicago, IL, United States.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Gann
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States; University of Illinois Cancer Center, Chicago, IL, United States.
authors.forename: Andre
authors.initials: A
authors.lastname: Kajdacsy-Balla
authors.affiliation: Department of Pathology, University Health Network, University of Toronto, ON, Canada.
authors.forename: Theodorus
authors.initials: T
authors.lastname: Van der Kwast
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States; University of Illinois Cancer Center, Chicago, IL, United States. Electronic address: lnonn@uic.edu.
authors.forename: Larisa
authors.initials: L
authors.lastname: Nonn
mesh_terms: D000368:Aged; D002454:Cell Differentiation; D002762:Cholecalciferol / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D007834:Lasers; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D011467:Prostate / Q000378:metabolism*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012008:Recurrence; D043244:Ribonuclease III / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D014807:Vitamin D; D002762:Cholecalciferol; C097949:1,25-dihydroxyvitamin D; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Prostate cancer; Prostate stroma; Vitamin D; microRNA