Tumor Suppressor microRNAs, miR-100 and -125b, are Regulated by 1,25-dihydroxyvitamin D in Primary Prostate Cells and in Patient Tissue

• Published in: Cancer prevention research (Philadelphia, Pa.) Vol. 6; no. 5; pp. 483 - 494
• Main Authors: GIANGRECO, Angeline A, VAISHNAV, Avani, WAGNER, Dennis, FINELLI, Antonio, FLESHNER, Neil, VAN DER KWAST, Theodorus, VIETH, Reinhold, NONN, Larisa
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2013
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - etiology; Adenocarcinoma - pathology; Adult; Aged; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Case-Control Studies; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Clinical Trials, Phase II as Topic; E2F3 Transcription Factor - genetics; E2F3 Transcription Factor - metabolism; Follow-Up Studies; Gene Expression Profiling; Humans; Laser Capture Microdissection; Male; Medical sciences; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; Middle Aged; Miscellaneous; Oligonucleotide Array Sequence Analysis; Polo-Like Kinase 1; Prevention and actions; Prognosis; Prostate - drug effects; Prostate - pathology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - etiology; Prostatic Neoplasms - pathology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Public health. Hygiene; Public health. Hygiene-occupational medicine; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol - antagonists & inhibitors; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Vitamin D - analogs & derivatives; Vitamin D - pharmacology; Human; Tissue; Regulation(control); Vitamin D; Steroid hormone; Cholecalciferol(1,25-dihydroxy); Primary; Patient; Urogenital system; Cell; Prostate; Tumor suppressor gene
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.capr-12-0253

MiR-100 and miR-125b are lost in many cancers and have potential function as tumor suppressors. Using both primary prostatic epithelial cultures and laser capture-microdissected prostate epithelium from 45 patients enrolled in a vitamin D3 randomized trial, we identified miR-100 and -125b as targets of 1,25-dihydroxyvitamin D3 (1,25D). In patients, miR-100 and -125b levels were significantly lower in tumor tissue than in benign prostate. Similarly, miR-100 and -125b were lower in primary prostate cancer cells than in cells derived from benign prostate. Prostatic concentrations of 1,25D positively correlated with these miRNA levels in both prostate cancer and benign epithelium, showing that patients with prostate cancer may still benefit from vitamin D3. In cell assays, upregulation of these miRNAs by 1,25D was vitamin D receptor dependent. Transfection of pre-miR-100 and pre-miR-125b in the presence or absence of 1,25D decreased invasiveness of cancer cell, RWPE-2. Pre-miR-100 and pre-miR-125b decreased proliferation in primary cells and cancer cells respectively. Pre-miR-125b transfection suppressed migration and clonal growth of prostate cancer cells, whereas knockdown of miR-125b in normal cells increased migration indicates a tumor suppressor function. 1,25D suppressed expression of previously bona fide mRNA targets of these miRNAs, E2F3 and Plk1, in a miRNA-dependent manner. Together, these findings show that vitamin D3 supplementation augments tumor suppressive miRNAs in patient prostate tissue, providing evidence that miRNAs could be key physiologic mediators of vitamin D3 activity in prevention and early treatment of prostate cancer.