title: Clinical significance of miRNA host gene promoter methylation in prostate cancer.
abstract: Only a part of prostate cancer (PCa) patients has aggressive malignancy requiring adjuvant treatment after radical prostatectomy (RP). Biomarkers capable to predict biochemical PCa recurrence (BCR) after RP would significantly improve preoperative risk stratification and treatment decisions. MicroRNA (miRNA) deregulation has recently emerged as an important phenomenon in tumor development and progression, however, the mechanisms remain largely unstudied. In the present study, based on microarray profiling of DNA methylation in 9 pairs of PCa and noncancerous prostate tissues (NPT), host genes of miR-155-5p, miR-152-3p, miR-137, miR-31-5p, and miR-642a, -b were analyzed for promoter methylation in 129 PCa, 35 NPT, and 17 benign prostatic hyperplasia samples (BPH) and compared to the expression of mature miRNAs and their selected targets (DNMT1, KDM1A, and KDM5B). The Cancer Genome Atlas dataset was utilized for validation. Methylation of mir-155, mir-152, and mir-137 host genes was PCa-specific, and downregulation of miR-155-5p significantly correlated with promoter methylation. Higher KDM5B expression was observed in samples with methylated mir-155 or mir-137 promoters, whereas upregulation of KDM1A and DNMT1 was associated with mir-155 and mir-152 methylation status, respectively. Promoter methylation of mir-155, mir-152, and mir-31 was predictive of BCR-free survival in various Cox models and increased the prognostic value of clinicopathologic factors. In conclusion, methylated mir-155, mir-152, mir-137, and mir-31 host genes are promising diagnostic and/or prognostic biomarkers of PCa. Methylation status of particular miRNA host genes as independent variables or in combinations might assist physicians in identifying poor prognosis PCa patients preoperatively.
authors.affiliation: Institute of Biosciences, Life Sciences Centre, Vilnius University, Vilnius LT-10257, Lithuania.
authors.forename: Kristina
authors.initials: K
authors.lastname: Daniunaite
authors.affiliation: Institute of Biosciences, Life Sciences Centre, Vilnius University, Vilnius LT-10257, Lithuania.
authors.forename: Monika
authors.initials: M
authors.lastname: Dubikaityte
authors.affiliation: Department of Biological DNA Modification, Institute of Biotechnology, Life Sciences Centre, Vilnius University, Vilnius LT-10257, Lithuania.
authors.forename: Povilas
authors.initials: P
authors.lastname: Gibas
authors.affiliation: National Cancer Institute, Vilnius LT-08660.|Urology Centre, Vilnius University, Vilnius LT-08661, Lithuania.
authors.forename: Arnas
authors.initials: A
authors.lastname: Bakavicius
authors.affiliation: Institute of Biosciences, Life Sciences Centre, Vilnius University, Vilnius LT-10257, Lithuania.
authors.forename: Juozas
authors.initials: J
authors.lastname: Rimantas Lazutka
authors.affiliation: National Cancer Institute, Vilnius LT-08660.
authors.forename: Albertas
authors.initials: A
authors.lastname: Ulys
authors.affiliation: National Cancer Institute, Vilnius LT-08660.|Faculty of Medicine, Vilnius University, Vilnius LT-03101, Lithuania.
authors.forename: Feliksas
authors.initials: F
authors.lastname: Jankevicius
authors.affiliation: Institute of Biosciences, Life Sciences Centre, Vilnius University, Vilnius LT-10257, Lithuania.|National Cancer Institute, Vilnius LT-08660.
authors.forename: Sonata
authors.initials: S
authors.lastname: Jarmalaite
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D030561:Databases, Nucleic Acid; D018572:Disease-Free Survival; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008745:Methylation; D035683:MicroRNAs / Q000737:chemistry* / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D011467:Prostate / Q000378:metabolism; D011468:Prostatectomy; D011470:Prostatic Hyperplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs