Helle Kristensen 1 , Christa Haldrup , Siri Strand , Kamilla Mundbjerg , Martin M Mortensen , Kasper Thorsen , Marie Stampe Ostenfeld , Peter J Wild , Christian Arsov , Wolfgang Goering , Tapio Visakorpi , Lars Egevad , Johan Lindberg , Henrik Grönberg , Søren Høyer , Michael Borre , Torben F Ørntoft , Karina D Sørensen Show Affiliations »
Abstract
PURPOSE: Available tools for prostate cancer diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE∼miR-452∼miR-224 genomic locus. EXPERIMENTAL DESIGN: GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 nonmalignant and 281 prostate cancer tissue samples. GABRE∼miR-452∼miR-224 promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE∼miR-452∼miR-224 methylation was evaluated by ROC, Kaplan-Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of posttransfection transcriptional profiling data. RESULTS: GABRE∼miR-452∼miR-224 was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC = 0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular adhesion and motility. Finally, in uni- and multivariate analyses, high GABRE∼miR-452∼miR-224 promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2. CONCLUSION: The GABRE∼miR-452∼miR-224 locus is downregulated and hypermethylated in prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of GABRE∼miR-452∼miR-224 may be selected for in prostate cancer. ©2014 AACR.
PURPOSE: Available tools for prostate cancer diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE ∼miR-452 ∼miR-224 genomic locus. EXPERIMENTAL DESIGN: GABRE /miR-452 /miR-224 transcriptional expression was quantified in 80 nonmalignant and 281 prostate cancer tissue samples. GABRE ∼miR-452 ∼miR-224 promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE ∼miR-452 ∼miR-224 methylation was evaluated by ROC, Kaplan-Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA ) of posttransfection transcriptional profiling data. RESULTS: GABRE ∼miR-452 ∼miR-224 was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer -specific aberrant promoter hypermethylation (AUC = 0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular adhesion and motility. Finally, in uni- and multivariate analyses, high GABRE ∼miR-452 ∼miR-224 promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2. CONCLUSION: The GABRE ∼miR-452 ∼miR-224 locus is downregulated and hypermethylated in prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of GABRE ∼miR-452 ∼miR-224 may be selected for in prostate cancer . ©2014 AACR.
Entities: Chemical
Disease
Gene
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Year: 2014
PMID： 24737792 DOI： 10.1158/1078-0432.CCR-13-2642
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531