Siri Strand

Hypermethylation of the GABRE~miR-452~miR-224 Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy

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  • Helle Kristensen, Authors' Affiliations: Departments of Molecular Medicine and Urology and Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland; Department of Urology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland; Departments of Oncology and Pathology and Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden., Denmark
  • Christa Haldrup, Denmark
  • Siri Strand
  • Kamilla Mundbjerg, Denmark
  • Martin M Mortensen, Denmark
  • Kasper Thorsen
  • Marie Stampe Ostenfeld, Denmark
  • Peter J Wild
  • ,
  • Christian Arsov
  • ,
  • Wolfgang Goering
  • ,
  • Tapio Visakorpi
  • ,
  • Lars Egevad
  • ,
  • Johan Lindberg, Denmark
  • Henrik Grönberg
  • ,
  • Søren Høyer, Denmark
  • Michael Borre
  • Torben F Orntoft
  • Karina Dalsgaard Sørensen

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. Clin Cancer Res; 20(8); 2169-81. ©2014 AACR.

Original languageEnglish
JournalClinical Cancer Research
Pages (from-to)2169-81
Number of pages13
Publication statusPublished - 15 Apr 2014

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