Hypermethylation of the GABRE∼miR-452∼miR-224 Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy
Hypermethylation of the GABRE∼miR-452∼miR-224 Promoter in Prostate Cancer Predicts Biochemical Recurrence after Radical Prostatectomy
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DOI：
10.1158/1078-0432.ccr-13-2642
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发表时间：
2014-04-15
影响因子：
11.5
通讯作者：
Sorensen, Karina D.
中科院分区：
文献类型：
--
作者：
Kristensen, Helle;Haldrup, Christa;Sorensen, Karina D.
目的：前列腺癌诊断和预后的现有工具是次优的，迫切需要新的生物标志物。在此，我们研究了GABRE类似于miR-452类似于miR-224基因组位点的调控和生物标志物潜力。实验设计：在80例非恶性和281例前列腺癌组织样本中定量GABRE/miR-452/miR-224转录表达。通过甲基化特异性qPCR（MethyLight）在35例非恶性前列腺癌、293例前列腺癌[根治性前列腺切除术（RP）队列1]和198例前列腺癌组织样本（RP队列2）中测定了与miR-452相似的GABRE和与miR-224相似的启动子甲基化。通过ROC、Kaplan-Meier、单因素和多因素考克斯回归分析评估GABRE类似于miR-452类似于miR-224甲基化的诊断/预后生物标志物潜力。通过活力、迁移和侵袭测定以及转染后转录谱数据的基因集富集分析（GSEA），研究了miR-224和miR-452在PC 3和DU 145细胞中的功能作用。结果：与非恶性前列腺组织相比，GABRE与miR-452和miR-224相似，在前列腺癌中显著下调，并且具有高度的癌相关性。特异性异常启动子超甲基化（AUC = 0.98）。功能研究和GSEA表明，miR-224和miR-452通过直接/间接调节与细胞周期和细胞粘附和运动相关的途径来抑制PC 3和DU 145细胞的增殖、迁移和侵袭。最后，在单因素和多因素分析中，类似于miR-452类似于miR-224启动子甲基化的高GABRE与RP队列1中的生化复发显著相关，这在RP队列2中得到了成功验证。GABRE类似于miR-452类似于miR-452，224位点在前列腺癌中下调和高甲基化，是一个新的有希望的前列腺癌诊断和预后的表观遗传学候选生物标志物。内含子miR-224和miR-452的肿瘤抑制功能在两种前列腺癌细胞系中得到证实，表明GABRE的表观遗传沉默类似于miR-452，类似于miR-224，可以在前列腺癌中选择。(C)2014年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 similar to miR-452 similar to 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 similar to miR-452 similar to 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 similar to miR-452 similar to 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 similar to miR-452 similar to 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 similar to miR-452 similar to 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 similar to miR-452 similar to 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 similar to miR-452 similar to miR-224 may be selected for in prostate cancer. (C) 2014 AACR.