High miR-449b expression in prostate cancer is associated with biochemical recurrence after radical prostatectomy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE62610 | GEO | 2014/10/23
SECONDARY ACCESSION(S): PRJNA264534
REPOSITORIES: GEO
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Project description:Purpose: Available tools for prostate cancer (PC) 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 non-malignant and 281 PC tissue samples. GABRE promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 non-malignant, 293 PC (radical prostatectomy (RP) cohort 1) and 198 PC tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE 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 post-transfection transcriptional profiling data. Results: GABRE~miR-452~miR-224 was significantly downregulated in PC compared to non-malignant 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 motility. Finally, in uni- and multivariate analyses, high GABRE 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 PC and is a new promising epigenetic candidate biomarker for PC diagnosis and prognosis. Tumor suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two PC cell lines, suggesting that epigenetic silencing of GABRE~miR-452~miR-224 may be selected for in PC.
2013-12-11 | GSE51053 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE26022: [Gene Expression Training Set] Protein-coding and MicroRNA Biomarkers of Recurrence of Prostate Cancer Following Radical Prostatectomy GSE26242: [Gene Expression Validation Set] Protein-coding and MicroRNA Biomarkers of Recurrence of Prostate Cancer Following Radical Prostatectomy GSE26245: [miRNA Training Set] Protein-coding and MicroRNA Biomarkers of Recurrence of Prostate Cancer Following Radical Prostatectomy GSE26247: [miRNA Validation Set] Protein-coding and MicroRNA Biomarkers of Recurrence of Prostate Cancer Following Radical Prostatectomy Refer to individual Series
2011-06-01 | E-GEOD-26367 | biostudies-arrayexpress
Project description:Purpose: Available tools for prostate cancer (PC) 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 non-malignant and 281 PC tissue samples. GABRE promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 non-malignant, 293 PC (radical prostatectomy (RP) cohort 1) and 198 PC tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE 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 post-transfection transcriptional profiling data. Results: GABRE~miR-452~miR-224 was significantly downregulated in PC compared to non-malignant 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 motility. Finally, in uni- and multivariate analyses, high GABRE 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 PC and is a new promising epigenetic candidate biomarker for PC diagnosis and prognosis. Tumor suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two PC cell lines, suggesting that epigenetic silencing of GABRE~miR-452~miR-224 may be selected for in PC. Affymetrix GeneChip Human Gene 1.0 ST Arrays were used for whole-genome transcriptional profiling of DU145 and PC3 cells at 48 hours post-transfection with either miR-224, miR-452, or scrambled miRNA mimics, or untransfected. All experiments were performed in duplicate. Transcript expression levels were determined after RMA16 normalization in GeneSpringGX 11.0 software (Agilent). PC3 and DU145 arrays were normalized separately. DU145 48 t Scr2a were excluded from the study because of bad performance of this microarray.
2013-12-11 | E-GEOD-51053 | biostudies-arrayexpress
Project description:The objective of this study was to utilize a microarray platform to determine the microRNA (miRNA) expression profile in prostate cancer tissue from patients who underwent radical prostatectomy and were followed for an average of 47 months. The GeneChipM-BM-. miRNA Array (Affymetrix) contains more than 46,000 probes, and more than 1,100 mature human miRNAs and transcripts. An expression level higher or lower than 1.1 with a p<0.05 were considered to be differentially expressed. When tumors with a GS<7 were compared with those with a GSM-bM-^IM-%7, five miRNAs were down-regulated and nine were up-regulated. In comparing tumors from patients with PSA <10 ng/mL vs. those with PSA M-bM-^IM-%10 ng/mL, 21 miRNAs were down-regulated and 29 were overexpressed. There was decreased expression of 21 miRNAs and increased expression of 22 miRNAs when pT2 and pT3 tumors were compared. The comparison of the expression profiles of men with vs. without recurrent disease (PSA>0.2 ng/mL) revealed that 14 miRNAs were down-regulated and 17 were up-regulated. Considering the three prognostic factors and biochemical recurrence, miR-335 was overexpressed in pT3 tumors in patients with PSA>10 ng/mL, miR-1202 was overexpressed in recurrent tumors in which PSA >10 ng/mL, and miR-885 and miR-1226 were overexpressed in recurrent pT3 tumors. Six miRNAs (miR- 361, 378, 548, 574, 652 and 892) had decreased expression in pT3 tumors in patients with PSA >10 ng/mL. miR-16 was down-regulated in recurrent pT3 tumors. miR-92 and miR-450 exhibited decreased expression in recurrent tumors in patients with PSA > 10 ng/mL. miR-28 was down-regulated in pT3 adenocarcinomas with a GS M-bM-^IM-% 7. The differentially expressed miRNAs in recurrent tumors were validated using qRT-PCR in 74 additional specimens. miR-21 was overexpressed in recurrent tumors, and in the Cox model, expression levels higher than 0.64 were indicative of biochemical recurrence with a risk of 2.4. These results, which were based on clinical specimens from patients treated in a standardized way and followed for an average of 47 months, provide an initial understanding of the role of miRNAs in prostatecancer progression; the foremost representative is miR-21, which has been implicated in the progression of various human cancers. Fifty-three patients underwent a radical prostatectomy performed by the same surgeon (MS) to treat localized PC between August 2000 and June 2002. The mean age was 65 years (SD: 7.5, range: 49 - 77). The mean Gleason score was 7 (SD: 1.1, range: 5 - 10); 15 tumors had a score of 5 or 6, and 38 had a score between 7 and 10. Twenty-four (45.3%) of the patients had pT2 tumors, and 29 (54.7%) had pT3 tumors. The control group consisted of three patients with lower urinary tract symptoms, a mean age of 55.3 years and a diagnosis of benign prostatic hyperplasia (BPH) who consented to open surgery.
2013-05-09 | E-GEOD-46738 | biostudies-arrayexpress
Project description:The objective of this study was to utilize a microarray platform to determine the microRNA (miRNA) expression profile in prostate cancer tissue from patients who underwent radical prostatectomy and were followed for an average of 47 months. The GeneChip® miRNA Array (Affymetrix) contains more than 46,000 probes, and more than 1,100 mature human miRNAs and transcripts. An expression level higher or lower than 1.1 with a p<0.05 were considered to be differentially expressed. When tumors with a GS<7 were compared with those with a GS≥7, five miRNAs were down-regulated and nine were up-regulated. In comparing tumors from patients with PSA <10 ng/mL vs. those with PSA ≥10 ng/mL, 21 miRNAs were down-regulated and 29 were overexpressed. There was decreased expression of 21 miRNAs and increased expression of 22 miRNAs when pT2 and pT3 tumors were compared. The comparison of the expression profiles of men with vs. without recurrent disease (PSA>0.2 ng/mL) revealed that 14 miRNAs were down-regulated and 17 were up-regulated. Considering the three prognostic factors and biochemical recurrence, miR-335 was overexpressed in pT3 tumors in patients with PSA>10 ng/mL, miR-1202 was overexpressed in recurrent tumors in which PSA >10 ng/mL, and miR-885 and miR-1226 were overexpressed in recurrent pT3 tumors. Six miRNAs (miR- 361, 378, 548, 574, 652 and 892) had decreased expression in pT3 tumors in patients with PSA >10 ng/mL. miR-16 was down-regulated in recurrent pT3 tumors. miR-92 and miR-450 exhibited decreased expression in recurrent tumors in patients with PSA > 10 ng/mL. miR-28 was down-regulated in pT3 adenocarcinomas with a GS ≥ 7. The differentially expressed miRNAs in recurrent tumors were validated using qRT-PCR in 74 additional specimens. miR-21 was overexpressed in recurrent tumors, and in the Cox model, expression levels higher than 0.64 were indicative of biochemical recurrence with a risk of 2.4. These results, which were based on clinical specimens from patients treated in a standardized way and followed for an average of 47 months, provide an initial understanding of the role of miRNAs in prostatecancer progression; the foremost representative is miR-21, which has been implicated in the progression of various human cancers.
2013-05-09 | GSE46738 | GEO
Project description:To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed paraffin-embedded (FFPE) radical prostatectomy specimens with known long term outcome to perform DASL expression profiling with a custom-designed panel of 522 prostate cancer relevant genes that we designed. We identified a panel of ten protein-coding genes and two miRNA genes that could be used to separate patients with and without biochemical recurrence (p < 0.001), as well as for the subset of 42 Gleason score 7 patients (p < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of recurrence for all cases (p = 0.013) and for a subset of 19 Gleason score 7 cases (p = 0.010), both of which were adjusted for relevant clinical information including T-stage, PSA and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.
2011-06-01 | GSE26245 | GEO
Project description:To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed paraffin-embedded (FFPE) radical prostatectomy specimens with known long term outcome to perform DASL expression profiling with a custom-designed panel of 522 prostate cancer relevant genes that we designed. We identified a panel of ten protein-coding genes and two miRNA genes that could be used to separate patients with and without biochemical recurrence (p < 0.001), as well as for the subset of 42 Gleason score 7 patients (p < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of recurrence for all cases (p = 0.013) and for a subset of 19 Gleason score 7 cases (p = 0.010), both of which were adjusted for relevant clinical information including T-stage, PSA and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.
2011-06-01 | GSE26247 | GEO
Project description:Radical prostatectomy remains one of the more widely-used treatment options for men with prostate cancer. However, few molecular biomarkers have been established to predict patients who are at high risk of biochemical failure. To our knowledge, this is the first such report on miRNA profiling in radical prostatectomy tissue using Nanostring. In addition, this is the first report to look at the prognostic value of miRNAs in the setting of biochemical failure and salvage radiation therapy post-radical prostatectomy.
2015-01-23 | GSE65061 | GEO
Project description:To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed paraffin-embedded (FFPE) radical prostatectomy specimens with known long term outcome to perform DASL expression profiling with a custom-designed panel of 522 prostate cancer relevant genes that we designed. We identified a panel of ten protein-coding genes and two miRNA genes that could be used to separate patients with and without biochemical recurrence (p < 0.001), as well as for the subset of 42 Gleason score 7 patients (p < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of recurrence for all cases (p = 0.013) and for a subset of 19 Gleason score 7 cases (p = 0.010), both of which were adjusted for relevant clinical information including T-stage, PSA and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.
2011-06-01 | GSE26242 | GEO
Project description:To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed paraffin-embedded (FFPE) radical prostatectomy specimens with known long term outcome to perform DASL expression profiling with a custom-designed panel of 522 prostate cancer relevant genes that we designed. We identified a panel of ten protein-coding genes and two miRNA genes that could be used to separate patients with and without biochemical recurrence (p < 0.001), as well as for the subset of 42 Gleason score 7 patients (p < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of recurrence for all cases (p = 0.013) and for a subset of 19 Gleason score 7 cases (p = 0.010), both of which were adjusted for relevant clinical information including T-stage, PSA and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens.
2011-06-01 | GSE26022 | GEO