Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction
Ali Hashemi Gheinani, … , Fiona C. Burkhard, Katia Monastyrskaya
Ali Hashemi Gheinani, … , Fiona C. Burkhard, Katia Monastyrskaya
Published January 26, 2017
Citation Information: JCI Insight. 2017;2(2):e89560. https://doi.org/10.1172/jci.insight.89560.
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Research Article Aging Muscle biology

Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction

Abstract

Bladder outlet obstruction (BOO) induces significant organ remodeling, leading to lower urinary tract symptoms accompanied by urodynamic changes in bladder function. Here, we report mRNA and miRNA transcriptome sequencing of bladder samples from human patients with different urodynamically defined states of BOO. Patients’ miRNA and mRNA expression profiles correlated with urodynamic findings. Validation of RNA sequencing results in an independent patient cohort identified combinations of 3 mRNAs (NRXN3, BMP7, UPK1A) and 3 miRNAs (miR-103a-3p, miR-10a-5p, miR-199a-3p) sufficient to discriminate between bladder functional states. All BOO patients shared cytokine and immune response pathways, TGF-β and NO signaling pathways, and hypertrophic PI3K/AKT signaling pathways. AP-1 and NFkB were dominant transcription factors, and TNF-α was the top upstream regulator. Integrated miRNA-mRNA expression analysis identified pathways and molecules targeted by differentially expressed miRNAs. Molecular changes in BOO suggest an increasing involvement of miRNAs in the control of bladder function from the overactive to underactive/acontractile states.

Authors

Ali Hashemi Gheinani, Bernhard Kiss, Felix Moltzahn, Irene Keller, Rémy Bruggmann, Hubert Rehrauer, Catharine Aquino Fournier, Fiona C. Burkhard, Katia Monastyrskaya

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Figure 6

Testing the 3-mRNA and 3-miRNA bladder dysfunction signatures in a blinded study.

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Testing the 3-mRNA and 3-miRNA bladder dysfunction signatures in a blind...
(A) Analysis of NRXN3, BMP7, and UPK1A mRNA expression in BOO patients of unknown urodynamic status and controls. Hierarchical clustering and heatmap of normalized Ct values of 3 signature mRNAs (y axis) in 40 patients and 11 controls (x axis). (B) Analysis of hsa-miR-103a-3p, hsa-miR-10a-5p, and hsa-miR-199a-3p miRNA expression in BOO patients. Hierarchical clustering and heatmap of normalized Ct values of 3 candidate miRNAs (y axis) in 38 BOO patients and 11 controls (x axis). Clustering of the miRNA results was similar to mRNA results, clearly separating controls from BOO patients. Using machine-based learning algorithms, the samples were allocated to phenotypic groups, represented by box border colors: green for DO (BOO with detrusor overactivity), blue for BO (BOO without detrusor overactivity), and orange for UA (underactive bladders) phenotypes. (C) 3D scatter plots for 3 mRNA biomarkers. Log2 fold change values of NRXN3, BMP7, and UPK1A mRNAs in bladder biopsies of 40 patients with unknown BOO states are plotted. Concentration ellipsoids are drawn to show the 3 patients groups (DO in green, BO in blue, and UA in orange). (D) 3D scatter plots and point identification for 3 miRNA biomarkers. Log2 fold change values of hsa-miR-103a-3p, hsa-miR-10a-5p, and hsa-miR-199a-3p miRNAs in bladder biopsies of 40 patients of unknown states of BOO are plotted. Ellipsoids are colored in green for DO-, blue for BO-, and orange for UA-allocated patients.