Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction
Ali Hashemi Gheinani, Bernhard Kiss, Felix Moltzahn, Irene Keller, Rémy Bruggmann, Hubert Rehrauer, Catharine Aquino Fournier, Fiona C. Burkhard, Katia Monastyrskaya
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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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 4

ROC curve analyses of mRNA and miRNA signatures to discriminate BOO patient groups.

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ROC curve analyses of mRNA and miRNA signatures to discriminate BOO pati...
(A) The ROC curves were calculated for individual mRNAs using NGS data. The area under the curve is calculated with 95% confidence interval. The data were validated by QPCR (n = 49 samples), and box-and-whisker plots for the response variables in the mRNA PCR data set classified by groups are shown. The results are shown as log2 fold change range, and the distribution of data are shown based on minimum, first quartile, median, third quartile, and maximum. (B) ROC curves for selected miRNAs. Area under ROC curve (AUC) for each marker is indicated. Box-and-whisker plots of QPCR validation (n = 28 samples) results are shown. The results are shown as log2 fold change range, and the distribution of data are shown based on minimum, first quartile, median, third quartile, and maximum. Neurexin 3 (NRXN3) and miR-103a-3p are regulated specifically in DO patients; bone morphogenetic protein 7 (BMP7) and miR-199a-3p are characteristic of UA patients; miR-10a-5p is specifically upregulated in the BO group; and uroplakin 1A (UPK1A) is shared between BO and UA groups. DO, obstructed patients with detrusor overactivity; BO, obstructed patients without detrusor overactivity; UA, obstructed patients with underactive bladders.