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 7

Gene enrichment analysis and pathway elements targeted by miRNAs in the DO, BO, and UA groups.

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Gene enrichment analysis and pathway elements targeted by miRNAs in the ...
(A) DO group. The word clouds show pathway elements in the mRNA data set and in the miRNA target data set. The radar graphs for biological functions of 40 mRNA data set pathways (yellow) and 35 expressed miRNA target pathways (red) in DO patients. In this group, there is little overlap between shown signaling hubs and miRNA-regulated signaling hubs; in addition, the miRNA-regulated pathways are assigned noticeably fewer biological functions. (B) BO group. The word clouds show pathway elements in the mRNA data set and in the expressed miRNA target data set. The biological functions of 95 mRNA data set pathways (violet) and 45 expressed miRNA target pathways (blue). Here, the top pathway elements from mRNA and expressed miRNA target data sets share important signaling molecules. Biological functions of 94 altered pathways are similar to those of 45 miRNA-regulated pathways, indicative of increasing involvement of BO miRNAs in the regulation of signaling. (C) UA group. The word clouds show pathway elements in the mRNA data set and the expressed miRNA target data set. The biological functions of 171 pathways based on the mRNA data set (brown) and 143 pathways based on the expressed miRNA target data set (khaki). The top regulatory elements from mRNA-based and expressed miRNA target-based pathways are highly similar in the UA group, and there is a considerable overlap in biological functions of mRNA-based and miRNA-regulated pathways. C, controls; DO, obstructed patients with detrusor overactivity; BO, obstructed patients without detrusor overactivity; UA, obstructed patients with underactive bladders.