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 2

Differentially expressed mRNAs and miRNAs in BOO-induced LUTD patients.

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Differentially expressed mRNAs and miRNAs in BOO-induced LUTD patients. ...
(A) Hierarchical clustering and heatmap of log2 fold change of 2,634 significantly regulated mRNAs (y axis) in 24 patients (x axis). (B) Hierarchical clustering of 343 significantly regulated miRNAs (y axis) and 24 samples (x axis). Hierarchical clustering of mRNAs and miRNAs revealed high expression profile similarity between DO and controls, whereas BO is similar to UA. (C) miRNA-mRNA tanglegram. Unique nodes, with a combination of patients not present in the other tree, are highlighted with dashed lines. Entanglement has the score of 0.05, indicating a very high similarity between the dendrograms of both mRNA and miRNA samples. (D) Principal component analysis of mRNA and miRNA expression was done based on profiles of 10,064 mRNAs (top) and 343 miRNAs (bottom) for each group (6 patients per group). The position of patients from each group on 3D plots indicates the similarity of mRNA or miRNA expression patterns. PCA confirms the sample clustering shown in the heatmaps, with controls clustered with DO and BO clustered with UA. The intergroup dispersity is low, indicating sample homogeneity. C, controls; DO, obstructed patients with detrusor overactivity; BO, obstructed patients without detrusor overactivity; UA, obstructed patients with underactive bladders.