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 8

Pathway analysis in all BOO patients and identification of 22 key signaling pathways.

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Pathway analysis in all BOO patients and identification of 22 key signal...
We investigated mRNAs and miRNAs differentially expressed in all bladder outlet obstruction (BOO) patients (n = 18) compared with controls (n = 6) and performed gene enrichment analysis using mRNAs and the expressed targets of 12 abundant miRNAs. (A) The word clouds show frequent pathway elements in the mRNA data set of all BOO patients and pathway elements targeted by abundant BOO miRNAs. Many signaling hubs in BOO are potentially miRNA regulated. (B) The radar graph for biological functions of significant (P < 0.05) BOO mRNA data set pathways (orange) and pathways built using expressed BOO miRNA targets (brown). The miRNA-controlled processes contribute to fewer biological functions. (C) Venn diagram of common regulated pathways (mRNA data sets, P < 0.05) in 3 patient groups (DO, BO, and UA) intersecting with the all BOO patient group; 22 common pathways are indicated. (D) Heatmap and clustering based on Z score of 22 common pathways. Z scores of the common pathways in all BOO patients resemble the scores in the BO group. (E) Radar graph for the biological functions of 22 common pathways of all BOO patients. The word cloud shows top pathway elements, and font size indicates the frequency of occurrence. Cellular growth, proliferation and development, and cytokine signaling were the main biological functions shared by all groups. (F) Hierarchical view of upstream analysis mechanistic network made of transcription factors and cytokines in 22 common pathways (mRNAs) of all BOO patients. TNF is the top upstream regulator, connected to 63 downstream elements, including NFkB, JUN, and MYC. C, controls; DO, obstructed patients with detrusor overactivity; BO, obstructed patients without detrusor overactivity; UA, obstructed patients with underactive bladders.