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

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

doi:10.1172/jci.insight.89560

Cited by 36 publications

(69 citation statements)

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“…MAPK1, PIK3 subunits PIK3R3, PIK3R1, PIK3CA and PK3CB, ATM, KRAS, NRAS and FGR were involved in 70% of the regulated pathways (Additional file 2 : Figure S1b). Pathway analysis information was further interrogated using the IPA Biological Function Classification Database, which allows for the identification of biological functions affected by specific miRNAs [ 30 ]. Cellular immune response, cellular growth, proliferation and development are most likely processes affected by LY294002-regulated miRNAs (Additional file 2 : Figure S1c).…”

Section: Resultsmentioning

confidence: 99%

“…Hierarchical clustering and the associated heatmap for miRNA profiling data was generated with the function heatmap2 in the R package gplots or GENE-E R package [ 30 ]. We used pairwise correlation matrix between items based on Pearson correlation method.…”

Section: Methodsmentioning

confidence: 99%

“…In order to identify upstream regulators and causal network master regulators that can potentially create the changes in phosphorylation levels of the proteins in our phosphoproteomics dataset, Phosphorylation Core Analysis tool in IPA was used to predict the affected canonical pathways [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

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miR-19b enhances proliferation and apoptosis resistance via the EGFR signaling pathway by targeting PP2A and BIM in non-small cell lung cancer

et al. 2018

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BackgroundEpidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K/AKT, KRAS/ERK and JAK/STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non-small cell lung cancer (NSCLC). In addition, such EGFR mutations increase the susceptibility of patients with NSCLC to tyrosine kinase inhibitor (TKI) therapy, but treated patients will invariably relapse with resistant disease. A global understanding of underlying molecular mechanisms of EGFR signaling may improve the management of NSCLC patients.Methodsmicroarray analysis was performed to identify PI3K/AKT-regulated miRNAs. Phosphoproteomic analysis and cell based assays were performed using NSCLC cell lines lentivirally transduced with anti-miR or miR overexpressing constructs.ResultsHere, we show that 17 miRNAs including members of the miR-17~ 92 cluster are dysregulated following PI3K/AKT inhibition of EGFR mutant NSCLC cells. Bioinformatics analysis revealed that dysregulated miRNAs act in a concerted manner to enhance the activity of the EGFR signaling pathway. These findings were closely mirrored by attenuation of miR-17~ 92 family member miR-19b in NSCLC cell lines which resulted in reduced phosphorylation of ERK, AKT and STAT and effector proteins in EGFR mutant NSCLC cells. Consistent with this finding, cell cycle progression, clonogenic growth and migration were reduced and apoptosis was enhanced. Co-treatment of NSCLC cells with the tyrosine kinase inhibitor (TKI) gefitinib and anti-miR-19b construct reduced migration and clonogenic growth in a synergistic manner suggesting that EGFR and miR-19b act together to control oncogenic processes. Serine/threonine phosphatase PP2A subunit PPP2R5E and BCL2L11 encoding BIM were identified as major targets of miR-19b by target validation assays. Consistent with this finding, PP2A activity was strongly enhanced in NSCLC transduced with anti-miR-19b construct, but not in cells co-transduced with anti-miR-19b and shPPP2R5E, suggesting that PPP2R5E is a major constituent of the PP2A complex. Accordingly, enhanced proliferation by miR-19b was due to targeting PPP2R5E. In contrast, apoptosis resistance was mainly due to targeting BCL2L11.ConclusionOur results provide insight into the importance of targeting PPP2R5E and BCL2L11 by miR-19b in oncogenic processes of NSCLC. Attenuation of miR-19b expression could potentially be exploited in adjuvant therapy of EGFR mutant NSCLC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0781-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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miR-19b enhances proliferation and apoptosis resistance via the EGFR signaling pathway by targeting PP2A and BIM in non-small cell lung cancer

et al. 2018

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“…Gheinani et al investigated the regulatory role of microRNAs (miRNAs) in BOO‐induced lower urinary tract dysfunction (LUTD), performing an integrated analysis of miRNA and mRNA paired expression profiling in bladder biopsies of human patients using comprehensive next‐generation sequencing‐derived transcriptome data. Gheinani et al identified common and unique miRNAs and their mRNA targets characteristic of BOO‐induced LUTD and specific for urodynamically defined states of the disease, allowing systematic examination of the association between bladder function and the underlying activated biological processes (pathways and networks). Gheinani et al concluded that molecular changes in BOO suggest increasing involvement of miRNAs in the control of bladder function from the overactive to underactive or acontractile states.…”

Section: Resultsmentioning

confidence: 99%

“…Gheinani et al identified common and unique miRNAs and their mRNA targets characteristic of BOO‐induced LUTD and specific for urodynamically defined states of the disease, allowing systematic examination of the association between bladder function and the underlying activated biological processes (pathways and networks). Gheinani et al concluded that molecular changes in BOO suggest increasing involvement of miRNAs in the control of bladder function from the overactive to underactive or acontractile states.…”

Section: Resultsmentioning

confidence: 99%

Pathophysiological mechanisms in detrusor underactivity: Novel experimental findings

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Jesus

Marcelissen

et al. 2019

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Underactive bladder (UAB) is a multifactorial symptom complex often related to detrusor underactivity (DU). Although recognized as a common cause of lower urinary tract symptoms and with significant effects on quality of life, UAB/DU is largely underresearched. Herein, we review upto-date knowledge on the pathophysiological mechanisms of UAB/DU, with an emphasis on the relationship between UAB and bladder outlet obstruction (BOO). Original articles and reviews concerning UAB/DU were identified through a search of the PubMed/Medline and Scopus databases. DU can result from several pathological mechanisms, which can be categorized as idiopathic, neurogenic, myogenic, or functional. The main etiological factors of UAB/DU are aging, diabetes mellitus, neurogenic disorders, and BOO. Although conventional models focus primarily on efferent nerve and myogenic mechanisms, contemporary views highlight the importance of the afferent pathway. Specifically, recent findings in BOO showed that afferent dysfunction, such as altered expression of muscarinic and purinergic P2X 3 receptors or diminished urothelial ATP may play a role in the initial and reversible stages of DU, with potential diagnostic and therapeutic implications. K E Y W O R D S bladder outlet obstruction, detrusor underactivity, lower urinary tract symptoms, pathophysiology

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Genes interconnecting AMPK and TREM-1 and associated microRNAs in rotator cuff tendon injury

et al. 2018

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Fatty infiltration and inflammation delay the healing responses and raise major concerns in the therapeutic management of rotator cuff tendon injuries (RCTI). Our evaluations showed the upregulation of 'metabolic check point' AMPK and inflammatory molecule, TREM-1 from shoulder biceps tendons collected from RCTI subjects. However, the epigenetic regulation of these biomolecules by miRNAs is largely unknown and it is likely that a deeper understanding of the mechanism of action can have therapeutic potential for RCTI. Based on this background, we have evaluated the miRNAs from RCTI patients with fatty infiltration and inflammation (FI group) and compared with RCTI patients without fatty infiltration and inflammation (No-FI group). NetworkAnalyst was employed to evaluate the genes interconnecting AMPK and TREM-1 pathway, using PRKAA1 (AMPK), TREM-1, HIFlα, HMGB1 and AGER as input genes. The most relevant miRNAs were screened by considering the fold change below -7.5 and the number of target genes 10 and more which showed 13 miRNAs and 216 target genes. The exact role of these miRNAs in the fatty infiltration and inflammation associated with RCTI is still unknown and the understanding of biological activity of these miRNAs can pave ways to develop miRNA-based therapeutics in the management of RCTI.

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

Cited by 36 publications

References 60 publications

miR-19b enhances proliferation and apoptosis resistance via the EGFR signaling pathway by targeting PP2A and BIM in non-small cell lung cancer

miR-19b enhances proliferation and apoptosis resistance via the EGFR signaling pathway by targeting PP2A and BIM in non-small cell lung cancer

Pathophysiological mechanisms in detrusor underactivity: Novel experimental findings

Genes interconnecting AMPK and TREM-1 and associated microRNAs in rotator cuff tendon injury

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