Cargando…

Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis

BACKGROUND: Interstitial cystitis, or bladder pain syndrome (IC/BPS), is a chronic bladder disorder characterized by lower abdominal pain associated with the urinary bladder and accompanied by urinary frequency and urgency in the absence of identifiable causes. IC/PBS can be separated into the class...

Descripción completa

Detalles Bibliográficos
Autores principales: Gheinani, Ali Hashemi, Akshay, Akshay, Besic, Mustafa, Kuhn, Annette, Keller, Irene, Bruggmann, Rémy, Rehrauer, Hubert, Adam, Rosalyn M., Burkhard, Fiona C., Monastyrskaya, Katia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653529/
https://www.ncbi.nlm.nih.gov/pubmed/34876093
http://dx.doi.org/10.1186/s12894-021-00934-0
_version_ 1784611684240850944
author Gheinani, Ali Hashemi
Akshay, Akshay
Besic, Mustafa
Kuhn, Annette
Keller, Irene
Bruggmann, Rémy
Rehrauer, Hubert
Adam, Rosalyn M.
Burkhard, Fiona C.
Monastyrskaya, Katia
author_facet Gheinani, Ali Hashemi
Akshay, Akshay
Besic, Mustafa
Kuhn, Annette
Keller, Irene
Bruggmann, Rémy
Rehrauer, Hubert
Adam, Rosalyn M.
Burkhard, Fiona C.
Monastyrskaya, Katia
author_sort Gheinani, Ali Hashemi
collection PubMed
description BACKGROUND: Interstitial cystitis, or bladder pain syndrome (IC/BPS), is a chronic bladder disorder characterized by lower abdominal pain associated with the urinary bladder and accompanied by urinary frequency and urgency in the absence of identifiable causes. IC/PBS can be separated into the classic Hunner’s ulcerative type and the more prevalent non-ulcerative disease. Our aim was to unravel the biological processes and dysregulated cell signaling pathways leading to the bladder remodeling in non-ulcerative bladder pain syndrome (BPS) by studying the gene expression changes in the patients’ biopsies. METHODS: We performed paired microRNA (miRNA) and mRNA expression profiling in the bladder biopsies of BPS patients with non-Hunner interstitial cystitis phenotype, using comprehensive Next-generation sequencing (NGS) and studied the activated pathways and altered biological processes based on the global gene expression changes. Paired mRNA-miRNA transcriptome analysis delineated the regulatory role of the dysregulated miRNAs by identifying their targets in the disease-induced pathways. RESULTS: EIF2 Signaling and Regulation of eIF4 and p70S6K Signaling, activated in response to cellular stress, were among the most significantly regulated processes during BPS. Leukotriene Biosynthesis nociceptive pathway, important in inflammatory diseases and neuropathic pain, was also significantly activated. The biological processes identified using Gene Ontology over-representation analysis were clustered into six main functional groups: cell cycle regulation, chemotaxis of immune cells, muscle development, muscle contraction, remodeling of extracellular matrix and peripheral nervous system organization and development. Compared to the Hunner’s ulcerative type IC, activation of the immune pathways was modest in non-ulcerative BPS, limited to neutrophil chemotaxis and IFN-γ-mediated signaling. We identified 62 miRNAs, regulated and abundant in BPS and show that they target the mRNAs implicated in eIF2 signalling pathway. CONCLUSIONS: The bladders of non-ulcerative BPS patients recruited in this study had alterations consistent with a strong cell proliferative response and an up-regulation of smooth muscle contractility, while the contribution of inflammatory processes was modest. Pathway analysis of the integrated mRNA-miRNA NGS dataset pinpointed important regulatory miRNAs whose dysregulation might contribute to the pathogenesis. Observed molecular changes in the peripheral nervous system organization and development indicate the potential role of local bladder innervation in the pain perceived in this type of BPS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12894-021-00934-0.
format Online
Article
Text
id pubmed-8653529
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-86535292021-12-08 Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis Gheinani, Ali Hashemi Akshay, Akshay Besic, Mustafa Kuhn, Annette Keller, Irene Bruggmann, Rémy Rehrauer, Hubert Adam, Rosalyn M. Burkhard, Fiona C. Monastyrskaya, Katia BMC Urol Research BACKGROUND: Interstitial cystitis, or bladder pain syndrome (IC/BPS), is a chronic bladder disorder characterized by lower abdominal pain associated with the urinary bladder and accompanied by urinary frequency and urgency in the absence of identifiable causes. IC/PBS can be separated into the classic Hunner’s ulcerative type and the more prevalent non-ulcerative disease. Our aim was to unravel the biological processes and dysregulated cell signaling pathways leading to the bladder remodeling in non-ulcerative bladder pain syndrome (BPS) by studying the gene expression changes in the patients’ biopsies. METHODS: We performed paired microRNA (miRNA) and mRNA expression profiling in the bladder biopsies of BPS patients with non-Hunner interstitial cystitis phenotype, using comprehensive Next-generation sequencing (NGS) and studied the activated pathways and altered biological processes based on the global gene expression changes. Paired mRNA-miRNA transcriptome analysis delineated the regulatory role of the dysregulated miRNAs by identifying their targets in the disease-induced pathways. RESULTS: EIF2 Signaling and Regulation of eIF4 and p70S6K Signaling, activated in response to cellular stress, were among the most significantly regulated processes during BPS. Leukotriene Biosynthesis nociceptive pathway, important in inflammatory diseases and neuropathic pain, was also significantly activated. The biological processes identified using Gene Ontology over-representation analysis were clustered into six main functional groups: cell cycle regulation, chemotaxis of immune cells, muscle development, muscle contraction, remodeling of extracellular matrix and peripheral nervous system organization and development. Compared to the Hunner’s ulcerative type IC, activation of the immune pathways was modest in non-ulcerative BPS, limited to neutrophil chemotaxis and IFN-γ-mediated signaling. We identified 62 miRNAs, regulated and abundant in BPS and show that they target the mRNAs implicated in eIF2 signalling pathway. CONCLUSIONS: The bladders of non-ulcerative BPS patients recruited in this study had alterations consistent with a strong cell proliferative response and an up-regulation of smooth muscle contractility, while the contribution of inflammatory processes was modest. Pathway analysis of the integrated mRNA-miRNA NGS dataset pinpointed important regulatory miRNAs whose dysregulation might contribute to the pathogenesis. Observed molecular changes in the peripheral nervous system organization and development indicate the potential role of local bladder innervation in the pain perceived in this type of BPS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12894-021-00934-0. BioMed Central 2021-12-07 /pmc/articles/PMC8653529/ /pubmed/34876093 http://dx.doi.org/10.1186/s12894-021-00934-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Gheinani, Ali Hashemi
Akshay, Akshay
Besic, Mustafa
Kuhn, Annette
Keller, Irene
Bruggmann, Rémy
Rehrauer, Hubert
Adam, Rosalyn M.
Burkhard, Fiona C.
Monastyrskaya, Katia
Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis
title Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis
title_full Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis
title_fullStr Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis
title_full_unstemmed Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis
title_short Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis
title_sort integrated mrna-mirna transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653529/
https://www.ncbi.nlm.nih.gov/pubmed/34876093
http://dx.doi.org/10.1186/s12894-021-00934-0
work_keys_str_mv AT gheinanialihashemi integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT akshayakshay integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT besicmustafa integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT kuhnannette integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT kellerirene integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT bruggmannremy integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT rehrauerhubert integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT adamrosalynm integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT burkhardfionac integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis
AT monastyrskayakatia integratedmrnamirnatranscriptomeanalysisofbladderbiopsiesfrompatientswithbladderpainsyndromeidentifiessignalingalterationscontributingtothediseasepathogenesis