Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis.
Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis.
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DOI：
10.1186/s12894-021-00934-0
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发表时间：
2021-12-07
期刊：
影响因子：
2
通讯作者：
Monastyrskaya K
中科院分区：
文献类型：
--
作者：
Gheinani AH;Akshay A;Besic M;Kuhn A;Keller I;Bruggmann R;Rehrauer H;Adam RM;Burkhard FC;Monastyrskaya K
间质性膀胱炎或膀胱疼痛综合征（IC/BPS）是一种慢性膀胱疾病，其特征是与膀胱相关的下腹疼痛，并伴有尿频和尿急，但无可识别的原因。IC/PBS可以分为经典的Hunner溃疡型和更普遍的非溃疡性疾病。我们的目的是通过研究非溃疡性膀胱疼痛综合征（BPS）患者活检组织中基因表达的变化，揭示导致膀胱重塑的生物学过程和失调的细胞信号通路。 我们使用全面的下一代测序（NGS）对具有非Hunner间质性膀胱炎表型的BPS患者的膀胱活检组织进行配对microRNA（miRNA）和mRNA表达谱分析，并基于全局基因表达变化研究激活的途径和改变的生物学过程。配对mRNA-miRNA转录组分析通过鉴定其在疾病诱导途径中的靶点来描绘失调的miRNA的调节作用。EIF 2信号传导和eIF 4和p70 S6 K信号传导的调节，响应于细胞应激而被激活，是BPS期间最重要的调节过程之一。在炎症性疾病和神经病理性疼痛中起重要作用的白三烯生物合成伤害性通路也被显著激活。使用基因本体过度表示分析识别的生物过程被聚类为六个主要功能组：细胞周期调节、免疫细胞的趋化性、肌肉发育、肌肉收缩、细胞外基质的重塑和周围神经系统的组织和发育。与Hunner溃疡型IC相比，非溃疡性BPS中免疫途径的激活是适度的，仅限于中性粒细胞趋化性和IFN-γ介导的信号传导。我们鉴定了62种在BPS中受调控且丰富的miRNA，并表明它们靶向与eIF 2信号通路有关的mRNA。在本研究中招募的非溃疡性BPS患者的膀胱具有与强烈的细胞增殖反应和平滑肌收缩性上调一致的改变，而炎症过程的贡献是适度的。整合的mRNA-miRNA NGS数据集的通路分析确定了重要的调节性miRNA，其失调可能有助于发病机制。观察到的周围神经系统组织和发育的分子变化表明局部膀胱神经支配在这种类型的BPS中感知到的疼痛中的潜在作用。在线版本包含补充材料，可通过10.1186/s12894-021-00934-0获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s12894-021-00934-0.
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影响因子：
4.6
作者：
Gheinani AH;Vögeli M;Baumgartner U;Vassella E;Draeger A;Burkhard FC;Monastyrskaya K
通讯作者：
Monastyrskaya K
DOI：
10.1111/iju.14229
发表时间：
2020-06
期刊：
International journal of urology : official journal of the Japanese Urological Association
影响因子：
--
作者：
Akiyama Y;Luo Y;Hanno PM;Maeda D;Homma Y
通讯作者：
Homma Y
影响因子：
6.6
作者：
Clemens, JQ;Meenan, RT;Calhoun, EA
通讯作者：
Calhoun, EA
影响因子：
6.6
作者：
Regauer, Sigrid;Gamper, Marianne;Viereck, Volker
通讯作者：
Viereck, Volker
影响因子：
23.4
作者：
Offiah I;Didangelos A;Dawes J;Cartwright R;Khullar V;Bradbury EJ;O'Sullivan S;Williams D;Chessell IP;Pallas K;Graham G;O'Reilly BA;McMahon SB
通讯作者：
McMahon SB