Differential expression of miRNAs involved in biological processes responsible for inflammation and immune response in lichen sclerosus urethral stricture disease

Abstract

Purpose To better understand the pathophysiology of lichen sclerosus (LS) urethral stricture disease (USD), we aimed to investigate expression profiles of microRNAs (miRNAs) in tissue samples from men undergoing urethroplasty. Methods Urethral stricture tissue was collected from 2005–2020. Histologic features diagnostic of LS were the basis of pathologic evaluation. Foci of areas diagnostic for LS or non-LS strictures were chosen for RNA evaluation. In an initial screening analysis, 13 LS urethral strictures and 13 non-LS strictures were profiled via miRNA RT-qPCR arrays for 752 unique miRNA. A validation analysis of 23 additional samples (9 LS and 14 non-LS) was performed for 15 miRNAs. Statistical analyses were performed using SPSS v25. Gene Ontology (GO) analysis was performed using DIANA-mirPath v. 3.0. Results In the screening analysis 143 miRNAs were detected for all samples. 27 were differentially expressed between the groups (false discovery p-value <0.01). 15 of these miRNAs individually demonstrated an area under the curve (AUC)>0.90 for distinguishing between between LS and non-LS strictures. 11-fold upregulation of MiR-155-5p specifically was found in LS vs. non-LS strictures (p<0.001, AUC = 1.0). In the validation analysis, 13 of the 15 miRNAs tested were confirmed to have differential expression (false discovery p-value <0.10). Conclusions To our knowledge this is the first study evaluating miRNA expression profiles in LS and non-LS USD. We identified several miRNAs that are differentially expressed in USD caused by LS vs other etiologies, which could potentially serve as biomarkers of LS USD. The top eight differentially expressed miRNAs have been linked to immune response processes as well as involvement in wound healing, primarily angiogenesis and fibrosis.

Deep Phenotyping the Anterior Urethral Stricture: Characterizing the Relationship Between Inflammation, Fibrosis, Patient History, and Disease Pathophysiology

“…As has been suggested by others, this pattern of focal fibrosis amongst a more widespread, organ-specific inflammatory effect, potentially implicates immune modulation rather than trauma as the cause. [16][17][18][19][20] The association of aUSD with systemic inflammation was evaluated in Aim 3 of the study, which hypothesized that higher levels of circulating inflammatory cytokines would be found in patients with inflammatory strictures, drawing upon previous studies that showed an association between systemic inflammatory conditions (eg, metabolic syndrome, diabetes) and inflammatory aUSD. 17 Cytokines are small proteins secreted by immune cells and the epithelium and are important in cell signaling.…”

“…As has been suggested by others, this pattern of focal fibrosis amongst a more widespread, organ-specific inflammatory effect, potentially implicates immune modulation rather than trauma as the cause. 16-20…”