Differential expression of miRNA involved in biological processes responsible for inflammation and immune response in Lichen Sclerosus Urethral Stricture Disease
Harjivan S. Kohli, MD1, Brandon Childs, MD1, Travis B. Sullivan, MS1, Artem Shevtsov, MD2, Eric Burks, MD2, Thomas Kalantzakos, BS1, Kimberly Rieger-Christ, PhD1, Alex J. Vanni, MD1.
1Lahey Hospital & Medical Center, Burlington, MA, USA, 2Boston University School of Medicine, Boston, MA, USA.
BACKGROUND: The pathophysiology of Lichen Sclerosus (LS) urethral stricture disease (USD) is poorly understood. MicroRNA (miRNA) are non-coding genetic material involved in the regulation of gene expression. We sought to examine the pathophysiology of LS and non-LS USD by comparing miRNA expression profiles in men undergoing urethroplasty.
METHODS: Total RNA was extracted from formalin-fixed, paraffin-embedded tissue samples from 13 LS urethral strictures and 13 non-LS urethral strictures collected from 2005-2017. The pathologic evaluation of strictures were based on histologic features considered diagnostic of LS. Representative portions of the FFPE block containing diagnostic areas foci of LS or non-LS strictures were selected by the pathologist for molecular evaluation. Each of these samples was profiled via miRNA RT-qPCR arrays for 752 unique miRNA. Statistical analyses were performed using SPSS v25. Gene Ontology (GO) analysis was performed using DIANA-mirPath v. 3.0.
RESULTS: There were no significant differences regarding patient age, BMI, smoking history, or medical comorbidities between the LS vs non-LS groups. Of the 143 miRNA detected for all samples, 27 were differentially expressed between the groups (false discovery p-value <0.01). 15 of these miRNA each achieved an area under the curve (AUC)>0.90 for discriminating between LS and non-LS strictures. MiR-155-5p specifically was found to be upregulated by 11 fold in LS vs. non-LS strictures (p<0.001, AUC=1.0).
To our knowledge this is a novel investigation into the pathophysiology of LS USD; no existing studies have evaluated the miRNA expression profiles in LS and non-LS USD. We have identified 18 distinct miRNA that differentiate USD caused by LS vs other etiologies. The top eight differentially expressed miRNA have been linked to immune response processes as well as involvement in wound healing, primarily angiogenesis and fibrosis. Our models demonstrate excellent predictive value for distinguishing LS vs non-LS USD samples and the differentially expressed miRNA identified in this study could potentially serve as biomarkers of LS.
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