A Variant in the Precursor of MicroRNA-146a is Responsible for Development of Erectile Dysfunction in Patients with Chronic Prostatitis via Targeting NOS1

Abstract

BackgroundThe morbidity of erectile dysfunction (ED) has been found to be substantially increased in patients with chronic prostatitis (CP). Accumulating evidence shows that single-nucleotide polymorphism (SNP) located in pre-miRNA or mature microRNA may affect the processing of microRNA (miRNA) and alter the expression of the miRNA, as well as its target gene. In this study we investigated the association between rs2910164 G/C polymorphism and risk of ED in patients with CP, as well as the underlying molecular mechanism.Material/MethodsComputational analysis was used to search for the target of miR-146a, and the luciferase reporter assay system was used to validate NOS1 to be the target gene of miR-146a. We also treated PC-3 cells with miR-146a mimics/inhibitors to verify the negative regulatory relationship between miR-146a and NOS1, and real-time PCR and Western blot analysis were used to estimate the expression of the NOS1 mRNA and miR-146a.ResultsThe binding site of miR-146a was found to be located within the 3′-UTR of the NOS1 by searching an online miRNA database (www.mirdb.org), and luciferase reporter assay was done to confirm that NOS1 is a direct target gene of miR-146a. We also found that mRNA and protein expression level of NOS1 in PC-3 cells treated with miR-146a mimics and NOS1 siRNA was substantially down-regulated compared with scramble control, while cells treated with miR-146a inhibitors showed increased expression of NOS1. In addition, 705 people were recruited for our research – 342 CP patients with ED and 363 CP patients without ED – and we found that the presence of minor allele of rs2910164 polymorphism is significantly associated with reduced risk of ED in patients with CP.ConclusionsThe findings indicate a decreased risk of ED in patients with CP who are carriers of miR-146a rs2910164 C allele, and this association might be due to its ability to compromise the expression of miR-146a, and thereby increase the expression of its target gene, NOS1.

The effect of Jiedu Huoxue decoction on rat model of experimental nonbacterial prostatitis via regulation of miRNAs

“…It has been confirmed that nitric oxide synthase 1 (NOS1) is the target gene of miR-146a. By real-time PCR and Western blot analysis, it was found that the risk of erectile dysfunction in patients with CP who are carriers of miR-146a rs2910164 C allele was significantly decreased, which may be due to its ability to compromise the expression of miR-146a, and increase the expression of NOS1 (Ding et al 2017). miR-96 governs androgen signalling and prostate cancer progression by regulating RARc signal axis (Long et al 2019).…”

“…Although the number of miRNAs in the human genome is less than that of protein-coding genes, they are believed to regulate more than half of the human RNAs. miRNAs play an immunoregulatory role by regulating the expression of the immune regulatory genes, which is a new direction of immunology research in recent years (Ding et al 2017;.…”

MiR-181c inhibits prostatic epithelial cell proliferation caused by chronic non-bacterial prostatitis through downregulating COX-2

“…miRNAs can regulate gene expression through a complete or incomplete pairing of their seed sequences with the 3 'untranslated region (3'UTR) of their target genes, which can degrade the mRNA of target genes or suppress the translation of target genes [33,34]. For example, Ding et al [35] found that inhibiting miR-146a up-regulated NOS1, which reduced the incidence of erectile dysfunction in patients with CP. In addition, Wang et al [30] found that up-regulation of miR-141 regulated Keap/ Nrf2 signaling pathway, and reduced the expression of COX-2, the value of locomotion score, eye score, average inflammatory cell count, improving prostatitis.…”

Regulation of NOS expression in vascular diseases

“…The different 5'-UTRs of the multiple NOS1-mRNA isoforms (see above) are likely to regulate the translatability of these different NOS1 mRNAs [16]. Several miRNAs have been shown to directly [46][47][48][49][50][51] or indirectly [52] modulate human NOS1 expression.…”