Integrated miRNA and mRNA expression profiling reveals dysregulated miRNA‐mRNA regulatory networks in eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps

Abstract

Background: The precise mechanisms underlying pathogenesis of different subtypes of chronic rhinosinusitis with nasal polyps (CRSwNP) are still unclear.Emerging evidence indicates that microRNAs may play a role in the pathogenesis of CRSwNP. This study aimed to identify the dysregulated microRNA-messenger RNA (miRNA-mRNA) regulatory networks in eosinophilic (E) and noneosinophilic (non-E) CRSwNP. Methods: Whole-transcriptome sequencing was performed on nasal tissues of patients with ECRSwNP and non-ECRSwNP, and control subjects. An integrated analysis of miRNA and mRNA expression was conducted to identify key mRNAs and miRNAs involved in the pathogenesis of ECRSwNP and non-ECRSwNP. The miRNAs of interest and their target genes were validated using quantitative realtime polymerase chain reaction (PCR). Results: A group of differentially expressed mRNAs (DE-mRNAs) and miR-NAs (DE-miRs) were identified in ECRSwNP patients vs control subjects, non-ECRSwNP patients vs control subjects, and non-ECRSwNP vs ECRSwNP patients, respectively. Pathway enrichment analysis showed distinct immune and inflammatory functions associated with DE-mRNAs and target genes of DE-miRs in ECRSwNP vs control and non-ECRSwNP vs control groups. The miRNA-mRNA regulatory networks constructed with Cytoscape highlighted the roles of miR-154, miR-221, and miR-223 family miRNAs relating to both ECRSwNP and non-ECRSwNP, and the roles of the let-7 and miR-34/449 families in the development of non-ECRSwNP. Assessment using real-time PCR for the expression of miRNAs and target genes demonstrated highly consistent data with the RNA sequencing data. Conclusion: ECRSwNP and non-ECRSwNP patients express distinct miRNA-mRNA regulatory networks compared with control subjects, thus providing

Immunomodulatory properties of mesenchymal stem cells: A potential therapeutic strategy for allergic rhinitis

“…Moreover, miR‐125b‐5p, miR‐100‐5p, miR‐182, miR‐22, miR‐146a‐5p, and miR‐206 have been reported to be highly enriched in MSC‐derived exosomes/EVs 151–154 . Among them, miR‐146a‐5p, miR‐125b‐5p, and miR‐223 are associated with the regulation of type 2 inflammation in the nasal mucosa 155–160 . Further, miR‐146a‐5p has been reported to ameliorate allergic airway inflammation by targeting various genes in different cells.…”

Epigenetic modifications in chronic rhinosinusitis with and without nasal polyps

“…miR-221 is also upregulated in CRSwNP and may be directly implicated in cell cycle, apoptosis, and inflammation ( Bu et al, 2021 ; Silveira et al, 2021 ). Bu et al (2021) have found the expression of miR-449a is higher in non-ECRSwNP samples, compared with that in ECRSwNP samples and healthy controls, and this change involves adenosine monophosphate-activated protein kinase (AMPK), Rap1, and the ErbB-signaling pathway, all regulators in neutrophil activity and neutrophilic inflammation. Meanwhile, Silveira et al (2021) have also reported a higher level of miR-449a in CRSwNP group, compared with that in control group.…”

“…In addition, miR-146a ( Xia et al, 2015 ), miR-614 ( Shin et al, 2020 ), and some other DE-miRs are also upregulated in CRS samples, highly through the pathway of mucin-type O-glycan biosynthesis ( Cha et al, 2021 ). Meanwhile, miR-3178, miR-585-3p, miR-3146, miR-320e, miR-142-3p, miR-154, miR-223, miR-205-5p, miR-222-3p, miR-378a-3p, miR-449b-5p, miR-22-3p, miR-21, miR-203a-3p, miR-677, miR-1037, and miR-79 are also overexpressed in CRSwNP samples ( Li et al, 2019c ; Xuan et al, 2019 ; Zhang et al, 2020b ; Bu et al, 2021 ; Qing et al, 2021 ; Silveira et al, 2021 ; He et al, 2022 ; Morawska-Kochman et al, 2022 ). Among them, miR-142-3p may regulate the inflammatory response through the lipopolysaccharide (LPS)-Toll-like receptor (TLR)-tumor necrosis factor-α (TNF-α) signaling pathway ( Qing et al, 2021 ); miR-3146 and miR-320e act in the mucin type O-glycan biosynthesis pathway in CRSwNP by targeting N-acetylgalactosaminyltransferase-like 6 (GALNTL6), N-acetylgalactosaminyltransferase 8 (GALNT8), and alpha-2,3-sialyltransferase 1 (ST3GAL1) genes ( Xuan et al, 2019 ); miR-223 plays in the mitogen-activated protein kinase (MAPK) signaling pathway ( Bu et al, 2021 ); miR-22-3p inhibits vascular endothelial (VE)-cadherin expression to regulate vascular permeability after binding to the specific site in the 3′-UTR of the human VE-cadherin mRNA ( Zhang et al, 2020b ); the TGF-β1-miR-21-PTEN-Akt axis may propel the EMT of CRSwNP ( Li et al, 2019c ); miR-677, miR-1037, and miR-79 may post-transcriptionally regulate gene expression in the Hippo signaling pathway ( He et al, 2022 ).…”

“…Different miRNAs have been observed in different subtypes of CRSwNP. For instance, let-7 and miR-34 are upregulated in non-ECRSwNP ( Bu et al, 2021 ), but miR-205-5p was overexpressed in ECRSwNP ( Silveira et al, 2021 ). Besides, the level of miR-205-5p is positively correlated with IL-5 concentration and eosinophil count in the NPs, and the patients with a higher miR-205-5p level always have a lower favorable 22-item Sino-Nasal Outcome Test (SNOT-22) score and less clinical presentations ( Silveira et al, 2021 ).…”

“…For example, some studies have reported that miR-125b is upregulated ( Zhang et al, 2012 ; Zhang et al, 2014 ; Ma et al, 2015 ; Xia et al, 2015 ), but Xuan et al (2019) have found that miR-125b-2-3p is downregulated. One shows that let-7 is overexpressed in non-ECRSwNP ( Bu et al, 2021 ), while another shows that let-7a-5p is significantly downregulated via the Ras-MAPK pathway in CRSwNP ( Zhang et al, 2021 ). Another controversy is about miR-146a in CRS and CRSwNP, a miRNA that has been proven either upregulated ( Xia et al, 2015 ) or downregulated ( Yan et al, 2020 ; Yu et al, 2021b ).…”