Identification and Validation of Potential miRNAs, as Biomarkers for Sepsis and Associated Lung Injury: A Network-Based Approach

Abstract

Sepsis is a dysregulated immune response disease affecting millions worldwide. Delayed diagnosis, poor prognosis, and disease heterogeneity make its treatment ineffective. miRNAs are imposingly involved in personalized medicine such as therapeutics, due to their high sensitivity and accuracy. Our study aimed to reveal the biomarkers that may be involved in the dysregulated immune response in sepsis and lung injury using a computational approach and in vivo validation studies. A sepsis miRNA Gene Expression Omnibus (GEO) dataset based on the former analysis of blood samples was used to identify differentially expressed miRNAs (DEMs) and associated hub genes. Sepsis-associated genes from the Comparative Toxicogenomics Database (CTD) that overlapped with identified DEM targets were utilized for network construction. In total, 317 genes were found to be regulated by 10 DEMs (three upregulated, namely miR-4634, miR-4638-5p, and miR-4769-5p, and seven downregulated, namely miR-4299, miR-451a, miR181a-2-3p, miR-16-5p, miR-5704, miR-144-3p, and miR-1290). Overall hub genes (HIP1, GJC1, MDM4, IL6R, and ERC1) and for miR-16-5p (SYNRG, TNRC6B, and LAMTOR3) were identified based on centrality measures (degree, betweenness, and closeness). In vivo validation of miRNAs in lung tissue showed significantly downregulated expression of miR-16-5p corroborating with our computational findings, whereas expression of miR-181a-2-3p and miR-451a were found to be upregulated in contrast to the computational approach. In conclusion, the differential expression pattern of miRNAs and hub genes reported in this study may help to unravel many unexplored regulatory pathways, leading to the identification of critical molecular targets for increased prognosis, diagnosis, and drug efficacy in sepsis and associated organ injuries.

Identification and Validation of Pathogenic Genes in Sepsis and Associated Diseases by Integrated Bioinformatics Approach

“…Significantly enriched levels of miR-181a, miR-92a , and miR-424 in the blood of ARDS patients may serve as diagnostic markers, and were found to be closely associated with inflammation and epithelial cell injury [ 58 ]. In numerous sepsis-associated organ injuries, such as those to the lungs, kidneys, and other organs, miRNAs play an important role in cellular signaling, which then regulates the immune response and molecular pathological outcomes [ 59 , 60 ]. Additional studies revealed a significant decrease in the levels of miR-124 in the serum of SLE patients [ 61 ] and an upregulation of miRNA-21 and miR-214 in CRS and CKD patients, respectively [ 26 , 62 ].…”

Analysis of miRNA Profiles and the Regulatory Network in Congenital Pulmonary Airway Malformations

“…Much progress has been made in identifying components of the regulatory networks that control lung morphogenesis, including transcription factors, receptors, and miRNAs. miRNAs are endogenous noncoding RNAs with regulatory functions that have shown effects in various lung diseases, such as lung cancer and COPD ( 25 , 26 ). An increasing number of miRNAs are emerging as potential biomarkers for the diagnosis and treatment of lung diseases.…”

An Insight into miR-1290: An Oncogenic miRNA with Diagnostic Potential

“…The study of Adyshev et al suggested that miR-1290 may reduce lung inflammation through targeting nonmuscle myosin light-chain kinase that decreases lung endothelium permeability [116]. Additionally, bioinformatics analysis identified miR-1290 in the set of miRNAs downregulated in serum from sepsis patients [117]. Moreover, it was revealed that the sponging of miR-1290 by hsa_circ_0056558 is involved in the regulation of CDK6 to suppress cell proliferation and differentiation while enhancing apoptosis in ankylosing spondylitis [118].…”