Signaling Enrichment Pathway Analysis of Targetome of microRNAs Whose Expression Are Changed in Natalizumab-treated Multiple Sclerosis Patients

Background and Aim: Multiple sclerosis (MS), one of the most enigmatic multi-component diseases whose etiology is not yet conclusively known, is a leading cause of neurological disability. Huge heterogeneity has been attributed to the MS such as genetical, phenotypical and most importantly response to therapy. Natalizumab (NTZ), approved as second-line therapy for MS patients, is thought to bind to the α۴ integrins on T lymphocytes, consequently prevents lymphocyte trafficking across the brain endothelial cell. Although this inhibitory mode of action of NTZ is accepted, additional hitherto unknown mechanisms that could probably take part in the therapeutic effect of NTZ is exist. The increasing body of evidence indicates changes in the transcriptome profile of NTZ-treated patients, especially in microRNAs (miRNAs) as key regulators of gene expression at post-transcriptional level. Therefore, the aim of the present study was to conduct an enrichment pathway analysis on the targets of miRNAs, whose expression are altered in patients undergoing NTZ treatment to delineate potential signaling pathways that are recruited by NTZ.Methods: Through literature review, I extracted all of the previously reported miRNAs whose changed expression after NTZ therapy were confirmed by quantitative real-time PCR (qRT-PCR). These miRNAs include miR-۱۹b, miR-۱۰۶b, miR-۳۲۶, miR-۱۸a, miR-۲۹a, miR-۲۰b, let-۷c, miR-۱۲۵a-۵p, miR-۶۴۲, miR-۱۲۶, miR-۱۷, miR-۱۵۵, miR-۲۶a, miR-۱۵۰ and, miR-۱۰b. miRTarBase and miRWalk۲.۰ databases were employed to obtain validated and predicted targetome of these miRNAs. Then the targets of each miRNA were inputted separately into the DAVID database. Afterward, enriched signaling pathways outcomes from the Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed.Results: The top five pathways that enriched by tragetome of these miRNAs were foxo signaling pathway (taretome of ۱۳ miRNAs), PI۳K-Akt signaling pathway (taretome of ۱۲ miRNAs), MAPK signaling pathway (taretome of ۱۰ miRNAs), HIF-۱ signaling pathway (taretome of ۱۰ miRNAs), and TGF-beta signaling pathway (taretome of ۹ miRNAs).Conclusion: All of the enriched pathways are involved in different phases of MS, either inflammation or neurodegeneration, hence these pathways are potentially contribute to the therapeutic effect of NTZ. Further experiments are warranted to delineate and confirm the role of these pathways, providing a focused insight into the mechanism of action of NTZ.

کلیدواژه ها:

Multiple sclerosis ، microRNA ، Natalizumab