Abstract
Background
Early-stage symptomology of necrotizing enterocolitis (NEC) is similar in presentation
to non-NEC sepsis, though the treatment plans differ based on antibiotic administration
and withholding of feeds. Improved diagnostics for NEC differentiation would allow
clinicians to more rapidly set individual patients on a targeted treatment path. Extracellular
vesicle-derived miRNAs, have previously demonstrated efficacy as disease biomarkers.
To determine if these miRNAs are differentially-expressed in NEC infants, we performed
transcriptomic analysis of urine-derived extracellular vesicle-derived miRNAs.
Methods
Urine was non-invasively obtained from infants in one of four groups (n ≥ 8) (Medical NEC, Surgical NEC, non-NEC sepsis, and healthy age-matched controls).
EV-derived miRNAs were isolated and transcriptomic analysis was performed.
Results
Multiple miRNAs, including miR-376a, miR-518a-3p and miR-604, were significantly altered
when comparing NEC to non-NEC sepsis and healthy controls, and could potentially be
used as specific NEC biomarkers. Additionally, Ingenuity Pathway Analysis demonstrated
that miRs differentially-expressed in NEC were associated with inflammatory disease
and intestinal disease. Signal transduction molecules associated with NEC including
TP53 and RPS15, which were also reduced transcriptionally in a rat model of NEC.
Conclusion
These data indicate that there is a pool of potential urine EV-derived miRNAs that
may be validated as NEC biomarkers in the differentiation of NEC from non-NEC sepsis
and from age-matched controls. Additionally, signal transduction molecules associated
with miRNAs differentially-expressed in human NEC are altered in a murine model of
NEC, suggesting potential crossover between murine models of the disease and actual
human presentation.
Level of Evidence
Level III Study of Diagnostic Test.
Keywords
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References
- Mortality of necrotizing enterocolitis expressed by birth weight categories.J Pediatr Surg. 2009; 44 (discussion 5-6): 1072-1075
- Necrotizing Enterocolitis.Pediatr Rev. 2017; 38: 552-559
- British association of paediatric surgeons congenital anomalies surveillance system necrotising enterocolitis c. one-year outcomes following surgery for necrotising enterocolitis: a UK-wide cohort study.Arch Dis Child Fetal Neonatal Ed. 2018; 103: F461-F466
- Biomarkers for the diagnosis of neonatal sepsis and necrotizing enterocolitis: clinical practice guidelines.Early Hum Dev. 2017; 105: 25-33
- Extracellular vesicles: exosomes, microvesicles, and friends.J Cell Biol. 2013; 200: 373-383
- Mechanisms and functions of extracellular vesicle release in vivo- what we can learn from flies and worms.Cell Adh Migr. 2017; 11: 135-150
- Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood.J Extracell Vesicles. 2014; 3
- Extracellular vesicles as circulating cancer biomarkers: opportunities and challenges.Clin Transl Med. 2018; 7: 14
- Comparison of small extracellular vesicles isolated from plasma by ultracentrifugation or size-exclusion chromatography: yield, purity and functional potential.J Extracell Vesicles. 2019; 81560809
- Identification and proteomic profiling of exosomes in human urine.Proc Natl Acad Sci U.S.A. 2004; 101: 13368-13373
- Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake.Cell Mol Neurobiol. 2016; 36: 301-312
- Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model.Stem Cells Transl Med. 2016; 5: 1620-1630
- Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury.Stem Cell Res. 2013; 10: 301-312
- Exosomal micrornas in milk from mothers delivering preterm infants survive in vitro digestion and are taken up by human intestinal cells.Mol Nutr Food Res. 2018; 62e1701050
- Human milk exosomes and their microRNAs survive digestion in vitro and are taken up by human intestinal cells.Mol Nutr Food Res. 2017; 61
- High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources.J Extracell Vesicles. 2016; 5: 32570
- Exosomal microRNA signatures in multiple sclerosis reflect disease status.Sci Rep. 2017; 7: 14293
- Serum exosome microRNA as a minimally-invasive early biomarker of AML.Sci Rep. 2015; 5: 11295
- miR-31-5p is a potential circulating biomarker and therapeutic target for oral cancer.Mol Ther Nucleic Acids. 2019; 16: 471-480
- Circulating exosomal microRNAs as biomarkers of colon cancer.PLoS ONE. 2014; 9: e92921
- Exosomal microRNA: a diagnostic marker for lung cancer.Clin Lung Cancer. 2009; 10: 42-46
- MicroRNAs direct rapid deadenylation of mRNA.Proc Natl Acad Sci U S A. 2006; 103: 4034-4039
- Comparative MiRNA expressional profiles and molecular networks in human small bowel tissues of necrotizing enterocolitis and spontaneous intestinal perforation.PLoS ONE. 2015; 10e0135737
- Inhibition of nuclear factor-kappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis.Pediatr Res. 2007; 61: 716-721
- Blocking NF-kappaB activation in Ly6c(+) monocytes attenuates necrotizing enterocolitis.Am J Pathol. 2019; 189: 604-618
- Expression of TLR-2, TLR-4, NOD2 and pNF-kappaB in a neonatal rat model of necrotizing enterocolitis.PLoS ONE. 2007; 2: e1102
- Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis.J Clin Invest. 2016; 126: 495-508
- Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation.Nat Commun. 2016; 7: 10872
- Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365.Exp Cell Res. 2018; 362: 386-393
- miR-200-containing extracellular vesicles promote breast cancer cell metastasis.J Clin Invest. 2014; 124: 5109-5128
- Cutadapt removes adapter sequences from high-throughput sequencing reads.EMBnet J. 2011; 17: 10
- from microRNA sequences to function.Nucleic Acids Res. 2019; 47: D155-D162
- annotating high confidence microRNAs using deep sequencing data.Nucleic Acids Res. 2014; 42 (Database issue): D68-D73
- Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.Genome Biol. 2009; 10: R25
- Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.Genome Biol. 2014; 15: 550
- Causal analysis approaches in Ingenuity Pathway Analysis.Bioinformatics. 2014; 30: 523-530
- Treatment of experimental necrotizing enterocolitis with stem cell-derived exosomes.J Pediatr Surg. 2018; 53: 1215-1220
- An enhanced Lactobacillus reuteri biofilm formulation that increases protection against experimental necrotizing enterocolitis.Am J Physiol Gastrointest Liver Physiol. 2018; 315: G408-G419
- Transcriptional cross talk between NF-kappaB and p53.Mol Cell Biol. 1999; 19: 3485-3495
- Inflammation and p53: a tale of two stresses.Genes Cancer. 2011; 2: 503-516
- Ribosomal proteins RPL37, RPS15 and RPS20 regulate the Mdm2-p53-MdmX network.PLoS ONE. 2013; 8: e68667
- Tumor-suppressor functions of the TP53 pathway.Cold Spring Harb Perspect Med. 2016; 6
- Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.Nature. 1992; 356: 215-221
- Discordant regulation of microRNA between multiple experimental models and human pulmonary hypertension.Chest. 2015; 148: 481-490
- Association of polymorphism in microRNA 604 with susceptibility to persistent hepatitis B virus infection and development of hepatocellular carcinoma.J Korean Med Sci. 2014; 29: 1523-1527
- Role of Host miRNA Hsa-miR-139-3p in HPV-16-induced carcinomas.Clin Cancer Res. 2017; 23: 3884-3895
- Differences in circulating microRNA signature in Prader-Willi syndrome and non-syndromic obesity.Endocr Connect. 2018; 7: 1262-1274
- Overexpression of miR-31-5p inhibits human chordoma cells proliferation and invasion by targeting the oncogene c-Met through suppression of AKT/PI3K signaling pathway.Int J Clin Exp Pathol. 2017; 10: 8000-8009
- Increased expression of microRNA-31-5p inhibits cell proliferation, migration, and invasion via regulating Sp1 transcription factor in HepG2 hepatocellular carcinoma cell line.Biochem Biophys Res Commun. 2017; 490: 371-377
- HOXA11-AS promotes the progression of oral squamous cell carcinoma by targeting the miR-518a-3p/PDK1 axis.Cancer Cell Int. 2019; 19: 140
- Surgical necrotizing enterocolitis.Semin Perinatol. 2017; 41: 70-79
- MicroRNA expression profiles across blood and different tissues in cattle.Sci Data. 2019; 6190013
- Tissue-specific expression patterns of MicroRNA during acute graft-versus-host disease in the rat.Front Immunol. 2016; 7: 361
Article info
Publication history
Published online: March 02, 2021
Accepted:
February 10,
2021
Received in revised form:
January 28,
2021
Received:
October 7,
2020
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
