Prevalence of inflammatory bowel disease has been on the rise in recent years, especially in pediatric populations. This study aimed to provide precise identification and stratification of pediatric patients with diagnosed ulcerative colitis (UC) according to the severity of their condition and the prediction for standard treatment according to the specific expression of candidate miRNAs. We enrolled consecutive, therapeutically naïve, pediatric UC patients with confirmed pancolitis. We examined formalin-fixed paraffin-embedded specimens of colonic tissue for the expression of 10 selected candidate miRNAs. We performed receiver operating characteristic curve analysis, using area under the curve and a logistic regression model to evaluate the diagnostic and predictive power of the miRNA panels. Sixty patients were included in the final analysis. As a control group, 18 children without macroscopic and microscopic signs of inflammatory bowel disease were examined. The combination of three candidate miRNAs (let-7i-5p, miR-223-3p and miR-4284) enabled accurate detection of pediatric UC patients and controls. A panel of four candidate miRNAs (miR-375-3p, miR-146a-5p, miR-223-3p and miR-200b-3p) was associated with severity of UC in pediatric patients and a combination of three miRNAs (miR-21-5p, miR-192-5p and miR-194-5p) was associated with early relapse of the disease. Nine patients out of the total were diagnosed with primary sclerosing cholangitis (PSC) simultaneously with ulcerative colitis. A panel of 6 candidate miRNAs (miR-142-3p, miR-146a-5p, miR-223-3p, let-7i-5p, miR-192-5p and miR-194-5p) identified those patients with PSC. Specific combinations of miRNAs are promising tools for potential use in precise disease identification and severity and prognostic stratification in pediatric patients with ulcerative pancolitis.

Central European Institute of Technology Masaryk University 625 00 Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

Department of Gastroenterology and Internal Medicine University Hospital Brno Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of Hope Comprehensive Cancer Center Duarte CA 91010 USA

Department of Pediatrics University Hospital Brno Faculty of Medicine Masaryk University 613 00 Brno Czech Republic

Department of Surgery University Hospital Brno Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

Zobrazit více v PubMed

Sartor R.B. Mechanisms of disease: Pathogenesis of Crohn’s disease and ulcerative colitis. Nat. Clin. Pract. Gastroenterol. Hepatol. 2006;3:390–407. doi: 10.1038/ncpgasthep0528. PubMed DOI

Cao B., Zhou X., Ma J., Zhou W., Yang W., Fan D., Hong L. Role of MiRNAs in inflammatory bowel disease. Dig. Dis. Sci. 2017;62:1426–1438. doi: 10.1007/s10620-017-4567-1. PubMed DOI

Wu C.P., Bi Y.J., Liu D.-M., Wang L.-Y. Hsa-miR-375 promotes the progression of inflammatory bowel disease by upregulating TLR4. Eur. Rev. Med. Pharmacol. Sci. 2019;23:7543–7549. PubMed

Rosen M.J., Karns R., Vallance J.E., Bezold R., Waddell A., Collins M.H., Haberman Y., Minar P., Baldassano R.N., Hyams J.S., et al. Mucosal expression of type 2 and Type 17 immune response genes distinguishes ulcerative colitis from colon-only Crohn’s disease in treatment-naive pediatric patients. Gastroenterology. 2017;152:1345–1357.e7. doi: 10.1053/j.gastro.2017.01.016. PubMed DOI PMC

Laborda T.J., Jensen M.K., Kavan M., Deneau M. Treatment of primary sclerosing cholangitis in children. World J. Hepatol. 2019;11:19–36. doi: 10.4254/wjh.v11.i1.19. PubMed DOI PMC

Jabandziev P., Pinkasova T., Kunovsky L., Papez J., Jouza M., Karlinova B., Novackova M., Urik M., Aulicka S., Slaby O., et al. Regional incidence of inflammatory bowel disease in a Czech pediatric population: 16 years of experience (2002–2017) J. Pediatr. Gastroenterol. Nutr. 2020;70:586–592. doi: 10.1097/MPG.0000000000002660. PubMed DOI PMC

Sýkora J., Pomahačová R., Kreslová M., Cvalínová D., Štych P., Schwarz J. Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J. Gastroenterol. 2018;24:2741–2763. doi: 10.3748/wjg.v24.i25.2741. PubMed DOI PMC

Kelsen J., Baldassano R.N. Inflammatory bowel disease: The difference between children and adults. Inflamm. Bowel Dis. 2008;14:S9–S11. doi: 10.1097/00054725-200810001-00005. PubMed DOI

Turunen P., Ashorn M., Auvinen A., Iltanen S., Huhtala H., Kolho K.-L. Long-term health outcomes in pediatric inflammatory bowel disease: A population-based study. Inflamm. Bowel Dis. 2009;15:56–62. doi: 10.1002/ibd.20558. PubMed DOI

Guariso G., Gasparetto M. Treating children with inflammatory bowel disease: Current and new perspectives. World J. Gastroenterol. 2017;23:5469–5485. doi: 10.3748/wjg.v23.i30.5469. PubMed DOI PMC

Naviglio S., Lacorte D., Lucafò M., Cifù A., Favretto D., Cuzzoni E., Silvestri T., Mucelli M.P., Radillo O., Decorti G., et al. Causes of treatment failure in children with inflammatory bowel disease treated with infliximab: A pharmacokinetic study. J. Pediatr. Gastroenterol. Nutr. 2019;68:37–44. doi: 10.1097/MPG.0000000000002112. PubMed DOI

Jabandziev P., Bohosova J., Pinkasova T., Kunovsky L., Slaby O., Goel A. The emerging role of noncoding RNAs in pediatric inflammatory bowel disease. Inflamm. Bowel Dis. 2020;26:985–993. doi: 10.1093/ibd/izaa009. PubMed DOI PMC

IBD Working Group of the European Society for Paediatric Gastroenterology HpaN Inflammatory bowel disease in children and adolescents: Recommendations for diagnosis—The Porto criteria. J. Pediatr. Gastroenterol. Nutr. 2005;41:1–7. doi: 10.1097/01.MPG.0000163736.30261.82. PubMed DOI

Levine A., Koletzko S., Turner D., Escher J.C., Cucchiara S., de Ridder L., Kolho K.-L., Veres G., Russell R.K., Paerregaard A., et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J. Pediatr. Gastroenterol. Nutr. 2014;58:795–806. doi: 10.1097/MPG.0000000000000239. PubMed DOI

Levine A., Griffiths A., Markowitz J., Wilson D.C., Turner D., Russell R.K., Fell J., Ruemmele F.M., Walters T., Sherlock M., et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: The Paris classification. Inflamm. Bowel Dis. 2011;17:1314–1321. doi: 10.1002/ibd.21493. PubMed DOI

Turner D., Hyams J., Markowitz J., Lerer T., Mack D.R., Evans J., Pfefferkorn M., Rosh J., Kay M., Crandall W., et al. Appraisal of the pediatric ulcerative colitis activity index (PUCAI) Inflamm. Bowel Dis. 2009;15:1218–1223. doi: 10.1002/ibd.20867. PubMed DOI

Bronský J., Beránková K., Černá Z., Čopová I., Durilová M., Hradský O., Karásková E., Mitrová K., Nevoral J., Poš L., et al. Czech Working Group for Paediatric Gastroenterology and Nutrition guidelines for diagnostics and treatment of inflammatory bowel diseases in children—1st edition update. Gastroenterol. Hepatol. 2017;71:11–18. doi: 10.14735/amgh201711. DOI

Zahm A.M., Hand N.J., Tsoucas D.M., Le Guen C.L., Baldassano R.N., Friedman J.R. Rectal microRNAs are perturbed in pediatric inflammatory bowel disease of the colon. J. Crohns Colitis. 2014;8:1108–1117. doi: 10.1016/j.crohns.2014.02.012. PubMed DOI PMC

Béres N.J., Szabó D., Kocsis D., Szűcs D., Kiss Z., Müller K.E., Lendvai G.A., Kiss A., Arató A., Sziksz E., et al. Role of altered expression of miR-146a, miR-155, and miR-122 in pediatric patients with inflammatory bowel disease. Inflamm. Bowel Dis. 2016;22:327–335. doi: 10.1097/MIB.0000000000000687. PubMed DOI

Béres N.J., Kiss Z., Sztupinszki Z., Lendvai G., Arató A., Sziksz E., Vannay Á., Szabó A.J., Müller K.E., Cseh Á., et al. Altered mucosal expression of microRNAs in pediatric patients with inflammatory bowel disease. Dig. Liver Dis. 2017;49:378–387. doi: 10.1016/j.dld.2016.12.022. PubMed DOI

Leon-Cabrera S., Vázquez-Sandoval A., Molina-Guzman E., Delgado-Ramirez Y., Delgado-Buenrostro N.L., Callejas B.E., Chirino Y.I., Pérez-Plasencia C., Rodríguez-Sosa M., Olguín J.E., et al. Deficiency in STAT1 signaling predisposes gut inflammation and prompts colorectal cancer development. Cancers. 2018;10:341. doi: 10.3390/cancers10090341. PubMed DOI PMC

Giles E.M., Sanders T.J., McCarthy N.E., Lung J., Pathak M., Macdonald T.T., Lindsay J.O., Stagg A.J. Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease. Mucosal Immunol. 2017;10:184–193. doi: 10.1038/mi.2016.44. PubMed DOI

Giroud M., Karbiener M., Pisani D.F., Ghandour R.A., Beranger G.E., Niemi T., Taittonen M., Nuutila P., Virtanen K.A., Langin D., et al. Let-7i-5p represses brite adipocyte function in mice and humans. Sci. Rep. 2016;6:28613. doi: 10.1038/srep28613. PubMed DOI PMC

Chen Y., Zhang L. Members of the microRNA-200 family are promising therapeutic targets in cancer. Exp. Ther. Med. 2017;14:10–17. doi: 10.3892/etm.2017.4488. PubMed DOI PMC

Lewis A., Felice C., Kumagai T., Lai C., Singh K., Jeffery R.R., Feakins R., Giannoulatou E., Armuzzi A., Jawad N., et al. The miR-200 family is increased in dysplastic lesions in ulcerative colitis patients. PLoS ONE. 2017;12:e0173664. doi: 10.1371/journal.pone.0173664. PubMed DOI PMC

Wang S., Huang Y., Zhou C., Wu H., Zhao J., Wu L., Zhao M., Zhang F., Liu H. The role of autophagy and related MicroRNAs in inflammatory bowel disease. Gastroenterol. Res. Pract. 2018;2018:1–10. doi: 10.1155/2018/7565076. PubMed DOI PMC

Duijvis N.W., Moerland P.D., Kunne C., Slaman M.M.W., Van Dooren F.H., Vogels E.W., De Jonge W.J., Meijer S.L., Fluiter K., Velde A.A.T. Inhibition of miR-142-5P ameliorates disease in mouse models of experimental colitis. PLoS ONE. 2017;12:e0185097. doi: 10.1371/journal.pone.0185097. PubMed DOI PMC

Lu Y., Gao J., Zhang S., Gu J., Lu H., Xia Y., Zhu Q., Qian X., Zhang F., Zhang C., et al. miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg) Cell Death Dis. 2018;9:1–10. doi: 10.1038/s41419-018-0298-2. PubMed DOI PMC

Qian M., Fang X., Wang X. Autophagy and inflammation. Clin. Transl. Med. 2017;6:24. doi: 10.1186/s40169-017-0154-5. PubMed DOI PMC

Sonkoly E., Ståhle M., Pivarcsi A. MicroRNAs and immunity: Novel players in the regulation of normal immune function and inflammation. Semin. Cancer Biol. 2008;18:131–140. doi: 10.1016/j.semcancer.2008.01.005. PubMed DOI

Lin J., Zhang X., Zhao Z., Welker N.C., Li Y., Liu Y., Bronner M.B. Novel MicroRNA signature to differentiate ulcerative colitis from Crohn disease: A genome-wide study using next generation sequencing. Microrna. 2016;5:222–229. doi: 10.2174/2211536605666161117113031. PubMed DOI

Sheedy F.J. Turning 21: Induction of miR-21 as a key switch in the inflammatory response. Front. Immunol. 2015;6:19. doi: 10.3389/fimmu.2015.00019. PubMed DOI PMC

Ludwig K., Fassan M., Mescoli C., Pizzi M., Balistreri M., Albertoni L., Pucciarelli S., Scarpa M., Sturniolo G.C., Angriman I., et al. PDCD4/miR-21 dysregulation in inflammatory bowel disease-associated carcinogenesis. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 2013;462:57–63. doi: 10.1007/s00428-012-1345-5. PubMed DOI

Persson T., Monsef N., Andersson P., Bjartell A., Malm J., Calafat J., Egesten A. Expression of the neutrophil-activating CXC chemokine ENA-78/CXCL5 by human eosinophils. Clin. Exp. Allergy. 2003;33:531–537. doi: 10.1046/j.1365-2222.2003.01609.x. PubMed DOI

Koukos G., Polytarchou C., Kaplan J.L., Oikonomopoulos A., Ziring D., Hommes D.W., Wahed R., Kokkotou E., Pothoulakis C., Winter H.S., et al. A microRNA signature in pediatric ulcerative colitis: Deregulation of the miR-4284/CXCL5 pathway in the intestinal epithelium. Inflamm. Bowel Dis. 2015;21:996–1005. doi: 10.1097/MIB.0000000000000339. PubMed DOI PMC

Zhang R., Liu Q., Peng J., Wang M., Li T., Liu J., Cui M., Zhang X., Gao X., Liao Q., et al. CXCL5 overexpression predicts a poor prognosis in pancreatic ductal adenocarcinoma and is correlated with immune cell infiltration. J. Cancer. 2020;11:2371–2381. doi: 10.7150/jca.40517. PubMed DOI PMC

Tenca A., Jaakkola T., Färkkilä M., Arola J., Kolho K.-L. Impact of paediatric onset primary sclerosing cholangitis on clinical course and outcome of inflammatory bowel disease: A case-control population-based study in Finland. Scand. J. Gastroenterol. 2019;54:984–990. doi: 10.1080/00365521.2019.1648547. PubMed DOI

Dyson J.K., Beuers U., Jones D.E.J., Lohse A.W., Hudson M. Primary sclerosing cholangitis. Lancet. 2018;391:2547–2559. doi: 10.1016/S0140-6736(18)30300-3. PubMed DOI

lncRNA PVT1 in the Pathogenesis and Clinical Management of Renal Cell Carcinoma