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Int. J. Mol. Sci. 2017, 18(2), 391; doi:10.3390/ijms18020391

Identification of Autophagy-Related Genes and Their Regulatory miRNAs Associated with Celiac Disease in Children

1
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
2
Pediatrics and Adolescentology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS San Matteo, 27100 Pavia, Italy
3
Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Fondazione IRCCS San Matteo, 27100 Pavia, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Kumiko UI-TEI
Received: 2 December 2016 / Revised: 27 January 2017 / Accepted: 6 February 2017 / Published: 12 February 2017
(This article belongs to the Special Issue microRNA Regulation 2017)
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Abstract

Celiac disease (CD) is a severe genetic autoimmune disorder, affecting about one in 100 people, where the ingestion of gluten leads to damage in the small intestine. Diagnosing CD is quite complex and requires blood tests and intestinal biopsy examinations. Controversy exists regarding making the diagnosis without biopsy, due to the large spectrum of manifesting symptoms; furthermore, small-intestinal gastroscopy examinations have a relatively complex management in the pediatric population. To identify novel molecular markers useful to increase the sensitivity and specificity in the diagnosis of pediatric CD patients, the expression levels of two key autophagy executor genes (ATG7 and BECN1) and their regulatory validated miRNAs (miR-17 and miR-30a, respectively) were analyzed by relative quantitative real-time-PCR on a cohort of confirmed CD patients compared to age-related controls. Among the investigated targets, the non-parametric Mann–Whitney U test and ROC analysis indicated the highest significant association of BECN1 with CD status in the blood, while in intestinal biopsies, all of the investigated sequences were positively associated with CD diagnosis. Nomogram-based analysis showed nearly opposite expression trends in blood compared to intestine tissue, while hierarchical clustering dendrograms enabled identifying CD and control subgroups based on specific genes and miRNA expression signatures. Next, using an established in vitro approach, through digested gliadin administration in Caco-2 cells, we also highlighted that the modulation of miR-17 endogenous levels using enriched exosomes increased the intracellular autophagosome content, thereby altering the autophagic status. Altogether, these results highlighted novel molecular markers that might be useful to increase the accuracy in CD diagnosis and in molecular-based stratification of the patients, further reinforcing the functional involvement of the regulation of the autophagy process within a digestive and autoimmune-related disorder as CD. View Full-Text
Keywords: microRNA; autophagy; celiac disease molecular markers microRNA; autophagy; celiac disease molecular markers
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MDPI and ACS Style

Comincini, S.; Manai, F.; Meazza, C.; Pagani, S.; Martinelli, C.; Pasqua, N.; Pelizzo, G.; Biggiogera, M.; Bozzola, M. Identification of Autophagy-Related Genes and Their Regulatory miRNAs Associated with Celiac Disease in Children. Int. J. Mol. Sci. 2017, 18, 391.

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