Identification of Circulating MicroRNAs in Biliary Atresia by Next‐Generation Sequencing

Peng, Xiaofang; Yang, Lei; Liu, Haiying; Pang, Shuyin; Chen, Yi-Hao; Fu, Jie; Chen, Yi; Wang, Zhe; Zhang, Ruizhong; Zhu, Bing; Yu, Jian; Invernizzi, Pietro

doi:10.1097/mpg.0000000000001194

Cited by 26 publications

(18 citation statements)

References 34 publications

(38 reference statements)

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“…Peng et al [146] describe an elevated expression of miR-200a which forms part of the miR-200 cluster, confirming the finding previously reported by Zhan et al [144] in serum samples. As expected, an overexpression of miR-122-5p in plasma from BA patients was found when compared to healthy controls but not when compared to other cholestatic diseases, which suggest that miR-122 is in fact a marker of liver injury.…”

Section: Circulatory Mirnas As Biomarkers In Paediatric Liver Diseasesupporting

confidence: 79%

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Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease

Calvopina

Coleman

Lewindon

et al. 2016

IJMS

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MicroRNAs (miRNAs) are short non-coding RNAs involved in biological and pathological processes of every cell type, including liver cells. Transcribed from specific genes, miRNA precursors are processed in the cytoplasm into mature miRNAs and as part of the RNA-induced silencing complex (RISC) complex binds to messenger RNA (mRNA) by imperfect complementarity. This leads to the regulation of gene expression at a post-transcriptional level. The function of a number of different miRNAs in fibrogenesis associated with the progression of chronic liver disease has recently been elucidated. Furthermore, miRNAs have been shown to be both disease-and tissue-specific and are stable in the circulation, which has led to increasing investigation on their utility as biomarkers for the diagnosis of chronic liver diseases, including those in children. Here, we review the current knowledge on the biogenesis of microRNA, the mechanisms of translational repression and the use of miRNA as circulatory biomarkers in chronic paediatric liver diseases including cystic fibrosis associated liver disease, biliary atresia and viral hepatitis B.

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Section: Circulatory Mirnas As Biomarkers In Paediatric Liver Diseasesupporting

confidence: 79%

“…In fact, a recent study compared plasma miRNA profiles in children with BA [146] to healthy controls. The study consisted in of an initial “discovery” phase with nine BA patients and nine healthy controls pooled in groups of three.…”

Section: Circulatory Mirnas As Biomarkers In Paediatric Liver Diseasementioning

confidence: 99%

Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease

Calvopina

Coleman

Lewindon

et al. 2016

IJMS

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“…The most abundant miRNA in the liver is miR‐122, which accounts for more than half of the total hepatic miRNA content . Multiple studies have reported increased circulatory levels of miR‐122 in pediatric CLDs such as biliary atresia, CFLD, nonalcoholic fatty liver disease (NAFLD), and hepatitis B . Our study shows increased circulatory miR‐122 levels in children with CFLD when compared to both CFnoLD and healthy controls.…”

Section: Discussionmentioning

confidence: 54%

MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis

et al. 2018

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Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on nonspecific assessments, whereas liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase (AST) to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical, and imaging assessments as follows: CFLD (n = 44), CF patients with no evidence of liver disease (CFnoLD; n = 40), and healthy controls (n = 40). Serum miRNAs were analyzed using miRNA sequencing (miRNA-Seq). Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p, and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, whereas miR-142-3p and let-7g-5p were down-regulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p, and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an area under the receiver operating characteristics curve (AUROC) = 0.91 (sensitivity = 83%, specificity = 92%; P < 0.0001). Expression levels of serum miR-18a-5p were correlated with increasing hepatic fibrosis (HF) stage in CFLD (r = 0.56; P < 0.0001), showing good diagnostic accuracy for distinguishing severe (F3-F4) from mild/moderate fibrosis (F0-F2). A unit increase of miR-18a-5p showed a 7-fold increased odds of having severe fibrosis with an AUROC = 0.82 (sensitivity = 93%, specificity = 73%; P = 0.004), indicating its potential to predict fibrosis severity. Conclusion: We identified a distinct circulatory miRNA profile in pediatric CFLD with potential to accurately discriminate liver disease and fibrosis severity in children with CF.

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“…Interestingly, when we coupled serum MMP-7 with GGT in a composite model we obtained higher sensitivity and specificity of 97% and 94%, at optimal cut-off, which provided positive and negative predictive values of 85% and 99% if one considers the prevalence of BA of 25.9% among infants with conjugated hyperbilirubinemia (30). Other candidate biomarkers previously reported include miR-140-3p (31), miR-200b/429 (14), miR-4429, and miR-4689 (32), but with lower sensitivity (66–83%) and specificity (79–83%) and no prospective validation. In a separate study, the use of 2-dimensional gel electrophoresis with tandem mass spectrometry found a combination of 11 proteins as biomarkers; the small cohort size and relatively large number of protein analytes selected in this study limit the interpretation of the results and its potential use in clinical practice (33).…”

Section: Discussionmentioning

confidence: 97%

Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

et al. 2017

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Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with gamma-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, is released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target.

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Identification of Circulating MicroRNAs in Biliary Atresia by Next‐Generation Sequencing

Abstract: Our findings indicate that patients with BA exhibit a distinct profile of circulating miRNAs and that plasma miR-140-3p may be a promising diagnostic biomarker for this disease.

Cited by 26 publications

References 34 publications

Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease

Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease

MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis

Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

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