Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma
Graham M. Strub, … , Mark W. Majesky, Jonathan A. Perkins
Graham M. Strub, … , Mark W. Majesky, Jonathan A. Perkins
Published September 8, 2016
Citation Information: JCI Insight. 2016;1(14):e88856. https://doi.org/10.1172/jci.insight.88856.
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Research Article Angiogenesis Dermatology

Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma

Abstract

Infantile hemangioma (IH) is the most common vascular tumor of infancy, and it uniquely regresses in response to oral propranolol. MicroRNAs (miRNAs) have emerged as key regulators of vascular development and are dysregulated in many disease processes, but the role of miRNAs in IH growth has not been investigated. We report expression of C19MC, a primate-specific megacluster of miRNAs expressed in placenta with rare expression in postnatal tissues, in glucose transporter 1–expressing (GLUT-1–expressing) IH endothelial cells and in the plasma of children with IH. Tissue or circulating C19MC miRNAs were not detectable in patients having 9 other types of vascular anomalies or unaffected children, identifying C19MC miRNAs as the first circulating biomarkers of IH. Levels of circulating C19MC miRNAs correlated with IH tumor size and propranolol treatment response, and IH tissue from children treated with propranolol or from children with partially involuted tumors contained lower levels of C19MC miRNAs than untreated, proliferative tumors, implicating C19MC miRNAs as potential drivers of IH pathogenesis. Detection of C19MC miRNAs in the circulation of infants with IH may provide a specific and noninvasive means of IH diagnosis and identification of candidates for propranolol therapy as well as a means to monitor treatment response.

Authors

Graham M. Strub, Andrew L. Kirsh, Mark E. Whipple, Winston P. Kuo, Rachel B. Keller, Raj P. Kapur, Mark W. Majesky, Jonathan A. Perkins

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Figure 1

C19MC miRNAs are specific biomarkers of infantile hemangioma.

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C19MC miRNAs are specific biomarkers of infantile hemangioma. (A) Multip...
(A) Multiplexed tissue miRNA analysis and unsupervised hierarchical clustering of IH, LM, and skin identified C19MC miRNAs as upregulated in IH. (B) Tissue from 22 additional infants and children with the indicated vascular anomalies as well as tissue from 5 healthy placentas were analyzed by qRT-PCR for GLUT-1 mRNA, the endothelial miR-126a-3p, and the C19MC miRNAs miR-517a-3p and miR-518d-5p. Only placenta and IH expressed the C19MC miRNAs miR-517a-3p and 518d-5p. GLUT-1 was expressed in placenta and IH; background signal in other samples is due to erythrocyte GLUT-1 expression. The y axis represents relative mRNA or miRNA compared with levels of GAPDH or RNU48, respectively. (C) Circulating miR-517c-3p and miR-126a-3p were analyzed by qRT-PCR in plasma from 60 additional infants and children with the indicated vascular anomalies and from 5 patients with no vascular anomalies. Only plasma from patients with IH had detectable levels of miR-517c-3p, while miR-126a-3p was detected in all samples. Infants and children with large (>2-cm) and proliferative (in patients younger than 9 mo of age) IH had significantly higher levels of circulating miR-517c-3p compared with infants and children with smaller or partially involuted tumors, while miR-126a-3p levels were not affected by tumor size or patient age. Statistical analysis was performed using single-factor ANOVA, comparing groups with n = 3 or greater samples. For miR-517c-3p, follow-up subgroup analysis was performed using Tukey’s test, following ANOVA (**P < 0.01). For miR-126a-3p, values did not reach significance (P = 0.62, ANOVA). The y axis represents the relative miRNA level compared with the average pooled miRNA from all the samples. All points illustrated on the qRT-PCR graphs represent individual patient samples, and error bars represent standard deviations. Pla, placenta; IH, infantile hemangioma; Skin, healthy skin adjacent to IH; TA, tufted angioma; KH, kaposiform hemangioendothelioma; PG, pyogenic granuloma; VM, venous malformation; NICH, noninvoluting congenital hemangioma; RICH, rapidly involuting congenital hemangioma; LM, lymphatic malformation; AVM, arteriovenous malformation; JNA, juvenile nasopharyngeal angiofibroma; No lesion, plasma from patient without vascular anomaly.