Reply: Urinary Excretion of MicroRNA-126 Is a Biomarker for Hemangioma Proliferation

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Thank you for your thoughtful comments about our recent article, “Urinary Excretion of MicroRNA-126 Is a Biomarker for Hemangioma Proliferation.”1 The National Institutes of Health Biomarkers Definition Working Group defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”2 There is no requirement that a biomarker represent a singular biological molecule only found in hemangiomas. The temporal changes in urinary microRNA-126 abundance provided the evidence that microRNA-126 expression correlates with hemangioma growth with significantly elevated levels during proliferation and no differences with unaffected healthy controls at 9 months of age, when hemangioma proliferation has generally ended.3 This evidence meets criteria for a biomarker as set forth by the National Institutes of Health Biomarkers Working Group. Although it may be possible that asthma, diabetes, cystic fibrosis, or other cancers affect microRNA-126 abundance, none of the subjects in our studies had these comorbidities. Further studies would have to be conducted to determine whether those conditions alter urinary microRNA-126 abundance in hemangioma patients.
The use of 8-oxo-2′-deoxyguanosine as a potential biomarker was considered when designing this study. We have previously reported elevated levels of 8-oxo-2′-deoxyguanosine in our mouse model of hemangioma caused by nox-4–driven DNA oxidation.4 However, elevated urinary levels of oxidized DNA are found with other cancers and can be induced by a variety of other environmental exposures such as sunburn or secondhand smoke and could be derived from any cell type. MicroRNA-126 is widely recognized as the master angio-microRNA, with expression limited almost exclusively to endothelial cells. In fetal endothelial cells, microRNA-126 is the most abundant microRNA expressed, which is consistent with the concept of hemangioma endothelial cells as fetal rests. MicroRNA-126 was selected as a potential biomarker because it was a more specific indicator of endothelial cells promoting hemangioma growth.
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