Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine Endothelin-1 Secretion

Giant congenital nevi are associated with clinical complications such as neurocutaneous melanosis and melanoma. Virtually nothing is known about why some individuals develop these lesions. We previously identified the sonic hedgehog (Shh) pathway regulator Cdon as a candidate nevus modifier gene. He...

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Bibliographic Details
Published in:Journal of investigative dermatology 2018-04, Vol.138 (4), p.893-902
Main Authors: Chitsazan, Arash, Ferguson, Blake, Villani, Rehan, Handoko, Herlina Y., Mukhopadhyay, Pamela, Gabrielli, Brian, Mooi, Wolter J., Soyer, H. Peter, Lambie, Duncan, Khosrotehrani, Kiarash, Morahan, Grant, Walker, Graeme J.
Format: Article
Language:English
Subjects:
Animals
Endothelin-1 - metabolism
Female
Gene Expression Regulation, Neoplastic
Hedgehog Proteins - biosynthesis
Hedgehog Proteins - genetics
Humans
Keratinocytes - metabolism
Keratinocytes - pathology
Male
Melanocytes - metabolism
Melanocytes - pathology
Mice
Mice, Knockout
Neoplasms, Experimental
Nevus, Pigmented - genetics
Nevus, Pigmented - metabolism
Nevus, Pigmented - pathology
Signal Transduction
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Skin Neoplasms - pathology
Transcriptional Activation
Tumor Cells, Cultured
Up-Regulation
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Summary:Giant congenital nevi are associated with clinical complications such as neurocutaneous melanosis and melanoma. Virtually nothing is known about why some individuals develop these lesions. We previously identified the sonic hedgehog (Shh) pathway regulator Cdon as a candidate nevus modifier gene. Here we validate this by studying Cdon knockout mice, and go on to establishing the mechanism by which Shh exacerbates nevogenesis. Cdon knockout mice develop blue nevi without the need for somatic melanocyte oncogenic mutation. In a mouse model carrying melanocyte NRASQ61K, we found that strain backgrounds that carry genetic variants that cause increased keratinocyte Shh pathway activity, as measured by Gli1 and Gli2 expression, develop giant congenital nevi. Shh components are also active adjacent to human congenital nevi. Mechanistically, this exacerbation of nevogenesis is driven via the release of the melanocyte mitogen endothelin-1 from keratinocytes. We then suppressed nevus development in mice using Shh and endothelin antagonists. Our work suggests an aspect of nevus development whereby keratinocyte cytokines such as endothelin-1 can exacerbate nevogenesis, and provides potential therapeutic approaches for giant congenital nevi. Furthermore, it highlights the notion that germline genetic variation, in addition to somatic melanocyte mutation, can strongly influence the histopathological features of melanocytic nevi.
ISSN:0022-202X
1523-1747
DOI:10.1016/j.jid.2017.10.032