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Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine Endothelin-1 Secretion
- Source :
- Journal of Investigative Dermatology, 138(4), 893-902. Nature Publishing Group, Chitsazan, A, Ferguson, B, Villani, R, Handoko, H Y, Mukhopadhyay, P, Gabrielli, B, Mooi, W J, Soyer, H P, Lambie, D, Khosrotehrani, K, Morahan, G & Walker, G J 2018, ' Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine Endothelin-1 Secretion ', Journal of Investigative Dermatology, vol. 138, no. 4, pp. 893-902 . https://doi.org/10.1016/j.jid.2017.10.032
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Keratinocytes
Male
Transcriptional Activation
Pathology
medicine.medical_specialty
Skin Neoplasms
Dermatology
Biochemistry
03 medical and health sciences
Mice
GLI1
GLI2
medicine
Tumor Cells, Cultured
Nevus
Animals
Humans
Hedgehog Proteins
Sonic hedgehog
skin and connective tissue diseases
Molecular Biology
Mice, Knockout
Nevus, Pigmented
biology
Endothelin-1
integumentary system
Melanoma
Cell Biology
Neoplasms, Experimental
medicine.disease
Up-Regulation
Gene Expression Regulation, Neoplastic
030104 developmental biology
Neurocutaneous melanosis
Giant Congenital Nevus
biology.protein
Cancer research
Melanocytes
Female
Smoothened
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 0022202X
- Database :
- OpenAIRE
- Journal :
- Journal of Investigative Dermatology, 138(4), 893-902. Nature Publishing Group, Chitsazan, A, Ferguson, B, Villani, R, Handoko, H Y, Mukhopadhyay, P, Gabrielli, B, Mooi, W J, Soyer, H P, Lambie, D, Khosrotehrani, K, Morahan, G & Walker, G J 2018, ' Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine Endothelin-1 Secretion ', Journal of Investigative Dermatology, vol. 138, no. 4, pp. 893-902 . https://doi.org/10.1016/j.jid.2017.10.032
- Accession number :
- edsair.doi.dedup.....74a9b3eb98db326fca4cb17be074061f