Wnt signaling potentiates nevogenesis

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to con...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (40), p.16009-16014
Main Authors: Pawlikowski, Jeff S., McBryan, Tony, van Tuyn, John, Drotar, Mark E., Hewitt, Rachael N., Maier, Andrea B., King, Ayala, Blyth, Karen, Wu, Hong, Adams, Peter D.
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cell Line, Tumor
Cell lines
Cells
Cellular senescence
Cellular Senescence - physiology
Cyclins
DNA Primers - genetics
Genetic vectors
Genotype & phenotype
HEK293 Cells
Humans
Immunoblotting
Immunohistochemistry
Melanocytes
Melanocytes - cytology
Melanocytes - physiology
Melanoma
Melanoma - etiology
Mice
Microarray Analysis
Nevus
Nevus - metabolism
Nevus - physiopathology
Real-Time Polymerase Chain Reaction
Repression
Ribonucleic acid
RNA
Rodents
Sequence Analysis, RNA
Skin
Tumors
Wnt Signaling Pathway - physiology
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Summary:Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1303491110