First published February 1, 2010 - More info
Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor–3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus, we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype.
Anna Mandinova, Vihren Kolev, Victor Neel, Bing Hu, Wesley Stonely, Jocelyn Lieb, Xunwei Wu, Claudia Colli, Rong Han, Mike Pazin, Paola Ostano, Reinhard Dummer, Janice L. Brissette, G. Paolo Dotto
Original citation: J. Clin. Invest.2009;119(10):3127–3137. doi:10.1172/JCI38543.
Citation for this corrigendum: J. Clin. Invest.2010;120(2):645. doi:10.1172/JCI38543C1.
During the preparation of this manuscript, Michael J. Pazin's name was inadvertently presented incorrectly in the author list. The correct author list appears above.
Michael J. Pazin's support information was inadvertently omitted from the Acknowledgments. The correct Acknowledgments section appears below.
We thank W. Austen for human skin material, D. Prowse for the FOXN1-ER retrovirus, D. Ornitz for FGFR3 constructs, and V. Rajashekara for skillful technical help. This work was supported by NIH grants AR39190, AR054856, AR045284, CA16038, and CA73796; by the Swiss National Foundation; by a grant from the European Union (Epistem, Sixth Framework Program, LSHB-CT-2005-019067); and in part by the Cutaneous Biology Research Center through the MGH/Shiseido Co. Ltd. Agreement. Michael J. Pazin is currently supported by the Intramural Research Program of the NIH National Institute on Aging.
The authors regret the errors.