A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans
Anna Mandinova, … , Janice L. Brissette, G. Paolo Dotto
Anna Mandinova, … , Janice L. Brissette, G. Paolo Dotto
Published September 1, 2009
Citation Information: J Clin Invest. 2009;119(10):3127-3137. https://doi.org/10.1172/JCI38543.
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Research Article Dermatology

A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans

Abstract

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.

Authors

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

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Figure 7

FOXN1 expression controls tumor formation in primary human keratinocytes and SCC cells.

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FOXN1 expression controls tumor formation in primary human keratinocytes...
(A) Human keratinocytes infected with 2 shRNA constructs targeting FOXN1 expression (shFOXN1) in parallel with empty vector control, were superinfected with a H-rasV12–expressing retrovirus (56). Cells (1 × 106) were injected at the dermal-epidermal junction of the back skin of nude mice. Tissue samples from 4 individual tumors and 2 controls were analyzed by immunohistochemistry with anti–pan-keratin and anti–human-specific vimentin antibodies. (B and C) SCC13 cells infected with a FOXN1-ER–expressing retrovirus or empty vector control were injected in parallel into the right and left suprascapular areas of NOD/SCID mice (5 × 105 cells per injection), After 1 week, animals were treated with 200 μg 4-OHT (see Methods) or vehicle control by i.p. injections for 5 weeks. Tumors (7 per condition) were separated from surrounding tissue for weight determination (B), and tissue samples were processed for H&E analysis (C). Similar results were obtained in a second similar experiment. Error bars denote SEM. Scale bars: 100 μm.