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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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 6

Increased FOXN1 expression in SCC cells induces FGFR3 expression and promotes differentiation.

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Increased FOXN1 expression in SCC cells induces FGFR3 expression and pro...
(A) The keratinocyte-derived SCC cell lines SCC13 and SCCO28 were infected with a retrovirus expressing FOXN1-ER fusion protein (34) or empty vector control. Cells with or without 200 nM 4-OHT treatment for 24 hours were analyzed, in parallel with control human keratinocytes, for levels of FOXN1 expression by immunoblotting, with γ-tubulin for equal loading control. Endogenous FOXN1 was detected at 69 kDa, and the higher–molecular weight band in the SCC cells corresponds to expression of the FOXN1-ER fusion protein. Lanes were run on the same gel but were noncontiguous (white line). (B–D) SCC13 and SCCO28 cells infected with the FOXN1-ER retrovirus or empty vector control were treated with 200 nM 4-OHT for 24 hours to induce activation of FOXN1-ER. Expression of involucrin (B), keratin1 (C), and FGFR3 (D) was analyzed by real-time RT-PCR using 36B4 for normalization. Error bars denote SEM. (E) SCCO28 cells were transduced with a FOXN1-expressing adenovirus (41) or GFP control and analyzed for expression of FGFR3 and keratin1 by immunoblotting, with γ-tubulin for equal loading control. Results were quantified by densitometric scanning of the immunoblots and normalization for γ-tubulin.