A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans
A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans
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DOI：
10.1172/jci38543
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发表时间：
2009-10-01
影响因子：
15.9
通讯作者：
Dotto, G. Paolo
中科院分区：
文献类型：
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作者：
Mandinova, Anna;Kolev, Vihren;Dotto, G. Paolo
脂溢性角化病（SKs）是一种常见的皮肤良性上皮性肿瘤，不会或很少进展为恶性肿瘤，原因尚不清楚。我们通过人类SKs和皮肤鳞状细胞癌（SCCs）的基因表达谱研究了这一点，发现先前与角化细胞肿瘤发展相关的几个基因在SKs和SCCs中类似地被调节，而其他基因的表达仅相差几倍。相比之下，酪氨酸激酶受体FGF受体-3 （FGFR3）和转录因子叉头盒N1 （FOXN1）在SKs中高表达，在SCCs中几乎检测不到。我们还发现，FGFR3活性的增加足以诱导FOXN1表达，抵消EGFR信号传导对FOXN1表达和分化的抑制作用，并以FOXN1依赖的方式诱导分化。原代人角质形成细胞中FOXN1表达的下调与致癌RAS共同诱导SCC样肿瘤，而FOXN1表达的增加则触发SCC细胞向良性sk样肿瘤表型转移，其中包括FGFR3表达的增加。因此，我们发现了FGFR3和FOXN1之间的正调控环，这是良性与恶性皮肤肿瘤表型的基础。
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.