Persechino Flavia, Ranieri Danilo, Guttieri Luisa, Nanni Monica, Torrisi Maria Rosaria, Belleudi Francesca
Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy.
Tissue Biology Research Unit, Department of Surgery, University Children's Hospital, CH-8032 Zurich, Switzerland.
Biology (Basel). 2021 Apr 15;10(4):331. doi: 10.3390/biology10040331.
Actinic keratosis (AK) is the ultra violet (UV)-induced preneoplastic skin lesion clinically classified in low (KIN I), intermediate (KIN II), and high (KIN III) grade lesions. In this work we analyzed the expression of Fibroblast Growth Factor Receptors (FGFRs), as well as of keratinocyte differentiation and epithelial-to-mesenchymal transition (EMT)-related markers in differentially graded AK lesions, in order to identify specific expression profiles that could be predictive for direct progression of some KIN I lesions towards squamous cell carcinoma (SCC). Our molecular analysis showed that the keratinocyte differentiation markers keratin 1 (K1), desmoglein-1 (DSG1), and filaggrin (FIL) were progressively downregulated in KIN I, II, and III lesions, while the modulation of epithelial/mesenchymal markers and the induction of the transcription factors Snail1 and Zinc finger E-box-binding homeobox 1 (ZEB1) compatible with pathological EMT, even if observable, did not appear to correlate with AK progression. Concerning FGFRs, a modulation of epithelial isoform of FGFR2 (FGFR2b) and the mesenchymal FGFR2c isoform compatible with an FGFR2 isoform switch, as well as FGFR4 upregulation were observed starting from KIN I lesions, suggesting that they could be events involved in early steps of AK pathogenesis. In contrast, the increase of FGFR3c expression, mainly appreciable in KIN II and KIN III lesions, suggested a correlation with AK late progression. Interestingly, the strong modulation of FIL, Snail1, as well as of FGFR2c, FGFR4, and of their ligand FGF2, observed in some of the KIN I samples, may indicate that they could be molecular markers predictive for those low graded lesions destined to a direct progression to SCC. In conclusion, our data point on the identification of molecular markers predictive for AK rapid progression through the "differentiated" pathway. Our results also represent an important step that, in future, will help to clarify the molecular mechanisms underlying FGFR signaling deregulation in epithelial tissues during the switch from the pre-neoplastic to the oncogenic malignant phenotype.
光化性角化病（AK）是紫外线（UV）诱导的癌前皮肤病变，临床上分为低级别（KIN I）、中级别（KIN II）和高级别（KIN III）病变。在本研究中，我们分析了不同分级的AK病变中，成纤维细胞生长因子受体（FGFRs）的表达，以及角质形成细胞分化和上皮-间质转化（EMT）相关标志物的表达，以确定可能预测某些KIN I病变直接进展为鳞状细胞癌（SCC）的特定表达谱。我们的分子分析表明，角质形成细胞分化标志物角蛋白1（K1）、桥粒芯糖蛋白-1（DSG1）和丝聚合蛋白（FIL）在KIN I、II和III病变中逐渐下调，而上皮/间质标志物的调节以及转录因子Snail1和锌指E盒结合同源框1（ZEB1）的诱导，即使可以观察到，似乎也与AK的进展无关，这些诱导与病理性EMT相符。关于FGFRs，从KIN I病变开始观察到FGFR2的上皮异构体（FGFR2b）和与FGFR2异构体转换相符的间充质FGFR2c异构体的调节，以及FGFR4的上调，表明它们可能是参与AK发病机制早期步骤的事件。相反，FGFR3c表达的增加主要在KIN II和KIN III病变中明显，提示与AK的晚期进展相关。有趣的是，在一些KIN I样本中观察到FIL、Snail1以及FGFR2c、FGFR4及其配体FGF2的强烈调节，这可能表明它们可能是预测那些注定直接进展为SCC的低级别病变的分子标志物。总之，我们的数据指向通过“分化”途径预测AK快速进展的分子标志物的鉴定。我们的结果也是重要的一步，未来将有助于阐明从癌前向致癌恶性表型转变过程中上皮组织中FGFR信号失调的分子机制。
