报道了成纤维细胞生长因子受体-2（FGFR2）在皮肤鳞状细胞癌（cSCC）中的潜在作用。为了证明FGFR2在UVB诱导的皮肤致癌和cSCC发展中的特定作用，我们构建了一种角质形成细胞特异性的诱导型麻醉诱导剂（tamoxifen）小鼠模型，该模型在转基因小鼠的雄性和雌性中使用4-羟基-麻醉诱导剂局部涂抹以诱导Cre重组酶，从而在表皮角质形成细胞中删除FGFR2。分析从FGFR2缺乏小鼠中在UVB照射后分离的表皮蛋白裂解物，显示明显降低的磷酸化FGFR（pFGFR；Y653/654）和p-FRS2α ，以及mTORC1信号传导的下游效应。与对照组相比，STAT1和STAT3的磷酸化明显降低，IRF-1，DUSP6，EGR1和PD-L1的水平也明显降低。FGFR2特异性消除角质形成细胞也显著抑制了UVB照射后的表皮过度增生、增生和炎症。最后，FGFR2特异性缺失显著抑制了UVB诱导的cSCC形成。总的来说，目前的数据证明了FGFR2在UVB诱导的致癌信号传导以及cSCC发展中的重要作用。此外，目前的临床前研究结果表明，抑制FGFR2信号传导可能提供了一种之前未被报道的预防和/或治疗UVB诱导的cSCC的策略。版权所有© 2023该作者。由Elsevier Inc.出版。保留所有权利。

A potential role for fibroblast growth factor receptor-2 (FGFR2) in cutaneous squamous cell carcinoma (cSCC) has been reported. To demonstrate the specific role of FGFR2 in UVB-induced skin carcinogenesis and development of cSCC, we generated a keratinocyte specific, tamoxifen inducible mouse model of FGFR2 deficiency. In this mouse model, topical application of 4-hydroxy-tamoxifen led to the induction of Cre recombinase to delete FGFR2 in epidermal keratinocytes of both male and female transgenic mice. Analysis of epidermal protein lysates isolated from FGFR2 deficient mice exposed to UVB showed significant reductions of phospho-FGFR (pFGFR; Y653/654) and p-FRS2α as well as downstream effectors of mTORC1 signaling. Phosphorylation of STAT1 and STAT3 was significantly reduced as well as levels of IRF-1, DUSP6, EGR1 and PD-L1 compared to the control groups. Keratinocyte specific ablation of FGFR2 also significantly inhibited epidermal hyperproliferation, hyperplasia and inflammation following exposure to UVB. Finally, keratinocyte specific deletion of FGFR2 significantly inhibited UVB-induced cSCC formation. Collectively, the current data demonstrate an important role of FGFR2 in UVB-induced oncogenic signaling as well a development of cSCC. In addition, the current preclinical findings suggest that inhibition of FGFR2 signaling may provide a previously unreported strategy to prevent and/or treat UVB-induced cSCC.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.