Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Department of Cosmetic Applications and Management, Yuhing Junior College of Health Care and Management, Kaohsiung, Taiwan.
J Mol Med (Berl). 2022 Jan;100(1):135-146. doi: 10.1007/s00109-021-02146-3. Epub 2021 Oct 23.
Fluoroscopy-induced chronic radiation dermatitis (FICRD) is a complication of fluoroscopy-guided intervention. Unlike acute radiation dermatitis, FICRD is different as delayed onset and usually appears without preexisting acute dermatitis. Unfortunately, the chronic and progressive pathology of FICRD makes it difficult to treat, and some patients need to receive wide excision and reconstruction surgery. Due to lack of standard treatment, investigating underlying mechanism is needed in order to develop an effective therapy. Herein, the Hippo pathway is specifically identified using an RNA-seq analysis in mild damaged skin specimens of patients with FICRD. Furthermore, specific increase of the Yes-associated protein (YAP1), an effector of the Hippo pathway, in skin region with mild damage plays a protective role for keratinocytes via positively regulating the numerous downstream genes involved in different biological processes. Interestingly, irradiated-keratinocytes inhibit activation of fibroblasts under TGF-β1 treatment via remote control by an exosome containing YAP1. More importantly, targeting one of YAP1 downstream genes, nuclear receptor subfamily 3 group C member 1 (NR3C1), which encodes glucocorticoid receptor, has revealed its therapeutic potential to treat FICRD by inhibiting fibroblasts activation in vitro and preventing formation of radiation ulcers in a mouse model and in patients with FICRD. Taken together, this translational research demonstrates the critical role of YAP1 in FICRD and identification of a feasible, effective therapy for patients with FICRD. KEY MESSAGES: • YAP1 overexpression in skin specimens of radiation dermatitis from FICRD patient. • Radiation-induced YAP1 expression plays protective roles by promoting DNA damage repair and inhibiting fibrosis via remote control of exosomal YAP1. • YAP1 positively regulates NR3C1 which encodes glucocorticoid receptor expression. • Targeting glucocorticoid receptor by prednisolone has therapeutic potential for FICRD patient.
荧光透视引导介入所致慢性放射性皮炎（FICRD）是荧光透视引导介入的一种并发症。与急性放射性皮炎不同，FICRD 起病较晚，通常在没有先前存在的急性皮炎的情况下出现。不幸的是，FICRD 的慢性和进行性病理使得治疗变得困难，一些患者需要接受广泛切除和重建手术。由于缺乏标准治疗方法，因此需要研究潜在机制，以便开发有效的治疗方法。在此，通过对 FICRD 患者轻度损伤皮肤标本的 RNA-seq 分析，特异性鉴定 Hippo 通路。此外，在轻度损伤皮肤区域，Yes 相关蛋白（YAP1）的特异性增加（Hippo 通路的效应物）通过正向调节参与不同生物学过程的众多下游基因，对角质形成细胞起保护作用。有趣的是，受照射的角质形成细胞通过含有 YAP1 的外体的远程控制，在 TGF-β1 处理下抑制成纤维细胞的激活。更重要的是，针对 YAP1 下游基因之一，即核受体亚家族 3 组 C 成员 1（NR3C1），其编码糖皮质激素受体，通过体外抑制成纤维细胞的激活并防止 FICRD 小鼠模型和患者中放射性溃疡的形成，显示出其治疗 FICRD 的潜力。总之，这项转化研究表明了 YAP1 在 FICRD 中的关键作用，并为 FICRD 患者确定了一种可行且有效的治疗方法。 关键信息： • FICRD 患者的放射性皮炎皮肤标本中 YAP1 过度表达。 • 辐射诱导的 YAP1 表达通过远程控制外泌体 YAP1 促进 DNA 损伤修复和抑制纤维化来发挥保护作用。 • YAP1 正向调节编码糖皮质激素受体的 NR3C1 表达。 • 通过泼尼松龙靶向糖皮质激素受体对 FICRD 患者具有治疗潜力。
