An innovative targeted therapy for fluoroscopy-induced chronic radiation dermatitis

Kai-Che Wei,Shih-Fan Lai,Yun-Chen Huang,Sun-Jang Lin,Wan-Ju Wei,Wei-Lun Huang,Ya-Chuan Tsai,Kuo-Chung Yang,Tsung-Hsien Chang,Ping-Chin Lai,Shin-Chih Lin,Shih-Chieh Lin

doi:10.1007/s00109-021-02146-3

Abstract

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.

Highlights

Radiation dermatitis is the most common type of radiation damage
Radiation-induced YAP1 expression plays a protective role by promoting DNA damage repair in epidermal keratinocytes and in inhibiting dermal fibro‐ sis in fibroblast cells after irradiation (Fig. 3)
Several studies revealed the crucial role of YAP1 in regu‐ lating chemotherapy-induced DNA damage repair [14, 15, 25]

Summary

Introduction

Radiation dermatitis is the most common type of radiation damage. The severity of radiation injury increases with accumulated exposure [1]. Radiation-induced YAP1 expression plays protective roles by promoting DNA damage repair and inhibiting fibrosis via remote control of exosomal YAP1. (e) YAP1 expression was determined by using western blot in skin tissues isolated from a skin radiation of mouse model was gradually reduced in the fibrotic region after radiation exposure (Fig. 2c), but not in the other types of cells.

Results

Conclusion