TY - JOUR
T1 - An innovative targeted therapy for fluoroscopy-induced chronic radiation dermatitis
AU - Wei, Kai Che
AU - Lai, Shih Fan
AU - Huang, Wei Lun
AU - Yang, Kuo Chung
AU - Lai, Ping Chin
AU - Wei, Wan Ju
AU - Chang, Tsung Hsien
AU - Huang, Yun Chen
AU - Tsai, Ya Chuan
AU - Lin, Shin Chih
AU - Lin, Sun Jang
AU - Lin, Shih Chieh
N1 - Funding Information:
This study was supported by research grants from the Ministry of Science and Technology (MOST 109–2636-B-006–006 for SJL and MOST 109–2314-B-075B-004 for KCW) and Kaohsiung Veterans General Hospital (VGHKS107-140 and VGHKS108-141 for KCW).
Funding Information:
We thank Yi-Shang Yeh at NCKU for technical assistance and Guan-Jun Chen at NTU for assisting with the animal study.
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s00109-021-02146-3
DO - 10.1007/s00109-021-02146-3
M3 - Article
C2 - 34689211
AN - SCOPUS:85117730767
SN - 0946-2716
VL - 100
SP - 135
EP - 146
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 1
ER -