Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy.
Weisi LuYunling XieBinjie HuangTeng-Hui MaHuaiming WangBoxiong DengShaomin ZouWencong WangQin TangZiqing YangXuri LiLei WangLekun FangPublished in: Science translational medicine (2021)
Radiation proctopathy (RP) is characterized by inflammation of colorectal tissue and is a common complication of radiation therapy for pelvic malignancies with high incidence but lacking effective treatment. Here, we found that platelet-derived growth factor C (PDGF-C) and fibrosis markers were up-regulated in tissue samples from patients with RP and in rectal tissues after irradiation in a mouse model of RP. Genetic deletion of Pdgf-c in mice ameliorated RP-induced injuries. Genome-wide gene expression profiling and in vitro assays revealed that the promotive effect of PDGF-C in RP development was mediated by activation of PDGF receptors (PDGFRs) and C-X-C motif chemokine receptor 4, a proinflammatory chemokine regulated by transcription factor ETS variant transcription factor 1. Treatment with crenolanib, a selective inhibitor of PDGFRs, prevented or reduced RP in mice after irradiation. These results reveal that inhibition of PDGF-C signaling may have therapeutic value for the treatment of RP.
Keyphrases
- growth factor
- genome wide
- transcription factor
- smooth muscle
- dna methylation
- vascular smooth muscle cells
- mouse model
- oxidative stress
- copy number
- gene expression
- metabolic syndrome
- radiation induced
- genome wide identification
- single cell
- risk factors
- radiation therapy
- rectal cancer
- insulin resistance
- binding protein
- high throughput
- dna binding
- smoking cessation