Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy
Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy
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血小板衍生生长因子 C 信号传导是放射性直肠病的潜在治疗靶点。
DOI：
10.1126/scitranslmed.abc2344
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发表时间：
2021-02-24
影响因子：
17.1
通讯作者：
Fang, Lekun
中科院分区：
文献类型：
--
作者：
Lu, Weisi;Xie, Yunling;Fang, Lekun
以大肠组织炎症为特征的放射治疗是盆腔恶性肿瘤放射治疗的常见并发症，发病率较高，但缺乏有效的治疗方法。在这里，我们发现，在RP小鼠模型中，来自RP患者的组织样本和照射后的直肠组织中血小板衍生生长因子C(PDGF-C)和纤维化标志物上调。小鼠PDGF-c基因缺失可减轻RP诱导的损伤。全基因组基因表达谱和体外分析表明，PDGF-C在RP发育中的促进作用是通过激活PDGF受体(PDGFRs)和C-X-C基序趋化因子受体4(C-X-C趋化因子受体4)介导的，C-X-C趋化因子受体4是由转录因子Ets变异体转录因子1调节的促炎趋化因子。这些结果提示，抑制PDGF-C信号转导可能对RP的治疗有一定的价值。
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.