Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis.
Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis.
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Smad7对放射性口腔粘膜炎的防治作用
作者：
我们报告K5.Smad7小鼠，表达Smad 7转基因的角蛋白-5启动子，是耐辐射诱导的口腔粘膜炎，疼痛的口腔溃疡。除了已知导致口腔粘膜炎的NF-κB活化外，我们还发现口腔粘膜炎中活化的TGF-β信号传导。Smad 7抑制这两种途径，以减轻炎症，生长抑制和凋亡。此外，Smad 7促进口腔上皮迁移以闭合伤口。进一步的分析表明，TGF-β信号Smads和它们的共阻遏物CtBP 1在转录上抑制Rac 1，而Smad 7消除了这种抑制。在小鼠角质形成细胞中敲低Rac 1可消除Smad 7诱导的迁移。局部应用Smad 7蛋白与细胞可渗透的Tat标签（Tat-Smad 7）的口腔粘膜显示预防和治疗放射性口腔粘膜炎的小鼠。因此，我们已经确定了新的分子机制参与口腔粘膜炎的发病机制，我们的数据表明，一种替代的治疗策略，以阻止口腔粘膜炎的多种病理过程。
We report that K5.Smad7 mice, which express Smad7 transgene by a keratin-5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to NF-κB activation known to contribute to oral mucositis, we found activated TGF-β signaling in oral mucositis. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-β signaling Smads and their co-repressor CtBP1 transcriptionally repressed Rac1, and Smad7 abrogated this repression. Knocking down Rac1 in mouse keratinocytes abrogated Smad7-induced migration. Topically applying Smad7 protein with a cell permeable Tat-tag (Tat-Smad7) to oral mucosa showed preventive and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified novel molecular mechanisms involved in oral mucositis pathogenesis and our data suggest an alternative therapeutic strategy to block multiple pathological processes of oral mucositis.