OBJECTIVES As a complication of diabetes mellitus (DM), one of the leading causes for death and disability for DM patients is diabetic foot ulcers (DFUs). Epithelial to mesenchymal transition (EMT) plays a critical role in wound healing of DFUs. miR-203 is specifically enriched in keratinocytes and has been shown to target interleukin 8 (IL-8), which acts as an activator for the EMT process. In this study, we explored the interaction between miR-203 and IL-8 in DFU rat models and human keratinocyte cells, underlying the mechanism of miR-203's function in DFUs progression. METHODS DFU rat models were used to test gene expression in DFU progression. Diabetic keratinocyte cell lines were used to validate in vitro. Wound healing and Transwell assays were applied to evaluate cell migration and invasion abilities. The EMT process was estimated by testing expression of E-cadherin, Vimentin and Slug. The interaction between miR-203 and IL-8 was determined by Luciferase assay. RESULTS Our results demonstrated that the wound-healing process had been slowed in DFUs, and the advanced glycation end products (AGEs) and the receptor for advanced glycation end products (RAGEs) in wound tissue were of a higher expression than those in normal rat. miR-203 was increased in skin tissues from DFU rat models, while IL-8 was decreased. Through knock-down of miR-203 in AGE-treated keratinocyte cells, it had been shown that the downregulation of miR-203 could promote cell proliferation and migration, and facilitate the EMT process. Meanwhile, Luciferase assay proved that miR-203 could directly target and inhibit IL-8. The repression of IL-8 could rescue the outcomes brought about by miR-203 inhibition. CONCLUSIONS The upregulation of miR-203 in DFU tissues impaired wound healing by the repress EMT process. Specific knock-down of miR-203 could promote wound healing through the reactivation of its target gene IL-8 and the downstream IL-8/AKT pathway.

中文翻译：

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miR-203 通过靶向 Interleukin-8 作为糖尿病足溃疡上皮-间质转化过程的抑制剂。


目的 作为糖尿病 (DM) 的并发症，糖尿病足溃疡 (DFU) 是 DM 患者死亡和残疾的主要原因之一。上皮间质转化（EMT）在 DFU 伤口愈合中发挥着关键作用。 miR-203 在角质形成细胞中特别富集，并已被证明可以靶向白细胞介素 8 (IL-8)，而白细胞介素 8 是 EMT 过程的激活剂。在本研究中，我们探讨了 DFU 大鼠模型和人角质形成细胞中 miR-203 和 IL-8 之间的相互作用，揭示了 miR-203 在 DFU 进展中的功能机制。方法 DFU 大鼠模型用于测试 DFU 进展中的基因表达。使用糖尿病角质形成细胞系进行体外验证。应用伤口愈合和Transwell实验来评估细胞迁移和侵袭能力。通过检测 E-cadherin、Vimentin 和 Slug 的表达来评估 EMT 过程。通过荧光素酶测定确定 miR-203 和 IL-8 之间的相互作用。结果我们的结果表明，DFU 中伤口愈合过程减慢，并且伤口组织中晚期糖基化终末产物（AGEs）和晚期糖基化终末产物受体（RAGEs）的表达高于正常大鼠。 DFU 大鼠模型皮肤组织中 miR-203 增加，而 IL-8 减少。通过敲低 AGE 处理的角质形成细胞中的 miR-203，表明 miR-203 的下调可以促进细胞增殖和迁移，并促进 EMT 过程。同时，荧光素酶实验证明miR-203可以直接靶向并抑制IL-8。 IL-8 的抑制可以挽救 miR-203 抑制带来的结果。 结论 DFU 组织中 miR-203 的上调通过抑制 EMT 过程而损害伤口愈合。特异性敲低 miR-203 可以通过重新激活其靶基因 IL-8 和下游 IL-8/AKT 通路来促进伤口愈合。