Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Jiangsu Center for the Collaboration and Innovation of Cancer, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Cancer Biotherapy Institute, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
J Invest Dermatol. 2020 Aug;140(8):1639-1649.e4. doi: 10.1016/j.jid.2019.12.032. Epub 2020 Jan 29.
AURKA regulates apoptosis and autophagy in a diverse range of diseases and exhibits promising clinical efficacy; however, the role of AURKA in regulating adipose-derived stem cells (ADSCs) and repairing diabetic wound remains unclear. Here, we showed that ADSCs subjected to high glucose stress displayed an obvious induction of AURKA and FOXO3a, and a significant increase in autophagy and apoptosis. AURKA was confirmed to regulate autophagy through FOXO3a. AURKA-mediated autophagy inhibited high-glucose-induced apoptosis of ADSCs. Furthermore, co-immunoprecipitation and chromatin immunoprecipitation assays were employed to investigate the interaction of AURKA and FOXO3a. FOXO3a bound to its own promoter and transactivated its own expression. AURKA was found to interact with FOXO3a to regulate FOXO3a activity. In diabetic mice, ADSCs overexpressing AURKA led to a decrease of apoptosis of ADSCs and promoted wound healing in the skin. Taken together, our data suggest that transcriptional regulation of FOXO3a by high-glucose-mediated AURKA is necessary for ADSCs autophagy. Our data reveal a potential therapeutic strategy for targeting AURKA involved in high-glucose-induced anti-apoptotic autophagy in ADSCs.
AURKA 在多种疾病中调节细胞凋亡和自噬，并表现出有前景的临床疗效；然而，AURKA 在调节脂肪来源干细胞 (ADSCs) 和修复糖尿病伤口中的作用尚不清楚。在这里，我们发现，高糖应激下的 ADSCs 明显诱导了 AURKA 和 FOXO3a 的表达，自噬和细胞凋亡明显增加。AURKA 通过 FOXO3a 调节自噬。AURKA 介导的自噬抑制了高糖诱导的 ADSCs 凋亡。此外，我们还进行了免疫共沉淀和染色质免疫沉淀实验来研究 AURKA 和 FOXO3a 的相互作用。FOXO3a 结合到其自身的启动子上，反式激活其自身的表达。发现 AURKA 与 FOXO3a 相互作用以调节 FOXO3a 活性。在糖尿病小鼠中，过表达 AURKA 的 ADSCs 导致 ADSCs 凋亡减少，并促进皮肤伤口愈合。总之，我们的数据表明，高糖介导的 AURKA 对 FOXO3a 的转录调控对于 ADSCs 的自噬是必要的。我们的数据揭示了一种潜在的治疗策略，即针对 AURKA 来靶向高糖诱导的 ADSCs 抗细胞凋亡自噬。
